bims-micgli Biomed News
on Microglia
Issue of 2026–05–31
89 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Immune receptor LAG3 regulates microglia function during Alzheimer's disease.
  2. Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia.
  3. Harnessing Microglial Repopulation: From Inflammatory Drivers to Therapeutic Allies in CNS Diseases.
  4. Neuroproteasomes regulate endogenous tau paired helical filament formation in an APOE genotype- and age-dependent manner.
  5. Lipid metabolic regulation of neuroinflammation in Alzheimer's disease.
  6. The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A ESCRT-mediated lysosomal repair.
  7. Alzheimer's Disease Risk Allele APOE4 Interacts with Arsenic Exposure to Drive Microglial Dysfunction.
  8. Early Regional Microglial Remodelling in the Hippocampus of the AppNL-G-F Alzheimer's Model.
  9. 3D cortical microtissue with innate microglia for studying real-time cell behavior across maturation and inflammatory response.
  10. Microglial Pruning of Excitatory Synapses in the Hippocampus Is Complement C3-Independent in Physiological and Neuroinflammatory States.
  11. Microglial ontogeny and in vitro reconstruction: Bridging development and modeling.
  12. Microglial state transitions dominate the brain immune response in the subacute phase after cardiac arrest.
  13. Tanycytic degeneration impairs tau clearance and contributes to Alzheimer's disease pathology.
  14. Live-Cell Imaging of Microglia in Organotypic Brain Slices Using Microcontact Printing.
  15. Physiological brain clearance architecture revealed by neuronal protein tracing.
  16. Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.
  17. Metabolic Competition Between Microglia and Neurons as Driver of Chronic Pain.
  18. Integrated Transcriptomic and Spatial Analyses Associate M2-like Myeloid Signatures with Neuroimmune Remodeling in Alzheimer's Disease.
  19. Apolipoprotein E Deficiency Attenuates Neuroinflammatory Responses and Demyelination in Experimental Autoimmune Encephalomyelitis.
  20. CD5L promotes phagocytic removal of amyloid β oligomers and improves cognitive function in a mouse model of Alzheimer's disease.
  21. Targeting microglia-mediated neuroinflammation in Alzheimer's disease: mechanisms and therapeutic approaches.
  22. Npc1 deficiency impairs brain vascular integrity in mouse model of Niemann-Pick disease type C1.
  23. Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.
  24. Microglial-Derived IGF-1 Serves as a Regulator for Neuroimmune Homeostasis During Viral-Induced Demyelination.
  25. Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer's disease pathology and systemic bone loss.
  26. Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation.
  27. Early sex-related transcriptional differences in CD8+ T cells responding to chronic viral infection reveal a sex bias in exhaustion.
  28. Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease.
  29. Microglial Ccl4-Ccr5 signaling links systemic inflammation to synaptic loss and memory deficits in chronic kidney disease.
  30. TREM2+ macrophages promote pancreatic regeneration through cholesterol-metabolism reprogramming and Hedgehog signaling activation following acute pancreatitis.
  31. The Interplay Between Immunometabolism and Neuroinflammation in Alzheimer's Disease.
  32. Astrocytic but not Microglial Antigen Presentation Shapes Protective Immunity to Toxoplasma gondii in the Brain.
  33. Long-term rapamycin treatment suppresses IL-17-producing gamma delta T cells and blunts neuroinflammation in aging.
  34. TMEM119+ microglia MHC class I restricted antigen presentation impacts CD8 T cell memory, effector status, and blood-brain barrier disruption during neurotropic virus infection.
  35. Circadian rhythm disruption aggravates periodontitis via orchestrating TREM2+ macrophage-mediated bone resorption.
  36. Behavior of neural networks in culture suggest that sporadic and genetic forms of Alzheimer's disease may not be equivalent.
  37. Chronic low-grade hippocampal inflammation blunts exercise-induced neurogenesis and alters the exercise-induced microglia transcriptome in the rat hippocampus.
  38. CNS1-dependent regulatory T cells shape recovery from acute lung injury.
  39. Maternal-fetal type I interferon signaling drives TREM2 dysregulation and synaptic dysfunction in neurodevelopmental disorders.
  40. An unexpected molecular explanation for how tau aggregation begins in Alzheimer's disease.
  41. The impact of lactate and lipid metabolism in microglia upon cognitive impairment following radiation-induced brain injury.
  42. Neocortical tau burden determines the degree of cognitive impairment in individuals with Braak stage V neurofibrillary degeneration.
  43. Deciphering cytokine-driven ADP-ribosylation signaling networks via Af1521-based mass spectrometry analysis of labile Glu/Asp-linkages.
  44. Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.
  45. Neuronal glycogen powers anticipatory brain responses to food.
  46. Microglia-mediated endotoxin tolerance: A protective role of LPS preconditioning in the central nervous system.
  47. Inhibition of endocannabinoid degradation in astrocytes reprograms glial reactivity and prevents seizure sequelae.
  48. Breaking the membrane heredity paradox through de novo protocell formation.
  49. Ciliogenesis associated kinase 1 accumulates in its inactive form during polycystic kidney disease progression.
  50. A miniaturized implantable electrochemical platform for continuous monitoring of metabolites in deep tissue.
  51. Single-nucleus analysis reveals human-specific oligodendrocyte polarization and conserved neuronal responses after severe traumatic brain injury.
  52. Satellite microglia-like cells in human dorsal root ganglia and changes with diabetic neuropathy.
  53. Modeling stimulus-induced stress responses in microglia-like cells using a commercial iPSC-dCas9-KRAB line.
  54. SNAP-23 mediated vesicular trafficking in oligodendrocytes is necessary to maintain adult myelin integrity in mice.
  55. Targeting Mitochondrial Dysfunction in Alzheimer's Disease Neurons: Lithium Boosts Oxidative Phosphorylation.
  56. TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.
  57. From Envelope to Encephalopathy: How HIV-1 gp120 Drives Neurocognitive Decline.
  58. Neuropilins in Multiple Sclerosis: Dual Roles of NRP-1 in Neuroinflammation and Neuroprotection.
  59. The physiological effects of APOE genotype in healthy young/middle-aged individuals.
  60. Granulocyte heterogeneity in immune-mediated and inflammatory diseases: Insights from single-cell transcriptomic analyses.
  61. Loss of SMARCAD1 Mitigates Tauopathy.
  62. A reparative neutrophil subpopulation accelerates spinal cord regeneration in zebrafish by controlling macrophage inflammation via Il-4.
  63. Channeling teamwork: ATP and lipids cooperate to gate P2X receptors.
  64. Organ formation in early human embryos captured in spatial cell atlas.
  65. TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy.
  66. MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
  67. Lysophospholipids in Synucleinopathies: A Conceptual Framework Linking Proteostasis and Neuroinflammatory Signaling.
  68. Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression.
  69. PVNOXT regulates acinar cell-mediated inflammatory response via DMVACh projections to the acinar cell.
  70. Human induced pluripotent stem cell-derived cortical grafts rebuild motor circuits after brain injury.
  71. Myeloid cell IL-15 production in the brain supports bystander CD8+ T cell neuropathic immune responses following virus infection.
  72. Walnut-Derived Extracellular Vesicles Orchestrate a Pre-Regenerative Niche via c-Myc Mediated Metabolic Reprogramming.
  73. Tauopathy primes co-filament assembly and dysfunction of TDP-43.
  74. Tenecteplase for Acute Non-Large Vessel Occlusion After Ischemic Stroke-Reply.
  75. ZFHX4 is necessary for dopaminergic neuron differentiation and controls cell cycle by regulating LIN28A.
  76. Molecular Mechanisms Underlying Alzheimer's Disease Pathogenesis: Comprehensive Overview.
  77. Proximity labeling reveals unique and shared interactomes of unmodified and pyroglutamate amyloid beta in human hippocampus in Alzheimer's disease.
  78. Lipidomics reveals TREM2-associated dysregulation of plasma lipid metabolism in Alzheimer's disease.
  79. Cutaneous T-cell lymphoma tumors undergoing radiotherapy demonstrate immune shifts from malignant inflammation to wound healing and suggest markers of treatment durability.
  80. Lifespan normative modeling of brain microstructure.
  81. Andrographolide attenuates microglial senescence in Alzheimer's disease mice by suppressing the STAT3 signaling.
  82. Fusion-positive rhabdomyosarcoma oncofusions share a common interactome.
  83. Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
  84. Mechanisms of ligand recognition and channel opening for P2X2 receptors in lipid nanodiscs.
  85. Specific Deletion of Interleukin-1 Beta in Microglia Improves Acute Outcome and Modulates Neurogenesis After Ischemic Stroke.
  86. The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke.
  87. Lymph node-targeted DNA engages TBK1/IFN-I-driven innate immunity to induce potent T cell responses and durable memory in mice and NHPs.
  88. Serum FAM19A5 elevation in NMOSD: astrocytic injury or reactive gliosis?
  89. Microglia-derived extracellular vesicles attenuate acute a-synuclein induced astrocyte inflammation.
  1. bioRxiv. 2026 May 12. pii: 2026.05.08.723911. [Epub ahead of print]
    Immune receptor LAG3 regulates microglia function during Alzheimer's disease.
    Andrew T Perl, Juan Wu, John D Dong, Ashley M Brooks, Andrew R Yoblinski, Tia T Vierling, Jian-Liang Li, Dana R Ruby, Daniel Radzicki, Serena M Dudek, Jesse D Cushman, Elizabeta Gjoneska.
      Alzheimer's Disease (AD) remains the leading cause of dementia globally, yet the exact etiology is not well defined and effective treatments remain unavailable. Here, we report that deletion of the immune checkpoint receptor lymphocyte activation gene 3 ( Lag3 ) in a familial AD mouse model, 5xFAD + , can rescue molecular, cellular and behavioral phenotypes of neurodegeneration. Specifically, we demonstrate that amyloidosis and microgliosis in the 5xFAD + mice are significantly reduced by Lag3 deletion. Moreover, we show that Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes in the 5xFAD + mice. Transcriptional profiling reveals that Lag3 deletion suppresses aberrant overexpression of disease associated microglia (DAM) genes in 5xFAD + microglia, effectively restoring homeostatic transcriptional programs. Finally, we observe reduced CD8 + T cell infiltration in the brain of 5xFAD + animals after Lag3 deletion which likely mediates molecular, cellular and behavioral effects resulting from microglia DAM gene activation. Our results highlight a previously unrecognized role for Lag3 in AD as a critical regulator of microglia function and suggest Lag3 might be a viable target for novel AD therapeutic interventions.
    Highlights: Immune receptor Lag3 deletion ameliorates amyloidosis and microgliosis during AD Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes Lag3 deletion reverses aberrant activation of DAM genes and restores microglia homeostasis Lag3 inhibition presents a viable approach for novel AD therapeutic interventions.
    DOI:  https://doi.org/10.64898/2026.05.08.723911
  2. bioRxiv. 2026 May 13. pii: 2026.05.12.724612. [Epub ahead of print]
    Impaired lipoprotein secretion by APOE4 leads to lysosomal and mitochondrial dysfunction in human microglia.
    Jasmin S Revanna, Karl Wessendorf-Rodriguez, Qiang Xiao, Thais S Sabedot, Michael S Cuoco, Snigdha Sarkar, Lucia Zhou-Yang, Christina K Lim, Victoria N Prozapas, Rowan S Wooldridge, Jean Paul Chadarevian, Joshua M Pratt, Sheila C Steiner, Ava Katz, Jerome Mertens, Jeffery W Kelly, Santiago Solé-Domènech, John T Melchior, Christian M Metallo, Jeffrey R Jones, Fred H Gage.
      While Apolipoprotein E4 (APOE4) is the greatest known genetic risk factor for late-onset Alzheimer's disease, its mechanistic role in the brain-resident macrophage, microglia, remains elusive. Microglia are important in the clearance of pathology in disease, heavily relying on lysosome functionality; therefore, we sought to understand the impact of APOE4 on microglial function. APOE44 microglia have been shown to have lipid accumulation, yet the mechanisms leading to this accumulation are unknown. Using induced pluripotent stem cell-derived microglia, we found that the APOE4 haplotype resulted in transcriptional state shifts in microglia, suppressing activated-response microglia (ARMs) and promoting a G2 senescent-like state. We found that APOE44 microglia accumulate cholesterol esters and provide less lipid support to fibroblast-induced neurons, decreasing their synaptic connections. APOE44 microglia secrete significantly less lipoproteins, leading to the accumulation of lipoproteins within the cells including the lysosomes. APOE44 microglia exhibit impaired lysosomal acidification and degradation capacity. Further, our results elucidated that APOE44 microglia are proinflammatory and shift away from fatty acid oxidation towards glycolysis, due to dysfunctional mitochondria. Taken together, our findings indicate that a loss-of-function in lipoprotein secretion drives intracellular lipid accumulation, including within lysosomes, ultimately disrupting the lysosome-endoplasmic reticulum-mitochondrial axis. This drives a proinflammatory and metabolically compromised microglial phenotype with impaired neuro-supportive functions.
    GRAPHICAL ABSTRACT:
    DOI:  https://doi.org/10.64898/2026.05.12.724612
  3. Glia. 2026 Jul;74(7): e70169
    Harnessing Microglial Repopulation: From Inflammatory Drivers to Therapeutic Allies in CNS Diseases.
    Guanyu Li, Hong Liu, Zhida Lan, Yimin Yuan, Jiali Li, Ziwei Dai, Chao Huang, Cheng He, Shangyao Qin, Zhida Su.
      Microglia, the tissue-resident macrophages of the central nervous system (CNS), execute essential functions in neural development, homeostasis, and repair. However, their persistent or dysregulated activation is a hallmark of diverse neurological disorders, where they transition from protective sentinels to drivers of chronic neuroinflammation and tissue damage. This duality has spurred the development of therapeutic strategies aimed not merely at suppressing microglial activity, but at fundamentally resetting the CNS immune landscape. Here, we review the paradigm of transient microglial depletion followed by endogenous repopulation, a strategy that effectively replaces a dysfunctional or pathologically primed microglial compartment with a rejuvenated cohort. Emerging evidence demonstrates that repopulated microglia exhibit a distinct phenotype-characterized by attenuated inflammatory profiles, upregulated homeostatic and neurotrophic gene expression, and enhanced phagocytic capacity-thereby conferring neuroprotection and promoting functional recovery across preclinical models of acute injury, neurodegeneration, and demyelinating disease. We critically evaluate the pharmacological and genetic tools used to achieve depletion, synthesize the context-dependent outcomes across disease spectra, and discuss the mechanistic basis for the superior therapeutic profile of the repopulation phase. Finally, we address the key translational challenges-including therapeutic windows, age- and sex-dependent effects, and the gap between rodent models and human biology-that must be overcome to transform this innovative strategy from a powerful experimental tool into a viable clinical modality for reprogramming CNS immunity.
    Keywords:  depletion; microglia; neuroinflammation; neurological disorder; repopulation; therapy
    DOI:  https://doi.org/10.1002/glia.70169
  4. Nat Neurosci. 2026 May 29.
    Neuroproteasomes regulate endogenous tau paired helical filament formation in an APOE genotype- and age-dependent manner.
    Victoria Paradise, Kalin D Konrad-Vicario, Chi Nguyen, Nyle A Sharif, Xiao Wang, Rijuta D Mukim, Malavika Sabu, Bianca T Corjuc, Joanna Bafia, Jack Fu, Gabriella C Maldonado, Michael Strickland, Sarah L Grauman, Helen Figueroa, Bradley T Hyman, David M Holtzman, Tal Nuriel, Kapil V Ramachandran.
      In Alzheimer's disease (AD), endogenous tau undergoes a pathogenic transition to form paired helical filaments (PHFs), but the cellular mechanisms driving this process have been elusive. Here, we identify the neuron-specific plasma membrane proteasome ('neuroproteasome') as a critical determinant of tau proteostasis. Selective inhibition of neuroproteasome function rapidly triggers the de novo formation of endogenous, sarkosyl-insoluble tau PHFs in primary neurons and mouse brain, which share key biochemical and ultrastructural features with PHFs from human AD brains. The APOE gene has three isoforms (E2, E3 and E4), with APOE4 being the largest genetic risk factor for AD. Neuroproteasome abundance at the plasma membrane is differentially modulated by ApoE isoforms (E2 > E3 > E4) and declines with age. ApoE4 neurons accumulate tau aggregates following modest neuroproteasome disruption, whereas ApoE2 neurons remain resistant. Our findings delineate a neuron-specific mechanism linking genetic and age-related risk factors to the formation of AD-relevant tau pathology, and position neuroproteasome function as a potential target to preserve proteostasis.
    DOI:  https://doi.org/10.1038/s41593-026-02297-x
  5. Front Immunol. 2026 ;17 1815719
    Lipid metabolic regulation of neuroinflammation in Alzheimer's disease.
    Tingting Li, Kanglin Guo, Yongxia Ma, Jianjun Zhao, Yanchun Cao, Run Zhang, Xiang Li, Jing Wei, Yufang Ma, Zongxia Zhu, Dongrong Zhao.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid deposition, tau pathology, and sustained neuroinflammation. Increasing evidence indicates that dysregulated lipid metabolism is not merely a metabolic disturbance but a critical modulator of inflammatory responses driving AD pathogenesis. The brain, one of the most lipid-enriched organs, relies on tightly controlled lipid homeostasis to maintain neuronal function and synaptic integrity. Alterations in fatty acid composition, apolipoprotein E (ApoE) isoforms, lipoprotein lipase activity, and lipid-derived signaling mediators profoundly reshape microglial activation states and inflammatory cascades. Obesity, insulin resistance, and gut microbiota dysbiosis further exacerbate systemic and central lipid imbalance, amplifying neuroinflammatory signaling through cytokine networks and blood-brain barrier disruption. Notably, polyunsaturated fatty acids and lipid mediators exert dual immunomodulatory effects, influencing β-amyloid aggregation, oxidative stress, and microglial polarization. This review synthesizes recent advances in understanding how lipid metabolism modulates neuroinflammation and microglia-neuron crosstalk in AD, highlighting emerging therapeutic strategies targeting lipid-inflammation axes as promising avenues for disease modification.
    Keywords:  Alzheimer’s disease; apolipoprotein E (APOE); fatty acids; gut–brain axis; lipid metabolism; metabolic dysregulation; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1815719
  6. EMBO J. 2026 May 29.
    The C9orf72/SMCR8 complex maintains microglial homeostasis via RAB8A ESCRT-mediated lysosomal repair.
    Shan Li, Shidong Xu, Feng Li, Qirui Zhao, Penghui Zhang, Qinghua Guan, Xiangxiang Sun, Jundong Bi, Hu Xiao, Yiyuli Tang, Cheng Peng, Qingfeng Chen, Yonghua Wang, Mei Yang.
      Microglia are critical regulators of neuroinflammation and neurodegeneration. Haploinsufficiency of C9orf72, the most frequently mutated gene in amyotrophic lateral sclerosis and frontotemporal dementia, has been linked to autophagy-lysosomal pathway defects, but the role of C9orf72 in microglia remains unclear. Here, we identify the C9orf72/SMCR8 complex as a key regulator of microglial homeostasis through promoting lysosomal membrane repair. Loss of C9orf72 and SMCR8 in mice causes age‑dependent neuroinflammation and microgliosis, with microglia adopting a disease-associated state. In aged brain and spinal cord tissue, microglia display lysosomal damage marked by galectin‑3 accumulation. Using a lysosomotropic agent to induce lysosomal damage in microglia, we find that C9orf72/SMCR8-deficient cells accumulate damaged lysosomes and show defective recruitment of phosphorylated RAB8A and the Endosomal Sorting Complexes Required for Transport (ESCRT) machinery to damaged lysosomes. Notably, mutant microglia accumulate GTP‑bound RAB8A, which becomes hyperphosphorylated and mislocalized to RAB7-positive, LAMP1-negative vesicles. The GTPase-activating activity of the C9orf72/SMCR8 complex is essential for lysosomal repair. Our findings reveal that the C9orf72/SMCR8 complex coordinates RAB8A-ESCRT-mediated lysosomal repair to safeguard microglial homeostasis and limit neuroinflammation.
    DOI:  https://doi.org/10.1038/s44318-026-00817-w
  7. bioRxiv. 2026 May 12. pii: 2026.05.09.723490. [Epub ahead of print]
    Alzheimer's Disease Risk Allele APOE4 Interacts with Arsenic Exposure to Drive Microglial Dysfunction.
    Alex J Marchi, Ashley M Brooks, Elizabeta Gjoneska.
      Alzheimer's disease (AD) is influenced by both genetic risk and environmental exposures, but how these factors interact in human microglia remains unclear. Here, we investigate whether the late-onset AD risk allele APOE4 impacts microglial vulnerability to arsenite exposure. To that end, we used CRISPR/Cas9 to generate an isogenic APOE4 +/+ iPSC-derived transcription factor-induced microglia-like cells (iTFM). We demonstrate that APOE4 +/+ iTFM exhibit decreased survival following arsenite exposure, as evidenced by a lower LC 50 compared to APOE3 +/+ controls. Transcriptomic profiling identified arsenite concentration as the primary driver of gene expression changes, while genotype contributed a secondary, distinct component of the response. Weighted gene co-expression network analysis revealed genotype-dependent modules enriched for phagocytic and oxidative stress pathways, including KEAP1-NFE2L2 signaling. These transcriptomic changes were further supported by functional assays. APOE4 +/+ iTFM had a high proportion of phagocytic cells and altered mitochondrial phenotypes including increased mitochondrial mass, reduced membrane potential, and reduced superoxide production, all of which were further perturbed by low dose arsenite exposure. These results support a gene-environment interaction-dependent increase in microglial vulnerability via reshaping of transcriptional and functional stress responses, and provide a human cell-based framework for studying environmentally mediated microglial contributions to AD.
    DOI:  https://doi.org/10.64898/2026.05.09.723490
  8. Neuropathol Appl Neurobiol. 2026 Jun;52(3): e70082
    Early Regional Microglial Remodelling in the Hippocampus of the AppNL-G-F Alzheimer's Model.
    Ryan J Bevan, Jessica F Minett, Alice L Smith, Ana Cardus Figueras, Philip R Taylor.
       AIMS: Microglia undergo profound structural and functional changes during Alzheimer's disease, yet the earliest stages of morphological remodelling that occur prior to amyloid deposition remain poorly defined. We hypothesised that microglia in the hippocampus of AppNL-G-F mice would exhibit early, region-specific structural adaptations before local plaque formation, reflecting an initial phase of disease-associated structural remodelling.
    METHODS: Two-month-old AppNL-G-F and wildtype mice were examined using high-resolution confocal microscopy of Iba1-labelled microglia in the dorsal CA1 apical field. Automated three-dimensional reconstructions were generated in Imaris, and quantitative morphometric analyses quantified cell density, Iba1 coverage, process topology and Sholl-based arbor complexity. Statistical analyses were performed using linear mixed-effects models incorporating sex as a fixed factor in all analyses.
    RESULTS: Microglial density and total Iba1 coverage were unaffected in AppNL-G-F mice at this age. In contrast, Sholl analysis revealed significant genotype-dependent reductions in process intersections and total process length, accompanied by reduced individual-cell territorial coverage, indicating an early contraction of the surveillance arbor independent of cell number.
    CONCLUSIONS: These findings demonstrate that hippocampal microglia in AppNL-G-F mice undergo an early, coordinated structural remodelling before local amyloid deposition becomes apparent. This preplaque adaptation defines an early structural remodelling of hippocampal microglia prior to evident local amyloid deposition, providing new insight into the earliest structural adaptations associated with neuroimmune engagement in AD pathogenesis.
    Keywords:   App NL‐G‐F ; Alzheimer's disease; hippocampus; microglia; microglia morphology
    DOI:  https://doi.org/10.1111/nan.70082
  9. bioRxiv. 2026 May 11. pii: 2026.05.06.723271. [Epub ahead of print]
    3D cortical microtissue with innate microglia for studying real-time cell behavior across maturation and inflammatory response.
    Alexander Del Toro, Kaylen Aguilar, Angelina Clark, Alexander Bautista, Nathan Ashby, Diane Hoffman-Kim.
      Microglia represent the immune component of the central nervous system (CNS) that displays dynamic responses to injury and disease. Across the developing and mature CNS, microglia emerge as immunocompetent cells that continuously survey their surroundings to maintain tissue homeostasis and respond to threats. There remains a gap in 3D in vitro models that contain microglia and can provide both developmental and mature functional hallmarks. Using a 3D neural multicellular model, cortical microtissues, derived from primary rat cortical cells, we conducted live imaging to monitor microglia dynamics from early, middle, and late stage microtissue maturation. We optimized a within-micromold imaging approach that allows for live microglia imaging without removing microtissues from their culturing environment. We confirm that microglia exhibit baseline surveillance characterized by relatively stationary somas and highly dynamic cell processes that continuously extend and retract. Following proinflammatory challenges, microglia engulf lipopolysaccharide particles, accompanied by dynamic shifts in motility patterns; and rapidly respond to laser-induced tissue damage through process extension, whole-cell displacement, and local recruitment. Lastly, we show that microtissue age in culture strongly influences both baseline and directed motility profiles. Collectively, these studies demonstrate that within a 3D microenvironment, microglia exhibit pronounced changes in morphology, surveillance area, motility, and injury response across microtissue maturation. Microtissues can serve as a valuable in vitro platform for both microglia developmental studies and investigations of brain inflammation related to CNS injuries, infections, and diseases.
    DOI:  https://doi.org/10.64898/2026.05.06.723271
  10. Glia. 2026 Jul;74(7): e70154
    Microglial Pruning of Excitatory Synapses in the Hippocampus Is Complement C3-Independent in Physiological and Neuroinflammatory States.
    Eric W Salter, Ashish Kadia, Lijia Zhang, Jonathan S Thacker, Sun-Lim Choi, Liam T Ralph, Gang Lei, Fuzi Jin, John Georgiou, Graham L Collingridge.
      A key feature of brain development is the refinement of exuberant synapses, known as synapse pruning. This phenomenon is executed by microglia, the resident immune cells of the brain. Evidence that microglia prune retinal inputs via activation of the complement cascade in the dorsolateral geniculate nucleus (dLGN) has led to the widely held view that complement-dependent synapse pruning occurs ubiquitously in the brain. However, evidence for developmental complement-dependent pruning in regions outside of the dLGN is largely absent. Here, we tested for complement-dependent synapse pruning by microglia in the hippocampus, a central region for learning and memory. We hypothesized that complement-dependent pruning by microglia occurs at VGLUT2+ synapses, where complement proteins are enriched in the hippocampus. We analyzed mice genetically lacking the central complement component C3 (C3-/-) that have broad inhibition of complement cascade activity. We found that microglia-mediated VGLUT2 engulfment was not significantly impaired in C3-/- compared to wildtype (WT) mice in the hippocampus in both late postnatal development and early adulthood. Further, functional synapse properties were not significantly altered in C3-/- compared to WT mice. Finally, we tested whether a complement-dependent pruning mechanism could be induced in the hippocampus via peripheral inflammation. Lipopolysaccharide (LPS) injections induced a neuroinflammatory phenotype associated with loss of VGLUT2+ synapses. However, in an LPS-induced neuroinflammatory state, VGLUT2+ synapse pruning by microglia was not affected in C3-/- mice. These findings uncover that C3 is not ubiquitously required for synapse engulfment in physiological and neuroinflammatory conditions in the hippocampus.
    Keywords:  complement cascade; hippocampus; microglia; synapse pruning
    DOI:  https://doi.org/10.1002/glia.70154
  11. Neurosci Res. 2026 May 22. pii: S0168-0102(26)00065-9. [Epub ahead of print]228 105078
    Microglial ontogeny and in vitro reconstruction: Bridging development and modeling.
    Mizuki Ono, Hinako Matsuo, Yuki Hattori.
      Microglia are the resident immune cells of the central nervous system (CNS) with a unique developmental origin distinct from other tissue macrophages. They arise from progenitors generated in the yolk sac during early embryogenesis, subsequently colonize the developing brain, and persist throughout life via self-renewal. Following brain entry, microglial progenitors undergo stepwise differentiation and maturation under the influence of the local microenvironment, giving rise to the transcriptional and functional diversity observed in mature microglia. In recent years, substantial progress has been made in elucidating the molecular and developmental mechanisms governing microglial ontogeny, from early progenitor specification to brain colonization and maturation. In parallel, in vitro approaches for generating microglia have advanced rapidly. These include the use of immortalized cell lines, primary microglial cultures, and, more recently, microglia-like cells derived from human induced pluripotent stem cells (iPSCs), which are increasingly used for disease modeling. While these systems do not fully recapitulate the in vivo environment, they provide powerful and complementary platforms for dissecting specific aspects of microglial biology. Recent efforts to incorporate microglia into transplantation and brain organoid models have enhanced their physiological relevance and applicability to human systems. In this review, we integrate current knowledge of microglial development with in vitro models and discuss how these insights can be leveraged to further refine experimental systems and advance human disease research.
    Keywords:  Brain; Culture; Development; Differentiation; Macrophage; Microglia; Organoid; iPSC
    DOI:  https://doi.org/10.1016/j.neures.2026.105078
  12. J Neuroinflammation. 2026 May 27.
    Microglial state transitions dominate the brain immune response in the subacute phase after cardiac arrest.
    Lihong Dang, Ran Zhang, Jin Zhang, Peibang He, Xinyuan Yu, Ata Ur Rehman, Ángela Del Águila, Vaibhav Jain, Jilin Tian, Emily Xu, Huaxin Sheng, Wei Yang.
      Cardiac arrest (CA) is a life-threatening medical emergency, and most victims are elderly. Despite advances in resuscitation, post-CA morbidity and mortality remain high, and this is thought to result largely from brain injury in which neuroinflammation plays a key role. Yet, how individual immune cell populations contribute to the immune response in the post-CA brain is still poorly understood. Here, using single-cell RNA-sequencing (scRNA-seq), we revealed the first immune landscape of the young and aged brain on day 3 after CA. Our data demonstrate that transitions in microglial states constituted a dominant immune change in the post-CA brain. We identified 5 CA-associated microglial states that included 3 major clusters defined by pro-inflammatory signatures, a proliferative phenotype, and high Spp1 expression. These 3 states exhibited age-dependent differences: the inflammatory subset was markedly expanded in aged mice, whereas the proliferative and Spp1⁺ clusters were more prominent in young mice. Such divergent responses likely underpin age-related disparities in neurologic outcome after CA. Notably, Spp1+ microglia displayed unique spatiotemporal dynamics. These cells were robustly induced by CA, and were enriched in selective brain regions including the basal ganglia where they were associated with a microinfarct-like injury pattern. Lastly, we found that microglial depletion worsened functional outcome after CA, suggesting an overall protective role for microglia. Together, these findings provide novel insights into microglial heterogeneity and age-dependent immune responses in the brain after CA, and highlight the central role of microglia in shaping post-CA recovery.
    Keywords:  OPN; PLX3397; aging; basal ganglia; globus pallidus; proliferation
    DOI:  https://doi.org/10.1186/s12974-026-03874-4
  13. Cell Press Blue. 2026 Apr 20. pii: 100003. [Epub ahead of print]1(1):
    Tanycytic degeneration impairs tau clearance and contributes to Alzheimer's disease pathology.
    Florent Sauvé, Ricardo Martinez-Gómez, Yvon Mbouamboua, Gaëtan Ternier, Sreekala Nampoothiri, Elian Dupré, Lolie Garcia, Marie Couralet, Julie Dewisme, Thibaud Lebouvier, Clément Danis, S Rasika, Marc Dhenain, Young-Bum Kim, Philippe Ciofi, Luc Buée, Isabelle Landrieu, Florence Pasquier, Matthieu Lilamand, Claire Paquet, Paolo Giacobini, Pascal Barbry, Claude-Alain Maurage, Ruben Nogueiras, Markus Schwaninger, Vincent Prevot.
      Alzheimer's disease (AD) is characterized by pathological Tau protein accumulation in the brain and cerebrospinal fluid (CSF), instead of timely efflux into the blood. However, the underlying mechanisms are unclear. We show, using animal and cellular models and patient tissues, that tanycytes of the hypothalamic median eminence, which bridge the blood and CSF, are involved in Tau transport and AD pathogenesis. In mice, tanycytes take up CSF-borne Tau and release it into pituitary portal capillaries, whence it enters the systemic circulation. Blocking tanycytic vesicular transport blunts CSF-to-blood Tau efflux and potentiates Tau pathology. In AD patients, plasma-to-CSF ratios of total and p181 Tau are decreased. Tanycytes from postmortem AD patient brains display dramatically fragmented processes and significant transcriptomic alterations by single-nucleus RNA sequencing, notably in vesicular-transport-related genes, explaining this clearance deficit. The involvement of tanycytic dysfunction in human pathophysiology and evidence for a brain-to-blood tanycytic shuttle has far-reaching implications.
    DOI:  https://doi.org/10.1016/j.cpblue.2026.100003
  14. Biomolecules. 2026 May 12. pii: 713. [Epub ahead of print]16(5):
    Live-Cell Imaging of Microglia in Organotypic Brain Slices Using Microcontact Printing.
    Björn Y P Richardsen, Christian Humpel.
      Microglia are brain immune cells that phagocytose cell debris and beta-amyloid plaques in patients with Alzheimer's disease. They develop from round amoeboid cells into ramified microglia or large macrophages, which can be studied in three-dimensional organotypic mouse brain slices. In a recent publication, we showed for the first time that we can track GFAP+ astrocytes and laminin+ vessels in organotypic brain slices using live-cell imaging . The aim of the present study was to use microcontact printing on organotypic brain slices to label microglia with Iba1 and CD11b antibodies and visualise them through live-cell imaging. We show that microglia can be easily labelled with antibodies and tracked via live-cell fluorescence microscopy for up to 20 days. Incubation in lipopolysaccharide (LPS) or granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulates the migration of round amoeboid microglia, whereas interleukin-10 induces their differentiation into ramified forms. Taken together, we show the first-time live cell imaging of microglia in organotypic mouse brain slices using microcontact printing.
    Keywords:  live-cell imaging; microcontact print; microglia; organotypic brain slice
    DOI:  https://doi.org/10.3390/biom16050713
  15. Cell. 2026 May 29. pii: S0092-8674(26)00515-5. [Epub ahead of print]
    Physiological brain clearance architecture revealed by neuronal protein tracing.
    Yuichi Chayama, Nalini R Rao, Daniela Perla, Zimo Zhang, Madigan Reid, Sophia Nelson, Xinlan Wen, Bella Ding, Jessica Blumenfeld, Amanda Apolonio, Sahith Doddipalli, Haoyue Zhou, Sena Gül Turhan, Pu-Yun Shih, Matthias Brendel, Ying-Hui Fu, Ali Ertürk, Zeynep Ilgin Kolabas, Yadong Huang, Andrew C Yang.
      The brain must efficiently clear protein waste to maintain homeostasis, yet physiological drainage pathways remain poorly defined. Standard tracer injection approaches may not reflect endogenous efflux. Here, we develop a non-invasive genetic system to trace neuron-derived protein clearance from the brain to cerebrospinal fluid (CSF) and border tissues. We identify distinct drainage routes and border hotspots missed by tracer injection, confirmed by bioorthogonal labeling of endogenous neuronal proteins. Pulse-chase kinetics reveal slow skull outflow versus rapid dural and nasal clearance. Transcriptomic analyses uncover border cells sampling neuronal antigens, including tolerogenic skull-resident B cells. Region-restricted reporter expression demonstrates compartmentalized clearance following a "nearest exit" principle, where anatomical origin dictates drainage pathway. Disease disrupts clearance through distinct mechanisms: inflammation drives vascular leakage into blood, while amyloid pathology causes parenchymal retention and border exit obstruction. These findings define brain clearance as a compartmentalized system of organized pathways and immune niches whose dysfunction may underlie regional vulnerability in neurological disease.
    Keywords:  Alzheimer’s disease; CNS drainage; brain borders; brain waste clearance; cerebrospinal fluid; dura; immune tolerance; neuroimmunology; skull
    DOI:  https://doi.org/10.1016/j.cell.2026.04.048
  16. J Neuroinflammation. 2026 May 26.
    Irisin-integrin αV/β5 coupling of α-synuclein phagocytosis and clearance.
    Yihan Liu, Shijie Shi, Jingyuan Zhang, Mengyao Huang, Mengxue Wang, Tingting Zhang, Wei Wang, Jie Xiang.
      Parkinson's disease-associated cognitive impairment (PD-CI) is closely linked to α-synuclein (α-syn) accumulation and synaptic dysfunction, yet effective disease-modifying strategies remain limited. Irisin is an exercise-inducible myokine with neuroprotective potential, but its receptor mechanisms and its role in α-syn clearance in PD-CI are poorly defined. Here, we observed that aerobic exercise markedly increased circulating irisin levels, reduced serum α-syn levels, and improved cognitive performance in a cohort of 21 PD patients. In addition, irisin signals through integrin αV/β5 to enhance microglial α-syn clearance, resulting in reduced α-syn burden and improved PD-CI. Mechanistically, irisin activates integrin αV/β5-FAK axis to promotes microglial phagocytic uptake of α-syn, while concurrently stabilizing HMGB1 to facilitate autophagy-lysosome mediated degradation of internalized α-syn, thereby coupling phagocytic uptake to efficient degradation. In summary, these results highlight a dual-module irisin-integrin αV/β5 mechanism that couples microglial phagocytosis and autophagy-lysosome clearance to reduce α-syn burden and ameliorate PD-CI.
    Keywords:  Clearance; Integrin αV/β5; Irisin; Phagocytosis; α-synuclein
    DOI:  https://doi.org/10.1186/s12974-026-03882-4
  17. Mol Neurobiol. 2026 May 26. pii: 651. [Epub ahead of print]63(1):
    Metabolic Competition Between Microglia and Neurons as Driver of Chronic Pain.
    Enso O Torres Alegre, Diana E Mora Jiménez.
      Chronic pain is traditionally framed as a consequence of neuroinflammation and maladaptive synaptic plasticity, with activated microglia releasing cytokines, chemokines, and growth factors that sensitize nociceptive circuits in the spinal dorsal horn. However, microglial activation is also accompanied by profound metabolic reprogramming-including a glycolytic shift, altered mitochondrial dynamics, and increased demand for biosynthetic intermediates-that has received comparatively little attention in pain neurobiology. Here, we propose that metabolic competition between activated microglia and neighboring neurons may constitute an underexplored mechanism contributing to persistent pain states. We argue that shifts in local energy allocation-particularly glucose, lactate, and nicotinamide adenine dinucleotide (NAD+) availability-could modulate neuronal excitability and sustain central sensitization even when classical inflammatory signaling is no longer dominant. Drawing on advances in immunometabolism, emerging single-cell/spatial metabolomics, and in vivo biosensor imaging, we integrate neuroimmunology with metabolic neurobiology to generate experimentally testable predictions. If validated, this framework could reposition cellular metabolism as a tractable therapeutic dimension for chronic pain management.
    Keywords:  Astrocyte–neuron lactate shuttle; Central sensitization; Chronic pain; Dorsal horn; Glycolysis; Immunometabolism; Metabolic reprogramming; Microglia; Mitochondrial dysfunction; Warburg effect
    DOI:  https://doi.org/10.1007/s12035-026-05952-3
  18. Int J Mol Sci. 2026 May 15. pii: 4430. [Epub ahead of print]27(10):
    Integrated Transcriptomic and Spatial Analyses Associate M2-like Myeloid Signatures with Neuroimmune Remodeling in Alzheimer's Disease.
    Sz-Bo Wang, Kuan-Nien Chou, Yi-Lin Chiu.
      Alzheimer's disease (AD) is characterized by progressive neurodegeneration and prominent neuroimmune remodeling, but the contribution of macrophage and myeloid states across disease severity remains incompletely defined. We integrated bulk transcriptomic, single-cell RNA sequencing (RNA-seq), and spatial transcriptomic datasets to characterize AD-associated myeloid immune changes across Braak stage and disease status. Across datasets, M2-like macrophage and myeloid signatures showed progressive enrichment with increasing neuropathological severity and were accompanied by pathway changes related to macrophage proliferation, TGF-β signaling, and myeloid homeostasis. Immune-feature-based classifiers identified macrophage-related variables among the informative features distinguishing AD from controls. CellChat analyses further inferred that M2-like myeloid populations occupied communication-enriched positions in single-cell and spatial interaction networks, including apolipoprotein E (ApoE), CX3C chemokine signaling, and fibronectin 1 (FN1)-associated signaling contexts. Collectively, these findings indicate that M2-like myeloid programs are consistently associated with AD severity and neuroimmune network remodeling. Rather than establishing a causal disease driver, this study highlights M2-like myeloid signatures as candidate neuroimmune components that warrant experimental validation in human-relevant systems.
    Keywords:  Alzheimer’s disease; M2-like myeloid signatures; immune deconvolution; neuroinflammation; single-cell RNA-seq; spatial transcriptomics
    DOI:  https://doi.org/10.3390/ijms27104430
  19. Mol Neurobiol. 2026 May 27. pii: 654. [Epub ahead of print]63(1):
    Apolipoprotein E Deficiency Attenuates Neuroinflammatory Responses and Demyelination in Experimental Autoimmune Encephalomyelitis.
    Xiaohui Lin, Xilin Wu, Xinyi Guo, Yuqi Zeng, Qinyong Ye, Jian Zhang.
      The precise etiology of multiple sclerosis (MS) remains incompletely understood, despite a well-established genetic predisposition. Clinical and epidemiological studies have identified an association between apolipoprotein E (ApoE) and MS progression; however, the underlying mechanisms remain largely unresolved. In this study, we investigated the role of ApoE in MS progression using an experimental autoimmune encephalomyelitis (EAE) model in ApoE knockout mice. EAE was induced in female C57BL/6 wild-type (WT) and ApoE knockout (ApoE KO) mice via immunization with myelin oligodendrocyte glycoprotein peptide (MOG35-55). Neurological deficit was assessed daily by clinical scoring from day 0 to day 28 post-immunization. On days 21 and 28 post-induction, spinal cord myelin density and ultrastructure were evaluated, and mRNA expression of myelin-related genes was quantified. In parallel, microglial activation was assessed through morphological analysis, along with quantification of inflammatory marker mRNA and protein levels. Compared with the WT-EAE group, ApoE KO-EAE mice exhibited significantly reduced neurological deficit scores during the peak phase of EAE, accompanied by attenuated demyelination and upregulation of proteolipid protein 1 (PLP1). Furthermore, the number of activated Iba-1⁺ myeloid cells was markedly decreased, with correspondingly blunted morphological transformation, and both mRNA and protein levels of pro-inflammatory cytokines in Iba-1⁺ myeloid cells were significantly downregulated. Collectively, ApoE deficiency alleviated Iba-1⁺ myeloid cells activation and neuroinflammation in EAE, mitigated demyelinating lesions, and improved neurological outcomes. These findings suggest that ApoE may contribute to MS progression, at least in part, by modulating Iba-1⁺ myeloid cells-mediated inflammatory responses.
    Keywords:  ApoE; Microglia; Multiple sclerosis; Neuroinflammation
    DOI:  https://doi.org/10.1007/s12035-026-05929-2
  20. Cell Rep. 2026 May 28. pii: S2211-1247(26)00546-2. [Epub ahead of print]45(6): 117468
    CD5L promotes phagocytic removal of amyloid β oligomers and improves cognitive function in a mouse model of Alzheimer's disease.
    Natsumi Maehara, Satoko Hattori, Akira Nakamura, Satoru Nagatoishi, Aika Hirota, Kai Kudo, Yuri Yoshikawa, Ryo Matsunaga, Kouhei Tsumoto, Tsuyoshi Miyakawa, Satoko Arai, Toru Miyazaki.
      Alzheimer's disease (AD), a neurodegenerative disorder, is the leading cause of dementia. Amyloid-beta (Aβ) and tau are major contributors to AD onset and progression. Here, we investigate the therapeutic potential of CD5L, a macrophage-specific secretory protein, in reducing Aβ accumulation and improving AD pathology. CD5L directly binds to Aβ, particularly the neurotoxic Aβ42, and blocks their aggregation. Moreover, CD5L enhances microglial phagocytosis against several forms of Aβ40 and Aβ42. In 5xFAD mice, a well-established AD murine model, forced expression of CD5L reduces Aβ plaque size and number. RNA sequencing shows that CD5L promotes phagocytic activity in microglia within the 5xFAD mouse brain. Furthermore, adeno-associated virus (AAV)-mediated delivery of CD5L improves cognitive function, as demonstrated by enhanced performance in the T-maze test. These findings highlight the role of CD5L in inhibiting Aβ aggregation and facilitating Aβ clearance via enhanced phagocytosis, offering a promising therapeutic strategy for AD.
    Keywords:  AIM/CD5L; Alzheimer’s disease; Aβ; CP: neuroscience; microglia; phagocytosis; self-pathogen
    DOI:  https://doi.org/10.1016/j.celrep.2026.117468
  21. Front Immunol. 2026 ;17 1818802
    Targeting microglia-mediated neuroinflammation in Alzheimer's disease: mechanisms and therapeutic approaches.
    Bang-Feng Li, Xiao-Ying Chen, Rui Xie, Yi-Fei Mo, Yao-Zhu Wu, Ya Meng, Xiao-Ling Han, Mu-He Chen, Yong-Jun Peng.
      While the recent approval of amyloid-beta (Aβ)-clearing monoclonal antibodies (mAbs) marks a milestone in treating Alzheimer's disease (AD), their modest clinical efficacy has catalyzed a paradigm shift, underscoring the necessity of targeting complementary pathological drivers. Neuroinflammation, once considered a secondary phenomenon, is now established as a third core pathological pillar of AD, with microglia at its epicenter. This review provides a comprehensive analysis of the multifaceted role of microglia in AD pathogenesis and evaluates the rapidly evolving landscape of microglia-targeted therapeutic strategies. We first delineate the dynamic and dichotomous function of microglia, which act as a "double-edged sword." Emerging evidence reveals a complex, three-stage functional arc: microglia are implicated in the initial seeding of Aβ plaques, then transition to a neuroprotective role by containing established plaques, and finally devolve into a chronic, pro-inflammatory state that drives neurodegeneration. We then delve into the core molecular mechanisms governing this plasticity, including the pivotal Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)-APOE signaling axis, the inhibitory receptor Cluster of Differentiation 33 (CD33), and key intracellular hubs like the NLRP3 inflammasome, which directly link genetic risk factors to microglial dysregulation. Based on this mechanistic understanding, we critically evaluate diverse therapeutic strategies, ranging from suppressing neurotoxic inflammation (e.g., TNF-α and NLRP3 inhibitors) to enhancing protective functions (e.g., TREM2 agonism and CD33 antagonism), eliminating senescent microglia (senolytics), and utilizing advanced nanoplatforms for brain-targeted delivery. Finally, we highlight the critical role of neuroinflammatory biomarkers within the emerging ATI(N) framework for enabling precision medicine. In conclusion, targeting microglia represents a vital therapeutic avenue that moves beyond amyloid-centric approaches, where a sophisticated understanding of their stage-dependent functions is paramount for developing effective immunomodulatory therapies to alter the devastating course of AD.
    Keywords:  Alzheimer’s disease; immunotherapy; microglia; neurodegeneration; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1818802
  22. Neurobiol Dis. 2026 May 27. pii: S0969-9961(26)00207-X. [Epub ahead of print] 107462
    Npc1 deficiency impairs brain vascular integrity in mouse model of Niemann-Pick disease type C1.
    Jing Kang, Ge Gao, Liang Qiao, Xiaoru Xu, Yifan Zhao, Lulu Xiao, Chenxu Cui, Huigen Feng, Yanli Liu, Paolo Salomoni, Xin Yan, Juntang Lin.
      Niemann-Pick disease type C1 is a rare and fatal neurodegenerative disorder caused by mutations in the NPC1 gene. Proper formation and function of vascular system are essential for maintaining homeostasis of the central nervous system. However, the vascular contribution to NPC1 pathogenesis remains largely unexplored. Here, we demonstrate that loss of Npc1, a transmembrane protein involved in intracellular cholesterol trafficking, results in vascular abnormalities in the mouse brain. Npc1-deficient mice exhibit distorted vascular architecture, increased blood-brain barrier (BBB) permeability, and enhanced microglia-endothelial cell contacts. Investigation of molecular perturbations upon endothelial Npc1 deficiency shows impairment of lipid metabolism and compromised Rap1 signaling and tight junctions in endothelial cells. These changes were in part reverted by release of lysosomal cholesterol. Collectively, these results suggest that Npc1 is involved in the regulation of brain vascular integrity and highlight brain endothelial cells as a potential therapeutic target for NPC1 disease.
    Keywords:  Blood-brain barrier; Cholesterol; Endothelial cells; Niemann-pick disease type C1
    DOI:  https://doi.org/10.1016/j.nbd.2026.107462
  23. Nat Neurosci. 2026 May 26.
    Microglial mitochondria transfer to astrocytes via GPNMB-enriched extracellular vesicles alleviates cognitive deficits in tauopathy mice.
    Chensi Liang, Yulan Zhou, Kai Zhuang, Shuzhong Wang, Li Zhong, Dan Can, Aiyu Lei, Huifang Li, Jie Zhang, Lige Leng.
      Alzheimer's disease (AD) is an irreversible neurodegenerative disease characterized by cognitive decline. The precise molecular mechanisms that underlie the pathogenesis of AD remain elusive. Here we show that glycoprotein nonmetastatic melanoma protein B (GPNMB) is produced by microglia and transferred to astrocytes through extracellular vesicles (EVs) in PS19 tau pathology mice. Tau is cleaved in microglia to generate N-terminal fragments that form a complex on mitochondria with Parkin/Nix and GPNMB, promoting the secretion of EVs containing mitochondria. Functional mitochondria transferred to astrocytes via EVs markedly improve astrocytic functions and attenuate the cognitive impairments and pathogenic features in PS19 mice. By contrast, microglial GPNMB deficiency eliminates mitochondrial EV secretion and mitochondrial transfer to astrocytes, thereby impairing astrocytic functions and exacerbating cognitive impairment in PS19-CcKO (CX3CR1 cre Gpnmb floxp) mice. GPNMB-enriched EVs from PS19 mice alleviate the pathological phenotypes of PS19 mice, offering potential insights for AD treatment.
    DOI:  https://doi.org/10.1038/s41593-026-02317-w
  24. Viruses. 2026 May 09. pii: 550. [Epub ahead of print]18(5):
    Microglial-Derived IGF-1 Serves as a Regulator for Neuroimmune Homeostasis During Viral-Induced Demyelination.
    Vanessa M Scarfone, Collin Pachow, Pauline U Nguyen, Anita Lakatos, Jamie-Jean De La Torre, Alisa Xie, Kellie Fernandez, Charlene Collado, Kaitlin Murray, Roberto Tinoco, Craig M Walsh, Trevor Owens, Agnieszka Wlodarczyk, Thomas E Lane.
      This study investigated the role of microglia-derived insulin-like growth factor 1 (IGF-1) in modulating host defense and disease progression in a viral model of neuroinflammation and demyelination. Intracranial infection of susceptible mice with the glial-tropic JHM strain of mouse hepatitis virus (JHMV) induces acute encephalomyelitis, followed by an immune-mediated demyelinating disease that mimics many clinical and histologic features of multiple sclerosis (MS). Utilizing an inducible fractalkine receptor (Cx3cr1) promoter-driven Cre-loxP recombinant system, we performed timed ablation of Igf1 in microglia to assess its impact on the central nervous system (CNS) response to JHMV. While the loss of microglial IGF-1 did not impair the control of viral replication, it significantly exacerbated spinal cord demyelination. CyTOF and imaging mass cytometry analysis of spinal cords indicated increased myelin damage was associated with increased accumulation of CD8+Ly6C+ effector T cells and reduced expression of TREM2 that impaired transition into a disease-associated microglia (DAM) phenotype capable of sensing and potentially mitigating myelin damage. Collectively, these findings argue that microglial IGF-1 is a non-redundant coordinator of the CNS immune responses that occur in response to CNS viral infection.
    Keywords:  coronaviruses; demyelination; neuroinflammation; neurovirology
    DOI:  https://doi.org/10.3390/v18050550
  25. J Neuroinflammation. 2026 May 28.
    Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer's disease pathology and systemic bone loss.
    Mei-Dan Wan, Xi-Xi Liu, Teng-Fei Wan, Yi-Wei Liu, Ya-Ling Jiang, Jing-Tao Zou, Bin Jiao, Qian-Qian Liu, Ling Jin, Ran Duan, Zun Wang, Chun-Gu Hong, Xin Wang, Xin-Yue Hu, Xin-Xin Liao, Jia Cao, Lu Shen, Hui Xie, Zhen-Xing Wang.
      Alzheimer's disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.
    Keywords:  Alzheimer's disease; Bone loss; Demethylation; Microglia; Neuron; OSK; Reprogramming
    DOI:  https://doi.org/10.1186/s12974-026-03854-8
  26. J Biomed Sci. 2026 May 23. pii: 53. [Epub ahead of print]33(1):
    Microglial MARCO facilitates Varicella zoster virus uptake and triggers TLR2-mediated neuroinflammation.
    Ji-Soo Lim, Soo-Jin Oh, Ji-Yeun Hur, Subin Oh, Seuk-Min Ryu, Rafael T Han, Hosun Park, Dawn M E Bowdish, Ok Sarah Shin.
       BACKGROUND: Varicella zoster virus (VZV) is a human neurotropic virus that can establish latency in sensory neurons. Microglia play a complex role during neurotropic virus infections; however, their role during VZV infection remains to be determined. In the present study, we explored the role of VZV-induced alterations in the morphodynamics and function of microglia in triggering neuroinflammation.
    METHODS: We prepared cell-free VZV and compared replication efficiencies of wild-type (YC01) and attenuated (MAV/06, MAV) VZV in two transformed human microglial cell lines (HMC3 and HIM) and human embryonic stem cell (ESC)-derived microglia (ESC-MG). Bulk RNA sequencing was used to assess molecular signatures of microglia following VZV infection in ESC-MG, and cytokine profiles were determined to further investigate neuroinflammation. To further examine the impact of VZV-induced microglial inflammation on neuronal responses, we generated ESC-derived sensory neurons (ESC-SN) and evaluated nociceptor expression and calcium flux as a readout for SN activities following microglial secretome treatment.
    RESULTS: VZV upregulates its gene and protein expression and triggered morphological changes in various microglia cultures. Transcriptomic analysis of YC01-infected ESC-MG revealed a robust induction of genes associated with antiviral innate immunity, alongside a pronounced upregulation of macrophage receptor with collagenous structure (MARCO). Functional studies demonstrated that MARCO facilitates VZV uptake in microglia by binding to the viral glycoprotein E (gE) via its C-terminal scavenger receptor cysteine-rich (SRCR) domain, thereby promoting viral entry and phagocytosis. Moreover, VZV infection elicited neuroinflammation in an ORF62-dependent manner, while MARCO activation triggered toll-like receptor 2 (TLR2)-mediated inflammatory signaling. This cascade further amplified the expression of pain-associated molecular mediators in an ESC-SN model, highlighting a potential mechanistic link between microglial MARCO and VZV-triggered neuropathic processes.
    CONCLUSION: Our results show, for the first time, that microglia are susceptible to VZV infection and identify MARCO as an important mediator for regulating TLR2-mediated neuroinflammation and promoting an upregulation of factors associated with neuropathic pain.
    Keywords:  MARCO; Microglia; Sensory neurons; TLR2; Varicella zoster virus
    DOI:  https://doi.org/10.1186/s12929-026-01256-9
  27. Front Immunol. 2026 ;17 1783098
    Early sex-related transcriptional differences in CD8+ T cells responding to chronic viral infection reveal a sex bias in exhaustion.
    Nyambura Kahia, Sean M Robertson, Megan Rodriguez, Paul Jerard Layug, Harman Vats, Kamali Kannan, Victor Spicer, Arzu Ozturk-Aptekmann, Olivia Wilkins, Janilyn Arsenio.
      CD8+ T cell diversity is essential to control infections and chronic antigen stimulation. In acute-resolving infection, effector cells mediate acute responses and memory cells provide long-lived protection against future exposures. In chronic infection and cancer, an altered state called exhaustion occurs. Exhausted CD8+ T cells are molecularly and functionally distinct from effector and memory cells. Differences in immune responses exist between biological sexes, however, how biological sex influences the timing and transcriptional programs of CD8+ T cell responses during chronic versus acute viral infection remains unknown. Here, we show that male and female CD8+ T cells exhibit transcriptional differences in their early responses during chronic but not acute viral infection in vivo. Using single-cell RNA-sequencing and immunophenotyping analyses, we show that female CD8+ T cells exhibit an early exhaustion-like program compared to males. These findings reveal new insights into sex-related differences in CD8+ T cell exhaustion development and early T cell responses that may contribute to sex differential immune responses.
    Keywords:  CD8 T cells; T cell exhaustion; infection; scRNA-seq; sex differences
    DOI:  https://doi.org/10.3389/fimmu.2026.1783098
  28. bioRxiv. 2026 May 17. pii: 2026.05.12.724684. [Epub ahead of print]
    Tau Ablation Rewires Brain Cell Programs in Health and Restores Function in Disease.
    Enrique Chimal-Juárez, Henika Patel, Nur Jury-Garfe, Luke C Dabin, Ruben Vidal, Jungsu Kim, Cristian A Lasagna-Reeves.
      Tau is a microtubule-associated protein with diverse roles in the healthy brain but contributes to neurodegenerative disorders when dysregulated. Although tau ablation has shown protective effects in several disease models, how its absence confers this protection remain unclear. Here, we performed and analyzed single-nucleus RNA sequencing on cortices of aged tau knockout ( Mapt ⁻/⁻ ) mice in a wild type background as well as in a vascular amyloid model to evaluate the effect on disease context. Comparisons in a wild type setting revealed that tau ablation induced compensatory remodeling across multiple cell types. Excitatory neurons expanded into a distinct subtype with unique glutamatergic signaling, astrocytes adopted synaptoprotective states, oligodendrocytes upregulated genes supporting connectivity and plasticity, and microglia engaged structural remodeling programs. In contrast, in disease, tau removal not only restored functions disrupted by vascular amyloid pathology, but also generated new phenotypes. Excitatory neurons rewired receptor and postsynaptic signaling, astrocytes and oligodendrocytes recovered wild-type-like gene programs related to neurotransmitter cycling, synaptic support, and myelin integrity, and microglia reprogrammed toward sensing and mounting responses. Together, these findings demonstrate that tau ablation reshapes brain cellular programs in a context-dependent manner, exerting adaptive responses in the otherwise healthy brain while restoring homeostatic functions under vascular amyloid pathology. These results position tau as a key regulator of neuronal-glial network balance and highlight the importance of understanding how tau influences distinct cellular programs within specific disease environments.
    DOI:  https://doi.org/10.64898/2026.05.12.724684
  29. J Neuroinflammation. 2026 May 25.
    Microglial Ccl4-Ccr5 signaling links systemic inflammation to synaptic loss and memory deficits in chronic kidney disease.
    Yaochen Cao, Jingyun Wang, Xitong Li, Xin Chen, Jinsheng Xiong, Tianyao Wang, Hongming Sun, Ziqiang Wang.
       BACKGROUND: Chronic kidney disease (CKD) is increasingly associated with cognitive impairment, yet the molecular pathways connecting systemic inflammation to synaptic dysfunction remain unclear. This study investigates the role of the Ccl4-Ccr5 axis in microglia-mediated synaptic phagocytosis during CKD-associated cognitive decline.
    METHODS: A 5/6 nephrectomy rat model was established in rats to induce CKD, validated by renal function markers. Cognitive performance was evaluated through spatial, contextual, and recognition memory tests. Hippocampal cellular alterations were analyzed using single-cell RNA sequencing and immunofluorescence for microglial activation and synaptic density. The functional roles of Ccr5 were assessed via in vivo and in vitro CRISPR-mediated knockdown or overexpression, while Ccl4-Ccr5 interactions were confirmed by co-immunoprecipitation.
    RESULTS: CKD rats showed significant cognitive deficits, increased hippocampal microgliosis, and synaptic loss. Ccr5 knockdown reduced microglial synaptic engulfment, restored synaptic plasticity, and improved memory, whereas Ccr5 overexpression enhanced phagocytic activity.
    CONCLUSIONS: These findings demonstrate that Ccl4-Ccr5 signaling drives pathological synaptic elimination by microglia, linking systemic inflammation to cognitive decline in CKD. Targeting this pathway may provide a therapeutic approach to preserve neuronal function.
    Keywords:  Ccl4-Ccr5 axis; Chronic kidney disease; Cognitive impairment; Microglia; Neuroinflammation; Synaptic phagocytosis
    DOI:  https://doi.org/10.1186/s12974-026-03852-w
  30. Cell Mol Gastroenterol Hepatol. 2026 May 27. pii: S2352-345X(26)00097-4. [Epub ahead of print] 101819
    TREM2+ macrophages promote pancreatic regeneration through cholesterol-metabolism reprogramming and Hedgehog signaling activation following acute pancreatitis.
    Pengli Song, Qi Peng, Xuerui Jin, Bin Li, Ruiyan Wang, Jing Jiang, Jie Shen, Jianbo Ni, Congying Chen, Xiaolu Ge, Xiao Han, Xingpeng Wang, Guoyong Hu.
      Monocyte-derived TREM2+ macrophage subpopulation plays a protective role in pancreatic repair following acute pancreatitis. TREM2 modulates macrophage phenotype switching by orchestrating cholesterol-metabolism reprogramming. Through secreting Desert hedgehog in a paracrine manner, TREM2+ macrophages activate Hedgehog signaling to promote pancreatic regeneration.
    BACKGROUND & AIMS: Macrophage phenotypic transition plays a crucial role in inflammation resolution and tissue repair following acute pancreatitis (AP). Triggering receptor expressed on myeloid cells 2 (TREM2), a damage-sensing immune receptor expressed in macrophages, has been associated with tissue repair in various disease contexts. Here, we aimed to investigate the role of TREM2+ macrophages in pancreatic regeneration following AP.
    METHODS: We used single-cell sequencing and immunohistochemistry to identify TREM2+ macrophage subpopulation and combined lineage tracing to confirm its origin. Circulating soluble TREM2 (sTREM2) levels were assessed in AP clinical cohorts. Functional analysis was conducted using LysMCreTrem2fl/fl mice. Transcriptomic profiling and pharmacological assays elucidated molecular mechanisms.
    RESULTS: We show that monocyte-derived TREM2+ macrophages accumulate in peri-ADM region during AP and are essential for pancreatic regeneration. Genetic ablation of TREM2 impaired pancreatic regeneration, characterized by persistent inflammation, stromal deposition, and compromised acinar redifferentiation and proliferation. Mechanistically, TREM2 deficiency impeded macrophage phenotype transition toward an anti-inflammatory/pro-reparative state, which is associated with cholesterol metabolic reprogramming. Furthermore, TREM2 deficiency reduced the paracrine expression of Desert Hedgehog (Dhh), thereby attenuating Hedgehog (Hh) signaling in progenitor-like epithelial cells. Pharmacological activation of the Hh signaling rescued pancreatic regeneration and stromal remodeling. Immunohistochemical analysis confirmed the presence of TREM2+ macrophages in pancreatic tissues from AP patients, and serum soluble TREM2 (sTREM2) levels inversely correlated with disease severity, further confirming the clinical relevance of TREM2+ macrophages in AP.
    CONCLUSIONS: TREM2+ macrophages play a protective role in pancreatic repair. Targeting the TREM2/Dhh axis offers a therapeutic framework for modulating macrophage function to treat pancreatitis or pancreatic insufficiency.
    Keywords:  Acute pancreatitis; Cholesterol metabolism; Hedgehog signaling; Regeneration; TREM2(+) macrophage
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101819
  31. Biomolecules. 2026 Apr 28. pii: 656. [Epub ahead of print]16(5):
    The Interplay Between Immunometabolism and Neuroinflammation in Alzheimer's Disease.
    Tiziana Di Crescenzo, Giulio Papiri, Valentina Membrino, Sonila Alia, Monia Cecati, Roberto Campagna, Mauro Silvestrini, Simona Luzzi, Arianna Vignini.
      Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by progressive cognitive decline and neuropathological hallmarks such as amyloid-β plaques and neurofibrillary tangles. In recent years, chronic neuroinflammation has emerged as a central mechanism linking genetic, metabolic, and immune dysfunctions in AD. Activated microglia and astrocytes release pro-inflammatory cytokines and reactive oxygen species that exacerbate synaptic and neuronal injury, while impaired clearance mechanisms and blood-brain barrier disruption further sustain inflammation. A growing body of research highlights the role of immunometabolism-the bidirectional interaction between immune activation and cellular metabolism-in shaping glial phenotypes and disease progression. Dysregulation of glucose, lipid, and amino acid metabolism, together with alterations in key metabolites such as lactate, NAD+, and reactive oxygen species, promotes a maladaptive inflammatory state. Genetic factors including APOE4 and TREM2 variants affect microglial lipid handling pathways, while systemic metabolic disorders and gut microbiota alterations amplify neuroinflammatory cascades. Natural bioactive compounds, particularly polyphenols, have gained attention for their ability to modulate immunometabolic pathways. By activating AMPK and SIRT1 and inhibiting mTOR and NLRP3 inflammasome signaling, polyphenols may tune mitochondrial function, redox homeostasis, and autophagy, promoting adaptation to chronic metabolic stress. Therefore, metabolic-immune interactions represent pleiotropic therapeutic avenues for AD. Understanding how immunometabolites and nutrient-sensing pathways regulate compartmentalized inflammation in the CNS may pave the way for novel interventions that combine metabolic precision with neuroprotective efficacy.
    Keywords:  AMPK; Alzheimer’s disease; NLRP3; SIRT1; immunometabolism; microglia; mitochondria; neuroinflammation; polyphenols
    DOI:  https://doi.org/10.3390/biom16050656
  32. Res Sq. 2026 May 11. pii: rs.3.rs-9544619. [Epub ahead of print]
    Astrocytic but not Microglial Antigen Presentation Shapes Protective Immunity to Toxoplasma gondii in the Brain.
    Sydney A Labuzan, Anne E Schuster, Michael A Kovacs, Maureen N Cowan, Mark J Lawson, Isaac W Babcock, Lydia A Sibley, Abigail G Kelly, Anne E Marchildon, Tajie H Harris.
      T cells play a pivotal role in orchestrating immune defense within the central nervous system (CNS) during many infections. Toxoplasma gondii , a brain-trophic protozoan parasite, establishes lifelong CNS infection that remains largely subclinical in immunocompetent hosts but can cause severe encephalitis in immunocompromised individuals. While CD8⁺ T cells are essential for controlling T. gondii during chronic infection through both cytokine production and cytolytic killing, the CNS-resident cells that functionally present antigen in the brain to promote T cell function or serve as cytolytic targets remain incompletely defined. Here, we investigated the contributions of CNS-resident macrophages and astrocytes, two key CNS-resident cell types, antigen presentation during chronic T. gondii infection. Using mice lacking MHCI or MHCII in CNS-resident macrophages, we found no impairment of immune responses or ability of the brain to control parasite, indicating dispensable function of resident macrophages as APCs during infection. However, deletion of MHCI on astrocytes led to deficits in parasite control, in turn promoting elevated CD4⁺ T cell cytokine production and recruitment of iNOS⁺ inflammatory monocytes. We observed increased presence of lytic parasite within the brain, which suggests that astrocyte MHCI may be necessary to control parasite replication throughout the CNS. Our findings underscore a previously underappreciated role for astrocytic MHCI within the CNS during infection and highlights the dispensability of CNS-resident macrophages to this process.
    DOI:  https://doi.org/10.21203/rs.3.rs-9544619/v1
  33. PLoS One. 2026 ;21(5): e0343183
    Long-term rapamycin treatment suppresses IL-17-producing gamma delta T cells and blunts neuroinflammation in aging.
    Clement Torrent, Caterina Gagliardi, Nina Fülle, Ignazio Antignano, Maria Eugenia Bernis, Miriam Stork, Daniele Bano, Melania Capasso, Lily Keane.
      Aging is the gradual accumulation of structural and functional changes in an organism over time, including immune remodeling and a progressive increase in basal inflammation, or inflammaging. The mTOR pathway is a central driver of aging-related diseases, such as cancer, chronic inflammation and neurodegeneration; pharmacological inhibition with rapamycin is associated with reduced aged-related morbidity and increased lifespan across species. Nonetheless, concerns remain about the use of rapamycin, a well-established immunosuppressant in transplant medicine, as an anti-aging intervention. Here, we evaluated the impact of prolonged low-dose dietary rapamycin on the aging immune system. Treatment did not significantly alter innate or adaptive immune cell populations, including brain resident microglia; however, it attenuated the age-associated accumulation of IL-17-producing γδ T cells, particularly in the peritoneal cavity. After a peripheral inflammatory LPS challenge, circulating IL-17 levels were significantly reduced and correlated with an attenuation of microglia inflammatory phenotype. These findings suggest that prolonged low-dose rapamycin exposure exerts minor systemic immune changes, while selectively limiting age-related γδ T cell expansion and neuroinflammation associated with systemic inflammation.
    DOI:  https://doi.org/10.1371/journal.pone.0343183
  34. bioRxiv. 2026 May 12. pii: 2026.05.08.722741. [Epub ahead of print]
    TMEM119+ microglia MHC class I restricted antigen presentation impacts CD8 T cell memory, effector status, and blood-brain barrier disruption during neurotropic virus infection.
    Marina Seady, Mark A Maynes, Javonte S Thelwell, Fang Jin, Michael J Hansen, Hadley E Jensen, Ryann K Witter, Carley A Owens, Asma Hassani, Cody L Lewis, Michael D Forston, Aaron J Johnson.
      The impact of microglia antigen presentation on CNS infiltrating CD8 T cells responses during neurotropic virus infection has been difficult to define. Using Theiler's murine encephalomyelitis virus (TMEV) infection of neurons as a model system, our laboratory has previously determined that H-2D b restricted, but not H-2K b restricted CD8 T cells are required for viral clearance, demonstrating the role of discrete MHC class I alleles. To determine the extent microglia antigen presentation impacts brain-infiltrating CD8 T cells, our laboratory generated novel single MHC class I conditional knockout mice in which H-2K b or H-2D b can be specifically deactivated in TMEM119+ microglia with tamoxifen administration. During TMEV infection, conditional knockout of H-2K b in microglia reduced antigen-specific CD8 T cell proliferation in the brain. Meanwhile, mice with deletion of D b in microglia had reduced levels of perforin in antigen-specific CD8 T cells. Furthermore, microglia specific deletion of H-2D b reduced CD8 T cell numbers in the brain and preserved blood-brain barrier (BBB) integrity. Microglial D b restricted antigen presentation was also essential for the reactivation of CD8 tissue resident memory (TRM) cells and BBB integrity during memory recall responses. These findings further our understanding of how brain infiltrating antiviral CD8 T cell responses are impacted by microglia, as well as define how this cellular interaction contributes to BBB disruption during neuroinflammation. These findings also have high significance to our understanding of how microglia impact CD8 TRM cell populations that reside in the brain long after virus infection is cleared.
    Graphical abstract:
    DOI:  https://doi.org/10.64898/2026.05.08.722741
  35. Life Sci. 2026 May 28. pii: S0024-3205(26)00312-7. [Epub ahead of print] 124503
    Circadian rhythm disruption aggravates periodontitis via orchestrating TREM2+ macrophage-mediated bone resorption.
    Pei Wu, Yizhou Wang, Sijing Chu, Zhonghua Duan, Xiaobo Li, Qiping Feng, Yuhua Wang.
      Circadian rhythm disruption (CRD) potently exacerbates periodontitis, yet how environmental circadian misalignment is sensed and transduced into localized inflammatory bone loss remains poorly understood. Using single-cell RNA sequencing of gingival tissues from a CRD-exacerbated mouse model, we identified a distinct macrophage subpopulation selectively expanded under CRD conditions and enriched along the osteoclastogenic trajectory. This subpopulation is characterized by high expression of Triggering Receptor Expressed on Myeloid cells 2 (TREM2). The CRD-driven accumulation of TREM2+ macrophages positively correlated with the severity of alveolar bone destruction and increased osteoclast activity, alongside downregulation of the core circadian regulators BMAL1 within the periodontal microenvironment. TREM2 displays robust circadian oscillations in vitro, and CUT&Tag sequencing demonstrates that BMAL1 rhythmically binds the Trem2 promoter, establishing a clock-TREM2 regulatory axis. CRD disrupts this time-gated mechanism, leading to sustained TREM2 overexpression that pre-activates macrophages and drives excessive bone resorption. Local TREM2 inhibition alleviates gingival inflammation and reduces bone loss. Under RANKL stimulation, Bmal1 knockdown elevates TREM2 and the osteoclast master regulator NFATc1 across all circadian phases, indicating that inflammation-induced BMAL1 reduction relieves the circadian restriction on TREM2 expression. Collectively, these findings show that CRD disrupts BMAL1-mediated circadian gating of TREM2, and that restoring BMAL1 rhythmicity or directly inhibiting TREM2 may represent a therapeutic strategy to mitigate periodontitis exacerbated by circadian disruption.
    Keywords:  BMAL1; Circadian rhythm disruption; Macrophage; Periodontitis; TREM2
    DOI:  https://doi.org/10.1016/j.lfs.2026.124503
  36. Alzheimers Dement. 2026 May;22(5): e71493
    Behavior of neural networks in culture suggest that sporadic and genetic forms of Alzheimer's disease may not be equivalent.
    Fulin Ma, Himanshu Akolkar, Ryad Benosman, Karl Herrup.
       INTRODUCTION: Alzheimer's disease (AD) research often assumes that familial and sporadic forms share a common pathogenesis. However, the cellular impacts of amyloid precursor protein (APP) mutations compared with age-related overexpression of APP or the deposition of amyloid beta (Aβ) are likely different.
    METHODS: Using high-density multi-electrode arrays, we compared neural activity in cultured neurons subjected to Aβ exposure or APP overexpression (via lentiviral delivery or genetic models). Effects on neuronal firing, synaptogenesis, axonal branching, and network connectivity were assessed in both developing and mature cultures.
    RESULTS: APP overexpression reduced individual neuron firing probability and impaired synaptogenesis and axonal branching during development. In contrast, Aβ disrupted synaptic connections in mature cultures and impaired network-level communication without blocking early structural development.
    DISCUSSION: These findings indicate that APP mis-regulation and Aβ toxicity contribute differently to neuronal behavior. These differences raise questions about the assumptions that familial and sporadic AD are similar if not identical conditions.
    Keywords:  APP; Alzheimer's disease; amyloid beta; familial Alzheimer's; multi‐electrode arrays; sporadic Alzheimer's; synaptic connectivity
    DOI:  https://doi.org/10.1002/alz.71493
  37. Brain Behav Immun. 2026 May 23. pii: S0889-1591(26)00563-5. [Epub ahead of print]137 106815
    Chronic low-grade hippocampal inflammation blunts exercise-induced neurogenesis and alters the exercise-induced microglia transcriptome in the rat hippocampus.
    Sarah Nicolas, Maria Giovanna Caruso, Sebastian Dohm-Hansen, Tara Foley, Paul J Lucassen, Joram D Mul, Aonghus Lavelle, Jane A English, Olivia F O'Leary, Yvonne M Nolan.
      Chronic low-grade neuroinflammation contributes to inflammageing by compromising hippocampal plasticity, with interleukin-1β (IL-1β) as a key mediator. The extent to which sustained hippocampal inflammation can interfere with the potential beneficial effects of exercise on plasticity and hippocampus-related behaviour remains unclear. Here we combined bilateral hippocampal IL-1β overexpression (IL-1β-OE), to mimic chronic low-grade neuroinflammation with voluntary wheel running, to mimic human exercise training, in adult male Sprague-Dawley rats. We assessed effects on multiple dorsal hippocampal-related behaviours, adult hippocampal neurogenesis, microglial reactivity, and immune cell infiltration. Hippocampal IL-1β-OE impaired pattern separation, independent of exercise training, and attenuated exercise-induced increases in neurogenesis in the dorsal hippocampus. Hippocampal IL-1β-OE promoted microglial lipid-droplet accumulation, which exercise paradoxically exacerbated. Transcriptomic profiling revealed that exercise in combination with hippocampal IL-1β-OE enriched immune and leukocyte trafficking pathways in microglia, while hippocampal IL-1β-OE alone increased hippocampal CD8+ T cell infiltration. These findings indicate that chronic hippocampal inflammation alters microglial and neurogenic responses to exercise, suggesting that inflammatory status critically influences exercise efficacy in supporting hippocampal plasticity.
    Keywords:  Behaviour; Chronic Neuro inflammation; Exercise; Hippo campal neurogenesis; Hippocampus; IL-1β; Microglia
    DOI:  https://doi.org/10.1016/j.bbi.2026.106815
  38. J Immunol. 2026 May 14. pii: vkag119. [Epub ahead of print]215(5):
    CNS1-dependent regulatory T cells shape recovery from acute lung injury.
    Morgan J McCullough, Miriya K Tune, Jason W Griffith, Brianna L Banten, Minghong He, Yongqiang Feng, Benjamin G Vincent, J Justin Milner, Ageliki Tsagaratou, Yisong Y Wan, Hong Dang, Claire M Doerschuk, Jason R Mock.
      Regulatory T cells (Tregs) play a crucial role in mediating recovery from acute lung injury (ALI). However, the complex roles of functionally heterogeneous Treg subsets in the lung during the resolution of acute inflammation remain unclear. To investigate the role of peripherally induced Tregs, we utilized mice lacking conserved noncoding sequence 1 (CNS1) of the Foxp3 locus, a genetic deletion that impairs peripheral Treg induction. We found that CNS1-deficient mice exhibit greater mortality and delayed resolution during ALI. Tregs induced via CNS1 modulated antiviral and proinflammatory immune responses in the lung during influenza. Mechanistically, single-cell RNA sequencing reveals that CNS1-deficient Tregs fail to fully engage the Treg transcriptional program that supports optimal suppressive and reparative function in the lung. Our findings highlight a critical role for CNS1-dependent peripherally induced Tregs in determining ALI severity, providing insight into how distinct Treg subpopulations may be therapeutically harnessed to mitigate tissue damage during respiratory disease.
    Keywords:  CNS1; Foxp3; conserved noncoding sequence 1; forkhead box P3; regulatory T cells; resolution of acute lung injury
    DOI:  https://doi.org/10.1093/jimmun/vkag119
  39. Neuron. 2026 May 26. pii: S0896-6273(26)00338-7. [Epub ahead of print]
    Maternal-fetal type I interferon signaling drives TREM2 dysregulation and synaptic dysfunction in neurodevelopmental disorders.
    Matteo Bizzotto, Shih Feng You, Matteo Tamborini, Elisa Faggiani, Raffaella Morini, Antonella Borreca, Rui Zhang, Ekaterina Aladyeva, Aasritha Nallapu, Claudio Ferrari, Oscar Harari, Davide Pozzi, Ricardo D'Oliveira Albanus, Celeste M Karch, Michela Matteoli, Fabia Filipello.
      Maternal infections during gestation cause perturbed neuroimmune interactions and increased risk of neurodevelopmental disorders in the offspring. Using a maternal immune activation model with polyinosinic:polycytidylic acid (poly(I:C)), we investigated how maternal infections reshape the progeny hippocampal landscape. Poly(I:C) increased maternal type I interferon (IFN-I), disrupting neuronal transcriptional trajectories and excitatory synapse homeostasis in juvenile offspring. Poly(I:C) offspring microglia exhibited reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of synapse elimination and brain development, accompanied by impaired phagocytosis and suppressed IFN-I-responsive substate. Consistently, a blunted IFN-I signature was observed in postmortem tissues from schizophrenic patients. TREM2 deficiency was associated with aberrant maternal IFN-I and altered neuronal and microglial signatures in poly(I:C) offspring, highlighting its regulatory role in neurodevelopmental pathologies. Blocking maternal IFN-I signaling restored synaptic defects and TREM2 function, suggesting that monitoring IFN-I responses during pregnancy and targeting defective IFN-I cascades in the newborn may represent viable therapeutic approaches to mitigate neurodevelopmental dysfunctions.
    Keywords:  TREM2; brain development; maternal immune activation; microglia; neurodevelopmental disorders; schizophrenia; type I interferon
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.043
  40. Nat Neurosci. 2026 May 29.
    An unexpected molecular explanation for how tau aggregation begins in Alzheimer's disease.
      
    DOI:  https://doi.org/10.1038/s41593-026-02298-w
  41. J Transl Med. 2026 May 26.
    The impact of lactate and lipid metabolism in microglia upon cognitive impairment following radiation-induced brain injury.
    Zeyuan Li, Yu Lin, Yi Lu, Lijing Zeng, Hongdan Guan, Fenghao Huang, Xianyi Zeng, Qiwei Yao, Rong Zheng.
       BACKGROUND: Radiation-induced brain injury (RIBI) is a serious complication that occurs after cranial radiotherapy. The main manifestations are delayed radiation effects characterized by neuroinflammation and damage to neural stem cell populations. Microglia, the resident immune cells of the central nervous system (CNS), have become key mediators in the pathological process of RIBI. This review aims to systematically elucidate how metabolic reprogramming of lactate and lipid pathways in microglia contributes to chronic neuroinflammation and cognitive impairment following RIBI, and to evaluate the therapeutic potential of targeting these metabolic pathways.
    MAIN BODY: Ionizing radiation (IR) triggers intense activation of microglia, which initiates and maintains a chronic neuroinflammatory state characterized by the release of cytotoxic mediators and changes in phagocytic function. Changes in lactate and lipid metabolism within microglia are crucial in their response to neuroinflammation and neurodegeneration. Activated microglia typically change their metabolism from oxidative phosphorylation (OXPHOS), which uses oxygen to generate energy, to a process called aerobic glycolysis, which leads to increased lactate production. This metabolic shift, combined with the role of lactate as a signaling molecule and a substrate for epigenetic modifications (lactylation), can significantly influence the inflammatory outcome. Additionally, dysregulation of lipid metabolism, such as accumulation of lipid droplets (LDs), represents a pro-inflammatory, dysfunctional state known as lipid droplet accumulation-type microglia (LDAM), and is associated with impaired phagocytosis and persistent inflammation. This article summarizes the pathological mechanisms of RIBI, with a focus on the complex roles of lactate and lipid metabolism in microglia. It explores how radiation induces microglial activation and metabolic transformation. The article also discusses the dual role of lactate, the effects of lipid dysregulation, and potential interactions between metabolic pathways. Finally, it highlights how these factors commonly relate to impaired inflammatory responses and disruptions in neural repair processes, such as neurogenesis and oligodendrocyte generation.
    CONCLUSIONS: By studying how changes in microglial metabolism lead to neuronal dysfunction and cognitive decline in RIBI, this review provides a new perspective for regulating microglial metabolic pathways to alleviate radiation-induced cognitive impairment.
    Keywords:  Cognitive impairment; Lactate metabolism; Lipid metabolism; Metabolic reprogramming; Microglia; Neuroinflammation; Radiation-induced brain injury
    DOI:  https://doi.org/10.1186/s12967-026-08309-5
  42. Acta Neuropathol. 2026 May 25. pii: 61. [Epub ahead of print]151(1):
    Neocortical tau burden determines the degree of cognitive impairment in individuals with Braak stage V neurofibrillary degeneration.
    Timothy E Richardson, Jonathan Cherry, Shrishtee Kandoi, Susan K Rohde, Madeline Uretsky, Fatima Tuz-Zahra, Kevin F Bieniek, Kurt Farrell, Marco M Hefti, Michael B Miller, Yorghos Tripodis, Thor D Stein, Carolina Maldonado-Díaz, Satomi Hiya, Thomas G Beach, María M Corrada, Brittany N Dugger, Margaret E Flanagan, Matthew P Frosch, Marla Gearing, Lea T Grinberg, Lawrence A Hansen, Debra Hawes, Elizabeth Head, C Dirk Keene, Julia Kofler, Edward B Lee, Peter T Nelson, Derek H Oakley, Richard J Perrin, Robert A Rissman, Shahriar Salamat, Julie A Schneider, Geidy E Serrano, Andrew F Teich, Juan C Troncoso, Thomas Wisniewski, Randall L Woltjer, John F Crary, Dennis W Dickson, Ann C McKee, Jamie M Walker.
      Alzheimer disease neuropathologic change (ADNC) is considered to be the most common cause of cognitive decline and dementia worldwide. ADNC level is determined using the density of neuritic plaques in combination with the topographical distribution of β-amyloid (Aβ) plaques and hyperphosphorylated tau (p-tau)-positive neurofibrillary tangles (NFTs). While cognitive decline correlates with the level of ADNC, there remains a great deal of variation in cognitive outcomes between individuals that is unaccounted for by current neuropathologic evaluation metrics. We leveraged quantitative computer-assisted positive pixel assessments to establish the neocortical p-tau burden in the middle frontal and superior temporal gyri of 61 individuals with Braak NFT stage V who had a wide range of cognitive outcomes and trajectories. Frontal and temporal neocortical p-tau burden varied between 0.2% and 53.7%. Both frontal and temporal p-tau burden directly affected cognitive outcome and correlated with function of multiple cognitive domains, including measures of language/semantic memory and attention/working memory. In multivariable analysis, only p-tau burden and microinfarcts significantly impacted cognitive decline, while Aβ, limbic-predominant age-related TDP-43 encephalopathy, Lewy body pathology, and other measures of cerebrovascular disease did not. Additionally, individuals with low mean neocortical p-tau burden (≤ 13%) had significantly better longitudinal cognitive trajectories over the final 15 years of life compared to those with high burden (≥ 23.5%). These results suggest that while all individuals with Braak stage V have some degree of neurofibrillary degeneration in the neocortex, the significant variation in cognitive decline observed between these individuals can be partially understood as a reflection of the variation in quantitatively assessed neocortical p-tau burden, which had a greater impact on progression to dementia than common comorbid neuropathologies associated with dementia risk. This argues for the incorporation of the density of ADNC-related pathology, in addition to its regional location, as an adjunct to future staging systems for Alzheimer disease.
    Keywords:  Aging; Alzheimer’s disease neuropathologic change (ADNC); Cerebrovascular disease (CVD); Cognitive reserve; Dementia with Lewy bodies (DLB); Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC); Resilience; Tau
    DOI:  https://doi.org/10.1007/s00401-026-03031-4
  43. Nat Commun. 2026 May 27.
    Deciphering cytokine-driven ADP-ribosylation signaling networks via Af1521-based mass spectrometry analysis of labile Glu/Asp-linkages.
    Sara C Buch-Larsen, Ivo A Hendriks, Kyuto Tashiro, Jonas D Elsborg, Sergey Y Vakhrushev, Jesper V Olsen, Bernhard Lüscher, Glen Liszczak, Ivan Ahel, Michael L Nielsen.
      ADP-ribosylation (ADPr) is a regulatory post-translational modification targeting nine amino acid residues, but glutamate/aspartate-linked ADPr (Glu/Asp-ADPr) is labile and remains challenging to detect using conventional mass spectrometry (MS)-based workflows. Using synthetic peptides, we show that ester-linked Glu/Asp-ADPr is lost under alkaline conditions, elevated temperatures, and by hydrolysis via wildtype Af1521. We developed an acidic enrichment workflow incorporating an Af1521 mutant that preserves Glu/Asp-ADPr, enabling site-specific, system-wide MS analysis. In cytokine-stimulated A549 and HeLa cells, we identified >600 Glu/Asp- and >200 Cys-ADPr sites. Glu/Asp-ADPr marks cytoplasmic, immune-related protein networks, contrasting with nuclear Ser-ADPr. Quantitative profiling revealed reproducible, cell type- and treatment-specific patterns. PARP10-mediated Glu/Asp ADPr of ubiquitin indicates direct crosstalk with ubiquitin signaling pathways. Interferon treatments revealed conserved antiviral PARP networks extensively modified on Glu/Asp residues. Together, our work establishes a robust MS-based workflow and provides a resource of site-specific ADPr events, revealing residue-specific ADPr in innate immune signaling.
    DOI:  https://doi.org/10.1038/s41467-026-73677-x
  44. Mol Neurodegener. 2026 May 28.
    Cholesterol metabolism in neurodegenerative diseases: mechanisms and therapeutic advances.
    Dezhen Tu, Yuxiao Zheng, Pingping Ding, Miao Shen, Wangyang Tang, Bin Wei, Hongyan Wang.
      Cholesterol metabolites are abundant in the central nervous system (CNS) that regulate cell membrane fluidity, signal transduction, and inter- and intracellular vesicular transport, as well as cell proliferation/cell death or migration. Brain cholesterol synthesis and metabolism are tightly coupled to the functional homeostasis of neurons, glial cells or microglia, and dysregulation of these processes has been strongly implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). This review provides a comprehensive overview of how cholesterol synthesis, esterification, efflux, uptake, and oxidation affect the CNS function, highlighting the function of key enzymes or metabolites in distinct brain cell types during neurodegeneration. Based on single-cell/nucleus RNA sequencing data from the brains of AD, PD, and HD patients, we summarize cell-type-specific genes in cholesterol metabolism pathways, shedding new light to understand cellular heterogeneity. The role of cholesterol-derived neurosteroids in neurodegenerative diseases is also discussed. Furthermore, how cholesterol metabolites modulate the formation, aggregation, and degradation of amyloid-β (Aβ), α-synuclein and huntingtin, as well as Tau protein phosphorylation are outlined. Finally, future research directions are proposed that aim to understand neurodegenerative diseases with new angle.
    Keywords:  Astrocyte; Cholesterol metabolism; Microglia; Neurodegeneration; Neuron; Oligodendrocyte
    DOI:  https://doi.org/10.1186/s13024-026-00951-3
  45. Nat Metab. 2026 May 27.
    Neuronal glycogen powers anticipatory brain responses to food.
      
    DOI:  https://doi.org/10.1038/s42255-026-01536-6
  46. Neurosci Biobehav Rev. 2026 May 23. pii: S0149-7634(26)00228-9. [Epub ahead of print]187 106771
    Microglia-mediated endotoxin tolerance: A protective role of LPS preconditioning in the central nervous system.
    La Dong, Janine Doorduin, Erik F J de Vries.
      Endotoxin tolerance (ET) represents a hyporesponsive state of the innate immune system that develops following prior exposure to endotoxins like lipopolysaccharide (LPS), a potent Toll-like receptor 4 (TLR4) agonist. While ET has been extensively studied in peripheral monocytes and macrophages, its implications within the central nervous system (CNS) remain insufficiently understood. As the resident innate immune cells of the CNS, microglia are central to the regulation of neuroinflammation and can either exacerbate or ameliorate neuronal injury depending on their activation state. Emerging evidence indicates that LPS preconditioning induces microglia-mediated ET, a state that attenuates excessive inflammation and preserves CNS homeostasis. In this review, we synthesize current insights into the concept of ET and elucidate the molecular mechanisms underlying microglial reprogramming, focusing on the coordination of signaling pathways, epigenetic modifications, and metabolic shifts that drive the tolerant phenotype. Within the framework of innate immune memory, we compare ET with trained immunity to highlight their distinct context-dependent effects. Evidence from in vitro co-culture systems and in vivo models of acute CNS injury, neurodegenerative disorders, epilepsy, and psychiatric-like behaviors indicates that LPS preconditioning-induced microglia-mediated ET can confer neuroprotection. We will address the paradox of neuroprotection by LPS preconditioning, underscore the translational potential of LPS-derived TLR4 modulators, and propose future directions for harnessing microglia-mediated ET as a therapeutic strategy for CNS diseases.
    Keywords:  Central nervous system; Endotoxin tolerance; Innate immune memory; Lipopolysaccharide preconditioning; Microglia; Toll-like receptor 4
    DOI:  https://doi.org/10.1016/j.neubiorev.2026.106771
  47. J Neuroinflammation. 2026 May 27.
    Inhibition of endocannabinoid degradation in astrocytes reprograms glial reactivity and prevents seizure sequelae.
    Chudai Zeng, Fei Gao, Mei Hu, Jian Zhang, Dexiao Zhu, Li Sun, Jianlu Lyu, Mingzhe Pan, Chu Chen.
       BACKGROUND: Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is characterized by a pathological cascade of excitotoxicity that leads to neuroinflammation, progressive neuronal loss, and subsequent cognitive decline. Despite its prevalence, effective therapies remain lacking. Previous studies have demonstrated that the dysregulation of the endocannabinoid system contributes to epileptic activity. In particular, inactivation of monoacylglycerol lipase (MAGL), the key rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG), an endogenous lipid mediator with anti-inflammatory and neuroprotective properties, suppresses seizures and reduces neuroinflammation. However, the cellular and molecular mechanisms underlying these protective effects remain unclear.
    METHODS: To dissect the cellular mechanisms underlying MAGL-mediated neuroprotection, we employed a kainic acid (KA)-induced status epilepticus model in mice with global, astrocyte-specific (aKO), and neuron-specific (nKO) deletion of mgll. We combined single-nucleus RNA sequencing (snRNA-seq) to map the transcriptomic landscape of glial responses with pharmacological interventions and AAV-mediated gene manipulation to validate key signaling pathways, as well as behavioral assays to assess functional recovery.
    RESULTS: We demonstrated that astrocyte-specific mgll deletion attenuated seizure susceptibility and hippocampal neuroinflammation, whereas neuron-specific, mgll deletion did not reproduce this broader protective phenotype. Transcriptomic profiling revealed that astrocytic MAGL deficiency fundamentally reshaped the glial response to injury by preventing the transition to pro-inflammatory reactive astrocyte states and suppressing the activation of disease-associated microglia (DAM). Mechanistically, we identified a signaling pathway in which the neuroprotective effects of MAGL inhibition depend on cannabinoid receptor 1 (CB1) activation and are mediated by downstream peroxisome proliferator-activated receptor γ (PPARγ) signaling. Genetic deletion of CB1 abolished the protective effects, whereas pharmacological blockade or AAV-mediated knockdown of PPARγ attenuated these effects. Furthermore, aKO mice exhibited reduced neuronal loss, preserved synaptic structural integrity and protection against post-seizure cognitive deficits.
    CONCLUSION: These findings reveal astrocytic MAGL as a crucial regulatory node after status epilepticus and support a model in which CB1-dependent mechanisms and astrocytic PPARγ-dependent regulation jointly contribute to 2-AG-mediated neuroprotection, attenuating neuroinflammation, preserving synaptic integrity, and reducing post-seizure behavioral deficits in this KA-induced SE model.
    Keywords:  2-arachidonylglycerol; Astrocyte; Cannabinoid receptor; Epilepsy; Monoacylglycerol lipase; Neuroinflammation
    DOI:  https://doi.org/10.1186/s12974-026-03883-3
  48. Nat Commun. 2026 May 28.
    Breaking the membrane heredity paradox through de novo protocell formation.
    Satyam Khanal, Alessandro Fracassi, Alexander Harjung, Michael D Burkart, Neal K Devaraj.
      Lipid membranes define cell boundaries, acting as gatekeepers for transport and signaling. A central paradigm in biology is that all cellular membranes descend from a common ancestral membrane, as they cannot be generated in the absence of pre-existing lipid structures. It is thus unclear whether lipid membranes can arise from membrane-less precursors. Here we demonstrate the de novo generation of lipid bilayers in the absence of any pre-existing membranes, membrane-bound proteins, or lipid nanostructure templates. Using acetate and cysteine as simple metabolites, lipid tails are constructed by soluble enzymes and spontaneously form diacyl lipids that assemble into vesicles. Pore-forming peptides facilitate precursor transport into vesicles, allowing the continuous generation of new lipids. Formation of glycolipid membranes creates compartments that can maintain proton gradients. Our findings demonstrate that lipid compartments can form without pre-existing membranes, establishing a unique route linking lipid synthesis to compartment formation and function.
    DOI:  https://doi.org/10.1038/s41467-026-73667-z
  49. bioRxiv. 2026 May 14. pii: 2026.05.13.724873. [Epub ahead of print]
    Ciliogenesis associated kinase 1 accumulates in its inactive form during polycystic kidney disease progression.
    Alice Serafin, Charlène Coquil, Aurore Dupuy, Mattias F Lindberg, Darren P Wallace, Pamela V Tran, Oxana Ibraghimov-Beskrovnaya, Yannick Le Meur, Emilie Cornec-Le Gall, Christelle Ratajczak, Laurent Meijer, Vincent J Guen.
      Ciliogenesis associated kinase 1 (CILK1) deficiency in human and mice results in kidney developmental defects including cystogenesis. However, the biology of CILK1 in autosomal dominant polycystic kidney disease (ADPKD), the most common inherited kidney disease, remains to be investigated. Here, we show that CILK1 is overexpressed in dedifferentiated cells of renal tissue from ADPKD human patients in comparison to normal control tissue samples. We demonstrate that CILK1 overexpression results in protein accumulation in a non-phosphorylated inactive form. Using mouse polycystic kidney disease models, we reveal that inactive CILK1 accumulation is progressive over the course of disease progression. We show that genetic inactivation of the Polycystic Kidney Disease 1 ( PKD1 ) gene is sufficient to trigger CILK1 accumulation. Altogether, these findings demonstrate that CILK1 regulation is altered in ADPKD and it represents a hallmark of disease progression.
    DOI:  https://doi.org/10.64898/2026.05.13.724873
  50. Sci Adv. 2026 May 29. 12(22): eadz8930
    A miniaturized implantable electrochemical platform for continuous monitoring of metabolites in deep tissue.
    Kenneth E Madsen, Dane Hintermueller, Elliot A Opel, Joseph G Ribaudo, Sara Saffari, Soongwon Cho, Joanna L Ciatti, Yu-Ting Huang, Amanda M Westman, Ralph G Nuzzo, Mitchell A Pet, John A Rogers.
      The loss or suppression of local metabolic function in living tissues brought about by a lack of oxygen availability (ischemia) serves as the origin for myriad life-threatening conditions including stroke, heart failure, and peripheral ischemic injury. Despite the pressing clinical need to evaluate local tissue health, platforms that support such analysis remain elusive. To address this need, we present a wireless, minimally invasive, multianalyte, electrochemical probe supporting the continuous profiling of local metabolites including K+ and pH, and the semicontinuous profiling of lactic acid. We validate the analytical capabilities of our sensing system by ion profiling in arterial whole blood. Furthermore, we use acute compartment syndrome as a model for tissue ischemia and use our percutaneously implanted probes to track metabolic changes in living muscle in real time.
    DOI:  https://doi.org/10.1126/sciadv.adz8930
  51. Nat Commun. 2026 May 27.
    Single-nucleus analysis reveals human-specific oligodendrocyte polarization and conserved neuronal responses after severe traumatic brain injury.
    Jiatong Ji, Honglu Chao, Chengzhi Chen, Xinyue Wang, Wenqian Shi, Jun Liao, Hai Qian, Hao Shi, Jingming Hu, Yangfan Ye, Yiming Tu, Xiao Xu, Zheng Li, Zhen Yue, Wei Yan, Xunning Hong, Huibo Wang, Huimei Chen, Enrico Petretto, Jing Ji.
      Severe traumatic brain injury (sTBI) is a leading cause of edema and neurological dysfunction. However, the molecular mechanisms driving injury progression remain poorly understood. Here, we present a single-nucleus transcriptomic atlas of human and male mouse cortex across multiple sTBI stages, providing a systematic landscape of dynamic, cell-type-specific responses to injury and edema. Cross-species analyses reveal both conserved and human-specific programs, including a polarized oligodendrocyte state absent in murine sTBI. This state shows increased ABCA1 and adhesion-related genes and is associated with edema progression. In vitro experiments support an ABCA1-linked role in lipid handling that may support oligodendrocyte-lineage cell function, reflected by the maintenance of myelin-associated marker expression. Analyses combining ligand-receptor interactions, co-expression, and perturbation experiments link microglial CALM2-HMGB1 signaling to oligodendrocyte ABCA1-associated lipid regulation during injury progression. These human-specific programs indicate that rodent models may not fully recapitulate human sTBI mechanisms, underscoring the need for caution when extrapolating cross species findings.
    DOI:  https://doi.org/10.1038/s41467-026-73036-w
  52. bioRxiv. 2026 May 14. pii: 2026.05.12.724479. [Epub ahead of print]
    Satellite microglia-like cells in human dorsal root ganglia and changes with diabetic neuropathy.
    Khadijah Mazhar, Jayden A O'Brien, Michael A Wilde, Harikrushnaa Srikanth, Andi Wangzhou, Victoria Pastor, Charlynn W Maina, Nora S Arefin, Marisol Mancilla Moreno, Ishwarya Sankanarayanan, Diana Tavares-Ferreira, Theodore J Price.
      Phagocytic and immune-like cells have been observed in the satellite envelope of neuronal somata in peripheral sensory ganglia of many species for several decades. These cells likely play an important role in normal function of sensory neurons and they may also play an important role in neuronal dysfunction and neurodegeneration seen with neuropathy. Recent findings have described a satellite macrophage population transcriptomically similar to microglia in peripheral ganglia of some mammalian species. The function of these cells, and the mechanisms by which they may influence neurons in neuropathy are unclear. We sought to understand the phenotype and localization of these cells in the human dorsal root ganglion (hDRG) using large-scale single nucleus and spatial transcriptomic datasets from individuals with and without a history of peripheral diabetic neuropathy. We observed a large population of macrophages that express classical microglia makers such as TMEM119 and P2RY12 in the hDRG, as previously described. Our findings confirm that these microglia-like cells (MLCs) localize to the satellite envelope around neuronal somata, yet are transcriptomically distinct from all glial cell types characterized in the hDRG. These MLCs exhibit changes in abundance and localization with diabetic painful neuropathy (DPN) in both the hDRG and sural nerves suggesting that they are not exclusively localized to the DRG. We conclude that microglia-like cells are likely the resident tissue macrophage (RTM) of the hDRG, and perhaps the peripheral nervous system (PNS) given their localization to the sural nerve and other ganglia, where they are predicted to regulate homeostatic neuronal functions and response to injury.
    Highlights: MLCs are likely the RTM of hDRGsMLCs localize to the satellite envelope and recede with Nageotte nodule formationMLC activation state and signaling shift with diabetic neuropathyMLCs are also present in other ganglia and sural nerve.
    DOI:  https://doi.org/10.64898/2026.05.12.724479
  53. Stem Cell Res. 2026 May 23. pii: S1873-5061(26)00113-3. [Epub ahead of print]94 104017
    Modeling stimulus-induced stress responses in microglia-like cells using a commercial iPSC-dCas9-KRAB line.
    Devin M Saunders, Nicola A Kearns, Bernard Ng, Faraz Sultan, Himanshu Vyas, Ricardo A Vialle, Eric M Clark, Sashini De Tissera, Jishu Xu, David A Bennett, Yanling Wang.
      Commercially available human iPSC lines with inducible CRISPR interference (CRISPRi) systems offer scalable platforms for gene function studies. One widely available line, the AICS-0090 dCas9-KRAB iPSC line developed by the Allen Institute, has been extensively validated for genomic integrity and stem cell potency. However, its utility in modeling specialized immune cell types such as microglia - and in assessing their functional responses to disease-relevant stimuli - has not been fully established. Here, we evaluated the AICS-0090 line for its ability to differentiate into microglia-like cells, support efficient gene knockdown, and respond to environmental stressors. We assessed its differentiation capacity by qPCR, flow cytometry, and immunocytochemistry, confirming reproducible expression of microglial surface markers at early and late timepoints. Gene knockdown efficiency was validated both at the single-gene level and in pooled CRISPRi screens. Focusing on functional responsiveness, we exposed the microglia-like cells to two distinct stimuli: aggregated amyloid-β (Aβ), a disease-associated trigger in Alzheimer's disease, and lipopolysaccharide (LPS), a classical inflammatory signal. Transcriptomic and functional analyses revealed stimulus-specific responses: aggregated Aβ induced limited activation of stress and inflammation pathways, whereas LPS elicited broader transcriptional reprogramming and cytokine release. Signatures from both conditions partially overlapped with ex vivo human and mouse microglial states. Together, these findings support the use of the AICS-0090 dCas9-KRAB iPSC-derived microglia-like cells as a flexible and tractable model for gene function interrogation under defined inflammatory contexts, with potential for future applications in neuroimmune modeling and perturbation-based screening.
    Keywords:  CRISPR interference; LPS; Stress response; aggregated Aβ; iPSCs, microglia-like cells; single-cell RNA sequencing
    DOI:  https://doi.org/10.1016/j.scr.2026.104017
  54. Nat Commun. 2026 May 25.
    SNAP-23 mediated vesicular trafficking in oligodendrocytes is necessary to maintain adult myelin integrity in mice.
    Chun Hin Chow, Mengjia Huang, Aryan Regmi, Jayant Rai, Hidekiyo Harada, Sarah Eide, Hong-Shuo Sun, Zhong-Ping Feng, Philippe P Monnier, Kenichi Okamoto, Liang Zhang, Olga L Rojas, Shuzo Sugita.
      Adult myelin is dynamic and requires continuous support from oligodendrocytes. Inability to sustain myelin health results in demyelination, evident in multiple sclerosis and neurodegenerative diseases. However, the molecular mechanism by which oligodendrocytes recycle and replenish materials to the myelin sheath remains unclear. Here, we investigate whether the SNARE-dependent vesicular trafficking is important for myelin turnover. We conditionally remove SNAP-23, one of the target SNARE proteins, in mature oligodendrocytes of adult mice. Induction of SNAP-23 deletion causes demyelination within 5-10 weeks. Demyelination is associated with an increase in immune cells, including infiltrated T cells, in the brain. Mechanistically, the removal of SNAP-23 in oligodendrocytes impairs vesicle fusion to the myelin and causes the accumulation of myelin proteins within the cells. Taken together, we show that SNAP-23-dependent transport in oligodendrocytes is necessary for adult myelin maintenance, with failure in vesicular transport leading to demyelination and subsequent neuroinflammation.
    DOI:  https://doi.org/10.1038/s41467-026-73381-w
  55. Cells. 2026 May 14. pii: 896. [Epub ahead of print]15(10):
    Targeting Mitochondrial Dysfunction in Alzheimer's Disease Neurons: Lithium Boosts Oxidative Phosphorylation.
    Benedict C Albensi, Aida Adlimoghaddam.
      Alzheimer's disease (AD) is characterized by the accumulation of amyloid beta (Aβ) and neurofibrillary tangles in brain tissue; however, AD is multifactorial, and different etiopathogenic mechanisms involve factors that can affect mitochondrial function, which are associated with AD. While high-dose lithium is a well-established mood stabilizer, accumulating evidence suggests that low-dose lithium provides significant neuroprotection by reversing AD pathology, cognitive impairment, and inflammation. Despite these findings, there is limited information on how lithium affects brain energy metabolism. In the current study, we investigated the effect of lithium (0, 0.1, 1, and 10 mM) on mitochondrial function in AD neurons. Neuronal cells were isolated from the hippocampi of embryonic day 14-17 (E15-E17) control (C57BL/6) mice and 3xTg-AD mice. Mitochondrial oxygen consumption rate (OCR), mitochondrial Cytochrome C Oxidase (COX) activity, total ATP activity, and the expression of mitochondrial complex protein involved in oxidative phosphorylation (OXPHOS) were measured in control vs. 3xTg-AD in the presence and absence of lithium treatment. In the present study, lithium treatment significantly increased (p < 0.05) mitochondrial OCR, COX, total ATP, and levels of mitochondrial complex protein subunits (Complex I-V) in 3xTg-AD neurons. However, lithium had no effect on energy metabolism in control neurons. Together, these data indicate that lithium improves mitochondrial function under pathological states. Overall, these results have important implications for the treatment of disorders in which brain energy regulation is compromised, including AD. Particularly, our results highlight a role for lithium in regulating bioenergetics in early-stage AD and suggest that neuronal cells may be a crucial therapeutic target for preventing AD.
    Keywords:  Alzheimer’s disease; bioenergetics; lithium; mitochondrial function; neurons; oxidative phosphorylation
    DOI:  https://doi.org/10.3390/cells15100896
  56. Free Radic Biol Med. 2026 May 28. pii: S0891-5849(26)00828-2. [Epub ahead of print]
    TGM2 drives microglial senescence by inhibiting autophagy via the PI3K/AKT/mTORC1 pathway.
    Zhiqiang Li, Yuxiang Tang, Dongyuan Zhang, Jiayi Li, Tianxiang Wang, Qiuxia Pan, Xianbin Meng, Xiaolin Tian, Haiteng Deng.
      Microglial senescence is increasingly recognized as a driver of age-related neurodegeneration by impairing autophagic clearance and exacerbating neuroinflammation. However, the molecular mechanisms coupling senescence to autophagy dysfunction remain unclear. Here we identify transglutaminase 2 (TGM2) as a critical regulator linking these processes. We show that TGM2 is selectively upregulated in senescent microglia, where it assembles a previously unrecognized signaling complex with 14-3-3γ (YWHAG) and PI3K (p85α). This complex sustains AKT phosphorylation, constitutively activates mTORC1, and thereby inhibits autophagic flux. Pharmacological inhibition of TGM2 with cystamine dihydrochloride (CD) reduces this complex, restores autophagy, attenuates senescence-associated secretory phenotype (SASP) and reactive oxygen species (ROS) level, and significantly reverses cognitive and motor deficits in aged mice. These findings support a model in which TGM2-related signaling is linked to microglial autophagy dysfunction and senescence, suggesting that targeting TGM2 may offer a novel therapeutic approach for age-related neurodegenerative disorders.
    Keywords:  Autophagy; Microglial Senescence; PI3K/AKT/mTORC1 Pathway; Transglutaminase2
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.05.324
  57. Viruses. 2026 Apr 24. pii: 495. [Epub ahead of print]18(5):
    From Envelope to Encephalopathy: How HIV-1 gp120 Drives Neurocognitive Decline.
    Maryline Santerre, Jenny Shrestha, Charles N S Allen, Natalia Shcherbik, Bassel E Sawaya.
      Although neurons are not productively infected by HIV-1, the envelope glycoprotein gp120, detectable in cerebrospinal fluid independently of active viral replication, gains intraneuronal access via lipid raft-mediated endocytosis, macropinocytosis, and retrograde axonal transport, contributing to persistent neurobiological dysfunction within the central nervous system. Once internalized, gp120 is associated with neuronal dysfunction involving convergent pathways, including excitotoxic calcium dysregulation, mitochondrial and metabolic failure, and inflammatory and senescence-associated amplification. These pathways converge on suppression of CREB and BDNF signaling, dismantling the transcriptional and neurotrophic programs required for synaptic maintenance and cognitive resilience. Extracellular vesicle-mediated dissemination and microRNA reprogramming extend gp120-associated neurobiological effects beyond sites of receptor engagement, while gut-derived metabolites, particularly quinolinic acid, lower the excitotoxic threshold through synergistic activation of NMDA receptors. Together, these mechanisms define HAND as a network disorder in which gp120 contributes to persistent neurocognitive dysfunction beyond active viral replication, identifying convergent therapeutic nodes where combination strategies targeting excitotoxicity, mitochondrial dysfunction, and neuroinflammation offer the most promising path toward durable neuroprotection.
    Keywords:  BDNF; CREB; HIV-1 gp120; NMDA receptor; calcium signaling; extracellular vesicles; mitochondrial dysfunction; neuroprotection; neurotoxicity; oxidative stress; senescence
    DOI:  https://doi.org/10.3390/v18050495
  58. Neuromolecular Med. 2026 May 28. pii: 30. [Epub ahead of print]28(1):
    Neuropilins in Multiple Sclerosis: Dual Roles of NRP-1 in Neuroinflammation and Neuroprotection.
    Pouya Goleij, Mehregan Babamohamadi, Mohammad Mahdi Heidari, Mohammad Amin Khazeei Tabari, Sajad Abolfazli, Soroush Mohammadi, Pantea Majma Sanaye, Reza Arefnezhad, Michael Aschner, Haroon Khan, Mostafa Rezaei Tavirani, Abolfazl Movafagh.
      Neuropilins (NRPs), particularly NRP-1, are multifunctional co-receptors involved in neuroinflammatory and neuroprotective processes. Altered NRP expression has been observed in multiple sclerosis (MS) lesions and peripheral circulation, suggesting early involvement in disease progression. This review addresses the dual role of NRPs in MS and experimental autoimmune encephalomyelitis (EAE), emphasizing expression patterns, signaling pathways, and therapeutic interventions. NRP-1 is expressed by endothelial cells, microglia, and macrophages, while Sema3A, a key ligand, is produced by reactive astrocytes and contributes to a non-regenerative microenvironment. NRP-1 is involved in regulating blood-brain barrier (BBB) integrity, contributes to leukocyte trafficking, and modulates inflammatory signaling via the IFN-γ-STAT1-CXCL10 axis. In EAE, endothelial-specific NRP-1 deletion reduces disease severity, demyelination, and immune infiltration. Immunologically, NRP-1 governs interactions among T cells, dendritic cells, and macrophages, facilitating regulatory T cell (Treg) function and peripheral tolerance. Trogocytosis-mediated NRP-1 transfer from dendritic cells to T cells and polysialylated NRP-2 on dendritic cells further influence immune modulation. Tuftsin, a tetrapeptide targeting NRP-1, promotes anti-inflammatory microglial polarization and Treg activation, improving EAE outcomes. Therapeutic interventions, such as Bu-Shen-Yi-Sui Capsule (BSYSC), FTX-101 (a Sema3A-NRP-1 inhibitor), and tuftsin restore BBB function, reduce inflammation, enhance remyelination, and improve clinical scores. NRP-1 signaling thus exhibits context-dependent dual roles: promoting inflammatory cascades while enabling neuroprotection through regulatory immune networks and oligodendrocyte precursor cell support, highlighting NRP-1 as a therapeutic target in MS.
    Keywords:  Blood-brain barrier; NRP-1; Neuroinflammation; Neuroprotection
    DOI:  https://doi.org/10.1007/s12017-026-08918-9
  59. Biol Rev Camb Philos Soc. 2026 May 29.
    The physiological effects of APOE genotype in healthy young/middle-aged individuals.
    Sherida M de Leeuw, Sheina Emrani, Julian Putter, Tal Nuriel.
      The apolipoprotein E ε4 (APOE4) allele is a risk factor for cardiovascular disease and for multiple neurodegenerative diseases, most notably Alzheimer's disease (AD). However, in healthy infants to adults, the encoded apolipoprotein E protein plays a role in many physiological functions, in both the periphery and in the brain, which can help us understand the biological contribution of this protein to disease. This review aims to describe the role of APOE genotype in a wide range of human physiological processes in healthy young/middle-aged individuals, including reproduction, cardiovascular health, inflammation, lipid metabolism, cognition, and brain structure/function, as well as how APOE genotype mediates the effects of external factors in these individuals, such as traumatic brain injury, pollution, lifestyle factors, and viral infections. The research covered in this review demonstrates that a person's APOE genotype affects a wide array of human physiological processes, from infancy to adulthood, with important differences observed in male and female study participants. We also discuss the evolutionary involvement and the 'antagonistic pleiotropy' hypothesis of APOE4. Understanding the biology and the mechanisms that are affected by APOE genotype in healthy young/middle-aged individuals is vital for understanding how this common allele contributes to the development of cardiovascular and neurodegenerative diseases, and how these diseases can be prevented.
    Keywords:  AD biomarkers; APOE; EEG; MEG; MRI; PET; SARS‐CoV‐2; TBI; age; apolipoprotein; atherosclerotic; body fat percentage; body mass; brain metabolism; brain structure; cholesterol; cognition; concussion; diet; fMRI; functional connectivity; inflammation; lifestyle; lipids; middle‐aged; pollution; sex; traumatic brain injury; virus infection; young
    DOI:  https://doi.org/10.1002/brv.70187
  60. Int Immunol. 2026 May 26. pii: dxag026. [Epub ahead of print]
    Granulocyte heterogeneity in immune-mediated and inflammatory diseases: Insights from single-cell transcriptomic analyses.
    Hiroshi Shimagami, Atsushi Kumanogoh, Masayuki Nishide.
      Neutrophils and eosinophils have long been regarded as terminal effectors of innate immunity. Technical advances in single-cell RNA sequencing define transcriptome-based granulocyte subsets beyond classical density- and surface marker-based classifications. These approaches reveal substantial heterogeneity in granulocyte differentiation states, activation programs, and tissue adaptation across human diseases. In microscopic polyangiitis, type II interferon pathways shape a pathogenic neutrophil activation state, and serum IFNγ levels at disease onset may serve as a potential biomarker for subsequent relapse. In infectious diseases, including COVID-19 and sepsis, the expansion of immunosuppressive ARG1- and IL1R2-expressing neutrophils is reported in severe disease and may reflect altered immune responses. MMP9-high neutrophils are enriched in cardiovascular disorders and may be linked to thrombosis and ischemic injury. In allergic diseases, spatial and single-cell analyses identify tissue-specific eosinophil states and their interactions with epithelial and macrophage compartments, highlighting context-dependent eosinophil activation within inflamed tissues. Despite emerging evidence for disease-associated granulocyte heterogeneity, whether these populations causally contribute to disease pathophysiology remains largely unclear. Experimentally validated functions and clinically applicable surrogate markers, such as surface markers or circulating proteins, are still needed. This review summarizes recent advances and current limitations in understanding granulocyte heterogeneity across immune-mediated and inflammatory diseases, and discusses how integrative single-cell approaches may support the development of clinically relevant biomarkers and targeted therapeutic strategies.
    Keywords:  Eosinophil; Neutrophil; Single-cell RNA sequencing; Spatial transcriptomics
    DOI:  https://doi.org/10.1093/intimm/dxag026
  61. Aging Cell. 2026 Jun;25(6): e70543
    Loss of SMARCAD1 Mitigates Tauopathy.
    Vaishnavi S Jadhav, Rebecca L Kow, Asia D Beale, Misa Baum, Pamela J McMillan, Caitlin S Latimer, Nicole F Liachko, Brian C Kraemer.
      Tauopathies are neurodegenerative diseases characterized by the accumulation of misfolded tau protein and include Alzheimer's disease (AD) and related dementia disorders. Identifying new strategies to treat tauopathy remains an important gap in the field. Using forward and reverse genetic approaches in C. elegans, we identified smrd-1, the C. elegans homolog of SMARCAD1, as a potent modifier of tauopathy phenotypes in a transgenic model of tauopathy. Loss of smrd-1 function rescues tauopathy-associated neuronal dysfunction and neurodegeneration in C. elegans models of tauopathy. Loss or reduction of smrd-1/SMARCAD1 decreases phosphorylated and total tau protein levels by reducing tau mRNA transcripts in C. elegans and mammalian HEK-tau cells. Loss of smrd-1 rescues tau-driven abnormal H3K9me3 chromatin methylation. Immunohistochemistry in human postmortem AD brain tissue showed SMARCAD1 depletion in a subset of cases that also exhibit depletion of MSUT2. Loss of smrd-1/SMARCAD1 rescues tau-mediated neurodegeneration via a tau mRNA lowering mechanism accompanied by changes in chromatin conformation.
    Keywords:   C. elegans ; SMARCAD1 ; smrd‐1 ; Alzheimer's disease; HEK‐tau; epigenetic; tau; tauopathy
    DOI:  https://doi.org/10.1111/acel.70543
  62. J Neuroinflammation. 2026 May 26.
    A reparative neutrophil subpopulation accelerates spinal cord regeneration in zebrafish by controlling macrophage inflammation via Il-4.
    Xiaobo Tian 田晓波, Alberto Docampo-Seara, Kim Heilemann, Friederike Kessel, Daniela Zöller, Anja Bretschneider, Thomas Becker, Catherina G Becker.
      In mammals, a dysregulated immune response is detrimental to spinal cord repair. In zebrafish, which are capable of spinal cord regeneration, the immune response promotes regeneration. Neutrophils are the first immune cells to arrive at a spinal cord injury site, but their role in successful regeneration is not fully understood. Here we show that ablating neutrophils, including a subpopulation that expresses the cytokine il4, increases expression of il1b (coding for Il-1β) mainly in macrophages/microglia and delays anatomical and functional recovery after a spinal cord injury in larval zebrafish. Experimentally reducing Il-1β levels rescues axonal regeneration. Disruption of il4 mimics the detrimental effect of neutrophil ablation for axonal regeneration and this is also rescued by reducing Il-1β levels. Moreover, after ablation of neutrophils, axonal regeneration and il1b expression levels are both rescued by over-expression of il4. Hence, after spinal cord injury, a pro-regenerative neutrophil subpopulation accelerates spinal cord regeneration in larval zebrafish by controlling expression of il1b mainly in macrophages/microglia. For this neutrophil action, il4 expression is necessary and sufficient.
    Keywords:  Axon regrowth; Behavioural recovery; Diphenyleneiodonium; Il-1β; Innate immune response; Macrophages/microglia; Nitroreductase ablation; Spinal cord regeneration
    DOI:  https://doi.org/10.1186/s12974-026-03878-0
  63. Sci Adv. 2026 May 29. 12(22): eaei2053
    Channeling teamwork: ATP and lipids cooperate to gate P2X receptors.
    Frank Bosmans, Toshimitsu Kawate.
      P2X receptor structures resolved in a lipid environment reveal how subtype-specific ligand recognition, drug sensitivity, and channel gating are coupled.
    DOI:  https://doi.org/10.1126/sciadv.aei2053
  64. Nature. 2026 May 27.
    Organ formation in early human embryos captured in spatial cell atlas.
    Varun K A Sreenivasan, Malte Spielmann.
      
    Keywords:  Developmental biology; Transcriptomics
    DOI:  https://doi.org/10.1038/d41586-026-01416-9
  65. Cell. 2026 May 26. pii: S0092-8674(26)00517-9. [Epub ahead of print]
    TPPP/p25 amyloid seeding activity as a specific biomarker for multiple system atrophy.
    Shuyi Zeng, Shenqing Zhang, Shengnan Zhang, Yun Fan, Wencheng Xia, Feiyang Chen, Chengan Huang, Shiran Lv, Jinxia Lu, Yunpeng Sun, Kaien Liu, Yunxia Li, Yaoyang Zhang, Jian Wang, Cong Liu, Dan Li.
      Detection of α-synuclein (α-syn) amyloid seeds in human biofluids has attracted great interest for clinical diagnosis of synucleinopathies. However, as a common biomarker, α-syn lacks specificity in reliably differentiating distinct disorders. Here, we report tubulin polymerization promoting protein (TPPP/p25) as a cerebrospinal fluid (CSF) biomarker for the specific diagnosis of multiple system atrophy (MSA). We demonstrate that native TPPP/p25 is self-protected against amyloid aggregation, while disease-related mutation disrupts this protection, triggering TPPP/p25 aggregation. Cryo-electron microscopy (cryo-EM) analysis reveals that the well-folded core domain (CORE) undergoes large conformational changes to mediate amyloid formation. Based on this insight, we developed a seed amplification assay using a minimized CORE (miniCORE) monomer, which detects TPPP/p25 amyloid seeds in CSF and robustly differentiates MSA from Parkinson's disease (PD) and other neurodegenerative diseases. Our findings establish misfolded TPPP/p25 as a promising, specific biomarker in biofluids for MSA diagnosis.
    Keywords:  CSF biomarker; MSA; SAA; TPPP/p25; cerebrospinal fluid biomarker; cryo-EM amyloid fibril structure; multiple system atrophy; seed amplification assay; tubulin polymerization promoting protein
    DOI:  https://doi.org/10.1016/j.cell.2026.04.050
  66. Protein Sci. 2026 Jun;35(6): e70653
    MICOS and MIMAS, multifunctional assemblies linking mitochondrial biogenesis, architecture, and function.
    Patrick Horten, Kuo Song, Nikolaus Pfanner, Heike Rampelt.
      Mitochondrial cristae architecture is central for optimal oxidative phosphorylation and a healthy mitochondrial physiology. The intricate architecture of the inner mitochondrial membrane relies on protein complexes that compartmentalize the membrane by imposing membrane curvature, forming membrane contact sites or membrane subdomains, regulating the partitioning of mitochondrial proteins between the different subcompartments and thereby enabling functional asymmetry, and by governing membrane dynamics. Studies in recent years have expanded our understanding of the machineries and mechanisms underlying the manifold functions of the inner membrane. This review focuses on the mitochondrial contact site and cristae organizing system (MICOS), a protein complex that stabilizes the narrow entry gates of cristae, and on a novel inner membrane megacomplex, the mitochondrial multifunctional assembly (MIMAS), as well as on their roles in organizing the inner membrane.
    Keywords:  cristae; membrane organization; metabolism; mitochondria; respiratory chain
    DOI:  https://doi.org/10.1002/pro.70653
  67. Brain Sci. 2026 Apr 30. pii: 485. [Epub ahead of print]16(5):
    Lysophospholipids in Synucleinopathies: A Conceptual Framework Linking Proteostasis and Neuroinflammatory Signaling.
    Tamotsu Tsukahara, Hisao Haniu, Yoshikazu Matsuda.
      Synucleinopathies, including Parkinson's disease and dementia with Lewy bodies, are characterized by progressive α-synuclein (α-Syn) aggregation accompanied by chronic neuroinflammatory changes. However, the mechanistic relationship between disrupted proteostasis and inflammatory signaling remains incompletely defined and may vary across disease stages and clinical subtypes. Lysophospholipids (LPLs) are bioactive lipids derived from membrane phospholipids that participate in diverse cellular processes. These functions are primarily mediated through G protein-coupled receptor (GPCR) signaling, but may also involve direct effects on membrane organization and biophysical properties. In addition to receptor-mediated pathways, the surrounding lipid environment may influence protein behavior, although its role in neurodegenerative processes remains to be fully elucidated. Within this framework, LPLs can be considered not only as signaling molecules but also as modulators of the cellular environment in which proteostasis and inflammatory responses occur. In this review, we adopt a lipid-centered perspective in which LPLs occupy an interface between lipid signaling, protein aggregation, and neuroinflammation. Rather than acting as a single initiating factor, altered lipid metabolism is likely to contribute through multiple interconnected pathways. Although current evidence is largely derived from preclinical studies, it supports a role for lipid-related mechanisms, particularly in early stages of synucleinopathy.
    Keywords:  gut–brain axis; lysophospholipids; microglia; mitochondrial dysfunction; neurodegenerative diseases; neuroinflammation; proteostasis; synucleinopathies; α-synuclein
    DOI:  https://doi.org/10.3390/brainsci16050485
  68. PLoS Biol. 2026 May 29. 24(5): e3003830
    Type II tRNA cleavage by SLFN14 endoribonuclease variants linked to inherited thrombocytopenia drives global translational repression.
    Chengchao Ding, Xinyi Ashley Liu, Fushun Zhang, Saori Uematsu, Shu-Bing Qian, Yan Xiang.
      Schlafens proteins (SLFNs) are interferon-inducible regulators of RNA metabolism that influence antiviral defense and cell fate. Human SLFN14 is a ribosome-associated endoribonuclease whose pathogenic variants cause autosomal dominant inherited thrombocytopenia (IT), but the molecular basis of this disorder remains unclear. Here, using HEK293T cells expressing human SLFN14 variants, we show that SLFN14 represses global protein synthesis through selective cleavage of type II tRNAs. IT-linked mutations alter SLFN14 RNA substrate specificity, enhancing depletion of type II tRNAs while reducing rRNA cleavage. This shift promotes ribosome stalling at codons decoded by type II tRNAs, triggering global translational arrest, stress signaling, and cell death. These findings reveal how altered RNA targeting by SLFN14 can drive disease and highlight selective tRNA targeting as a mechanism than regulates translation and cell fate.
    DOI:  https://doi.org/10.1371/journal.pbio.3003830
  69. J Neuroinflammation. 2026 May 25.
    PVNOXT regulates acinar cell-mediated inflammatory response via DMVACh projections to the acinar cell.
    Hui Fang, An Liu, Jun-Fa Yang, Min Liu, Yin-Ying Zheng, Hong-Yan Zhang, Jin-Rong Guo, Piao-Piao Luo, Da-Shuai Yang, Rui Wang, Fu Lai, Qiu-Ping Chen, Tao Xu, Hua Wang, Zhen-Hua Ren.
      The central nervous system regulates glandular secretions by modulating visceral organ functions. However, the anatomical and functional connections between the brain and digestive enzyme-producing pancreatic acinar cells remain poorly defined. Using the hypertriglyceridemia-associated acute pancreatitis (HTGP) mouse model, we aimed to describe a functional transneuronal circuit connecting the hypothalamus to pancreatic acinar cells in mice. This circuit originates from a subpopulation of oxytocin neurons in the paraventricular hypothalamic nucleus (PVNOXT), and reaches the exocrine pancreas via acetylcholinergic neurons in the dorsal motor nucleus of the vagus (DMVACh) to innervate acinar cells. Silencing of PVNOXT neurons suppresses digestive enzyme secretion and inhibits the inflammatory response in HTGP. Conversely, stimulation of these neurons induces inflammation by dysregulating secretory pathways in acinar cells. Single-cell RNA sequencing revealed that WD repeat and FYVE domain-containing 1 (Wdfy1), a gene expressed in the OXT neuron subpopulation, plays a critical role in the acinar cell-mediated inflammatory response, and its function is essential for the PVNOXT-DMVACh axis.
    Keywords:  Acinar cells; Functional transneuronal circuit; Inflammatory response; Pancreas
    DOI:  https://doi.org/10.1186/s12974-026-03870-8
  70. Neural Regen Res. 2026 May 14.
    Human induced pluripotent stem cell-derived cortical grafts rebuild motor circuits after brain injury.
    Myles D Gladen, Zane R Lybrand.
      Traumatic brain injury causes irreversible neuronal loss, and no existing therapy can replace lost cortical tissue and restore its circuitry. We investigated whether human induced pluripotent stem cell-derived cortical organoids could not only repair motor deficits but also reveal how grafted neurons integrate into the adult brain. Cortical organoids were generated via a modified dual-SMAD inhibition protocol and transplanted into the motor cortex of NOD-SCID mice after controlled cortical impact. Mice receiving grafts achieved full recovery of contralateral forelimb motor function within 28 days, while non-transplanted controls showed persistent deficits. Grafts are selectively projected to the canonical efferent motor pathway targets bilaterally, with minimal off-target integration. Strikingly, we identified abundant perinuclear synaptic puncta in host neurons that colocalized with graft-derived axons, human-specific cytoplasmic labeling, and the excitatory synapse marker post-synaptic density protein 95. These structures, present in both local and long-range motor-associated regions, provide the first structural evidence of graft-derived synaptic input directly onto host neuronal cell bodies, suggesting specific organoid cell types are integrating into the host network. Our findings establish that human induced pluripotent stem cell-derived cortical organoids can restore motor function after traumatic brain injury and reveal a cellular integration signature that advances understanding of how transplanted human neurons connect with the injured adult brain.
    Keywords:  central nervous system; cerebral organoids; induced pluripotent stem cells; motor recovery; network establishment; regeneration; structural synapse formation; traumatic brain injury
    DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01272
  71. J Immunol. 2026 May 14. pii: vkag102. [Epub ahead of print]215(5):
    Myeloid cell IL-15 production in the brain supports bystander CD8+ T cell neuropathic immune responses following virus infection.
    Jennifer N Berger, Alayna Rosales, Dustin Heiden, Camille Merrick, Brendan Monogue, J David Beckham, Leslie Berg.
      The central nervous system (CNS) includes a uniquely regulated immune response that supports homeostasis, response to injury, and response to pathogens. Recent work has shown that virus-associated immune responses in the CNS may contribute to neuronal injury and long-term outcomes such as neurocognitive decline. However, the fundamental mechanisms that regulate acute infiltration of immune cells from vascular compartments into the CNS are not well defined. Using an attenuated Venezuelan equine encephalitis virus TC83 (referred to as TC83) to inoculate via olfactory and intracranial injections, we show that infection in the CNS and olfactory pathways results in rapid infiltration of both CD4+ and CD8+ T cells as early as 3 and 5 d postinfection. CNS-infiltrating CD8+ T cells exhibit a bystander, memory phenotype (CD49d+, Tbet+, NKG2D+, Eomes+); are cytotoxic; and are recruited independent of antigen-specific responses. We show that infiltration of CD8+ bystander T cells is supported by microglia and infiltrating macrophage expression of IL-15 and IFN expression in the CNS. These innate antiviral immune signals support activation of bystander CD8+ T cells in the CNS that contribute to tissue injury independent of virus replication at early time points postinfection. These data support a mechanism by which IL-15 stimulates bystander memory CD8+ T cells to enter the CNS and contribute to injury independent of antigen-specific stimulation.
    Keywords:  IL-15; bystander T cells; neuroimmunology
    DOI:  https://doi.org/10.1093/jimmun/vkag102
  72. Glia. 2026 Jul;74(7): e70168
    Walnut-Derived Extracellular Vesicles Orchestrate a Pre-Regenerative Niche via c-Myc Mediated Metabolic Reprogramming.
    Junyang Gao, Genzhong Xu, Nianci Huo, Yuan Liu, Hui Zhou, Jiaqi Liu, Saichao Zhou, Siyao Liu, Ningning Yang, Nan Zhou.
      Peripheral nerve injury (PNI) remains a major regenerative challenge, in part because the post-injury microenvironment can disrupt Schwann cell (SCs) homeostasis. Walnuts (Juglans regia) have long been used in ethnomedicine for perceived neurotrophic or neuroprotective benefits, a view historically linked to their resemblance to the brain. To examine whether this traditional concept can be leveraged as a nanotherapeutic approach, we isolated walnut-derived extracellular vesicles (WEVs) and evaluated their effects on peripheral nerve repair. We found that WEVs are readily internalized by SCs and can help establish a "pre-regenerative niche," defined here as a permissive metabolic microenvironment that supports repair. Mechanistically, WEVs appear to engage a c-Myc-mediated transcriptional program that shifts SC metabolism toward aerobic glycolysis and increases lactate export, consistent with activation of a glia-to-neuron lactate shuttle. In parallel, WEVs may stabilize the glial bioenergetic hub by limiting stress-induced mitophagy. In a rat sciatic nerve compression model, these changes were associated with preserved mitochondrial ultrastructure in the acute phase, followed by enhanced remyelination, improved motor and sensory outcomes, and attenuated muscle atrophy. Collectively, our findings suggest a mechanistic basis for the reported neuroprotective value of walnuts and identify WEVs as a niche-modulating nanotherapeutic candidate that may promote regeneration by aligning glial metabolic plasticity with neuronal energy demands.
    DOI:  https://doi.org/10.1002/glia.70168
  73. bioRxiv. 2026 May 14. pii: 2026.05.11.723888. [Epub ahead of print]
    Tauopathy primes co-filament assembly and dysfunction of TDP-43.
    Meghraj S Baghel, Grace D Burns, Aswathy Peethambaran Mallika, Xiaoke K Chen, Fangbing Liu, Shruti Renganathan, Tong Li, Juan C Troncoso, Philip C Wong.
      While most Alzheimer's disease (AD) which is associated with L imbic P redominant A ge-related T DP-43 E ncephalopathy (LATE) exhibits accelerated brain atrophy, the pathogenic mechanism remains elusive. We show here, in mice harboring depositions of amyloid-β and tau, the age-dependent emergence of TDP-43 proteinopathy. We demonstrate that TDP-43 dysfunction facilitates caspase 3-mediated endoproteolysis of tau, accelerates tauopathy and exacerbates neuron loss. Unexpectedly, we found that the emergence and spread of TDP-43 proteinopathy is associated with the spread of tauopathy and correlated with co-filament assembly of tau and TDP-43. Importantly, TDP-43 dysfunction precedes such co-filament assembly and TDP-43 cytoplasmic aggregates. Consistent with the idea that tauopathy could prime co-filament assembly and proteinopathy of TDP-43 to exacerbate neurodegeneration, we found tau co-filament assembly with TDP-43 in AD and AD-LATE cases. These findings suggest that TDP-43 dysfunction accelerates tauopathy, which, in turn, primes co-filament assembly and dysfunction of TDP-43 to exacerbate neuron loss in AD-LATE, a pathogenic mechanism disclosing novel targets and therapeutic strategies.
    DOI:  https://doi.org/10.64898/2026.05.11.723888
  74. JAMA. 2026 May 27.
    Tenecteplase for Acute Non-Large Vessel Occlusion After Ischemic Stroke-Reply.
    OPTION Investigators
      
    DOI:  https://doi.org/10.1001/jama.2026.4819
  75. Stem Cell Reports. 2026 May 28. pii: S2213-6711(26)00141-4. [Epub ahead of print] 102930
    ZFHX4 is necessary for dopaminergic neuron differentiation and controls cell cycle by regulating LIN28A.
    Elena Valceschini, Borja Gomez Ramos, Jochen Ohnmacht, Aurelien Ginolhac, Marie Catillon, Deborah Gerard, Anthoula Gaigneaux, Dimitrios Kyriakis, Kamil Grzyb, Enrico Glaab, Anne Grünewald, Alexander Skupin, Thomas Sauter, Rejko Krüger, Lasse Sinkkonen.
      Parkinson's disease (PD) involves selective degeneration of midbrain dopaminergic neurons (mDANs), yet the regulatory networks governing their development remain incompletely understood. ZFHX4 has been linked to neurodevelopment across species and shows reduced expression in the PD midbrain. Through integrative analysis of our multiomic data of mDAN differentiation, we show that ZFHX4 is a super-enhancer-controlled transcription factor induced during mDAN specification. Importantly, ZFHX4 is necessary but not sufficient for mDAN differentiation. Genome-wide profiling of ZFHX4 binding revealed targeting to active promoters, and transcriptomic profiling after ZFHX4 depletion identified primary target genes enriched for cell-cycle regulation. Consistently, ZFHX4-depleted cells showed reduced proliferation and accumulated in G2 phase, impairing cell-cycle progression. LIN28A, an RNA-binding protein involved in stem-cell maintenance and microRNA maturation, is among the strongest upregulated genes upon ZFHX4 depletion, with direct ZFHX4 binding at the locus. Our findings indicate that ZFHX4 regulates mDAN maturation through a mechanism involving the LIN28A-miR-9 axis.
    Keywords:  LIN28; Parkinson's disease; ZFHX4; cell cycle; chromatin; dopaminergic neurons; neurodevelopment; super-enhancers; transcription factors
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102930
  76. Int J Mol Sci. 2026 May 21. pii: 4651. [Epub ahead of print]27(10):
    Molecular Mechanisms Underlying Alzheimer's Disease Pathogenesis: Comprehensive Overview.
    Filomena Lo Vecchio, Annamaria la Torre, Carolina Gravina, Grazia D'Onofrio, Antonio Greco.
      Alzheimer's disease (AD) is a progressive, multifactorial neurodegenerative disorder ranking first as cause of dementia in the elderly. It is characterized by the progressive deterioration of the central nervous system, leading to impaired cognitive function and reduced ability to perform daily activities. Pathological hallmarks of AD include the accumulation of β-amyloid plaques and neurofibrillary tangles which ultimately cause neuronal death and synaptic loss. The vast majority of AD cases are sporadic, with aging representing the primary non-modifiable risk factor contributing to disease susceptibility and progression. However, several factors encompassing genetic predisposition, systemic inflammation, chronic diseases, infections, traumatic brain injury, lifestyle factors, and environmental exposures may affect AD onset. This work aims to describe and discuss the main molecular pathways involved in AD pathophysiology and to examine how these mechanisms cross-interact in promoting neurodegeneration and disease progression.
    Keywords:  Alzheimer’s disease; autophagy; mitochondrial dysfunction; neurofibrillary tangles; stress response; β-amyloid
    DOI:  https://doi.org/10.3390/ijms27104651
  77. bioRxiv. 2026 May 17. pii: 2026.05.13.724866. [Epub ahead of print]
    Proximity labeling reveals unique and shared interactomes of unmodified and pyroglutamate amyloid beta in human hippocampus in Alzheimer's disease.
    Alia O Alia, Kristy Urquhart, Hannah Carson, Bryan Killinger, Christopher Janson, Liudmila Romanova.
      Amyloid plaques are a hallmark neuropathological feature of Alzheimer's disease (AD), composed of insoluble amyloid beta (Aβ) peptide. Aβ undergoes post-translational modifications that alter their biophysical properties, aggregation kinetics, and neurotoxicity, creating a heterogeneous pool of species that differentially affect AD pathogenesis. Pyroglutamate-modified Aβ (pEAβ) is a particularly aggregation-prone and proteolytically resistant variant that preferentially accumulates within plaque cores, is implicated in early plaque seeding, and is a major target of emerging anti-amyloid immunotherapies. However, the molecular environment surrounding pEAβ versus unmodified Aβ (pan-Aβ) in the human hippocampus remains incompletely defined. Here, we used Biotinylation by Antibody Recognition (BAR), an in-situ proximity labeling approach, to map and compare the protein-protein interactions (proteomes) of pEAβ and pan-Aβ in formalin-fixed postmortem human hippocampal tissue from pathologically confirmed AD cases and cognitively normal (CN) controls. Differential proteomic analysis identified 48 significantly enriched proteins in AD pEAβ captures, 28 in AD pan-Aβ captures, and 15 in CN pan-Aβ captures. Whereas no significant enrichment was detected in CN pEAβ captures, supporting pEAβ as a pathology-associated species. pEAβ in AD demonstrated the largest variant-specific signature with 31 unique proteins, pan-Aβ showed 11 unique proteins in AD, and 14 unique proteins in CN, 16 proteins were shared between AD pEAβ and AD pan-Aβ, with PCSK1N shared across AD pEAβ, and AD/CN pan-Aβ. Pathway enrichment analysis revealed broader biological disruptions linked to pEAβ, including synaptogenesis signaling, clathrin-mediated endocytosis, mitochondrial division signaling, and neurotransmitter release. Shared pathways included SNARE signaling, glutamatergic receptor signaling, and netrin signaling. These findings demonstrate that pEAβ engages an expanded, variant-specific interactome in human AD hippocampus and designate intracellular trafficking, synaptic signaling, and mitochondrial pathways as network-level vulnerabilities relevant to pEAβ pathology in AD. Notably, comparison of CN versus AD pan-Aβ further distinguished protein networks associated with physiological Aβ engagement versus pathological pan-Aβ deposition.
    DOI:  https://doi.org/10.64898/2026.05.13.724866
  78. J Alzheimers Dis. 2026 May 25. 13872877261450934
    Lipidomics reveals TREM2-associated dysregulation of plasma lipid metabolism in Alzheimer's disease.
    Tongtong Zhang, Miao He, Yan Wang, Peiyang Gao, Xinyi Xia, Jiangting Li, Yunsi Yin, Guodong Zhao, Ouyang Chen, Miao Qu, Yi Tang, Qi Qin.
      BackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is a genetic risk factor for Alzheimer's disease (AD). While TREM2 facilitates central nervous system lipid clearance, its influence on peripheral lipid metabolism remains unclear.ObjectiveTo investigate the association between plasma sTREM2 and peripheral lipid profiles in AD and to explore the mechanistic role of TREM2 in peripheral lipid regulation.MethodsWe conducted a cross-sectional study of 59 AD patients and 54 healthy controls and measured plasma biomarkers including sTREM2 as well as performed targeted lipidomics profiling. Mechanistic exploration was performed via plasma and hippocampal lipidomics in Trem2 knockout and APP/PS1 mice.ResultsPlasma sTREM2 levels were elevated in AD and were negatively correlated with the plasma p-tau217/Aβ42 ratio and p-tau217. Multivariate analysis revealed a distinct lipidomics signature in AD, in which 30 lipid species were significantly altered. We prioritized significantly altered biomarkers to inform a composite biomarker panel combining sTREM2 with a set of sphingomyelins, phosphatidylinositols, diacylglycerols, fatty acids, and cholesteryl esters, which showed strong discrimination between AD and controls (AUC = 0.93). In a mouse model of APP/PS1, we found that Trem2 knockout partially normalized plasma sphingomyelins and hexosylceramide levels. Finally, cross-tissue comparisons further suggested that TREM2 exerted distinct effects on peripheral sphingolipid metabolism that were less evident in hippocampal tissue.ConclusionsOur findings associate TREM2 with lipid dysregulation in AD and support development of a plasma sTREM2-lipid panel for patient classification.
    Keywords:  Alzheimer's disease; TREM2; lipidomics; plasma; sphingolipids
    DOI:  https://doi.org/10.1177/13872877261450934
  79. J Am Acad Dermatol. 2026 May 25. pii: S0190-9622(26)02766-0. [Epub ahead of print]
    Cutaneous T-cell lymphoma tumors undergoing radiotherapy demonstrate immune shifts from malignant inflammation to wound healing and suggest markers of treatment durability.
    JoJo Holm, Eleanor Ostroff, Lauren P Clarke, Katherine De Jong, Yanzhen Pang, Madeline J Hooper, Spencer Evans, Kurt Q Lu, Stephanie M Rangel, Bharat Mittal, Joan Guitart, Ralph R Weichselbaum, Ziyou Ren, Xiaolong A Zhou.
      
    Keywords:  cutaneous T-cell lymphoma; immune remodeling; proteomics; radiotherapy; spatial transcriptomics; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.jaad.2026.05.066
  80. Nat Commun. 2026 May 27. pii: 4693. [Epub ahead of print]17(1):
    Lifespan normative modeling of brain microstructure.
    Alzheimer’s Disease Neuroimaging Initiative
      Normative models of brain metrics based on large populations could be extremely valuable for detecting brain abnormalities in patients with a variety of disorders, including degenerative, psychiatric and neurodevelopmental conditions, but no such models exist for the brain's white matter (WM) microstructure. Here we present a large-scale normative model of brain WM microstructure - based on 19 international diffusion MRI datasets covering almost the entire lifespan (totaling N = 54,583 individuals; age: 4-91 years). We extracted regional diffusion tensor imaging (DTI) metrics using a standardized analysis and quality control protocol and used hierarchical Bayesian regression (HBR) to model the statistical distribution of derived WM metrics as a function of age and sex. We extracted the average lifespan trajectories and corresponding centile curves for each WM region. We illustrate the utility of the method by applying it to detect and visualize profiles of WM microstructural deviations in a variety of contexts: in mild cognitive impairment, Alzheimer's disease, and 22q11.2 deletion syndrome - a neurogenetic condition that markedly increases risk for schizophrenia. The resulting large-scale model provides a common reference to identify disease effects on the brain's microstructure in individuals or groups, and to compare disorders, and discover factors affecting WM abnormalities. The derived normative models are a valuable resource publicly available to the community, adaptable and extendable to future datasets as the available data expands.
    DOI:  https://doi.org/10.1038/s41467-026-72875-x
  81. iScience. 2026 Jun 19. 29(6): 116033
    Andrographolide attenuates microglial senescence in Alzheimer's disease mice by suppressing the STAT3 signaling.
    Haochang Song, Meng Yang, Shengquan Wu, Qihui Dai, Weihong Qin, Weiheng Xie, Yuzhi Chen, Xiaoyun Jiang, Xiaojun Zhang, Xiuqin Deng, Chuang Ouyang, Yunman Zhang, Xinguang Liu, Yingjie Zhu, Gonghua Huang.
      Andrographolide (AP), a diterpenoid extracted from Andrographis paniculata, has emerged as a promising treatment for Alzheimer's disease (AD) in preclinical studies, but the underlying mechanisms remain incompletely defined. Here, we demonstrated that AP treatment improved cognition performance and reduced amyloid-β (Aβ) plaque accumulation in 5×FAD transgenic mice of both sexes, by mitigating microglial senescence. Proteomic analysis revealed that AP markedly decreased cholesterol content in the cerebral cortex. Using an in vitro low-density lipoprotein-induced senescence model, we found that AP significantly alleviated senescence in BV2 microglia while enhancing their phagocytic capacity. Mechanistically, AP mitigated microglial senescence by inhibiting STAT3 signaling. Overall, these findings identify a previously unrecognized immunometabolic mechanism for AP in the treatment of AD.
    Keywords:  cell biology; neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2026.116033
  82. Nat Commun. 2026 May 28.
    Fusion-positive rhabdomyosarcoma oncofusions share a common interactome.
    S P Zimmerman, C D Delaney, B K Lau, L B DeGraw, G H Rupprecht, M J A Groot Koerkamp, T de Souza, J Drost, R A Schoot, M T Meister, J F Shern, L M Wagner, G G Wang, K C Wood, C M Linardic, C M Counter.
      Fusion-positive rhabdomyosarcoma (FP-RMS) arises from at least seven distinct oncofusions sharing a common PAX3/7 N-terminal DNA-binding domain fused to divergent C-terminal partners. How different oncofusions produce the same cancer was unknown. Here we show they are functionally interchangeable, associate with a shared protein network we term the common interactome, bind overlapping target genes, and drive a similar core transcriptional program. The common interactome contains the C-terminal partners of known oncofusions and a newly identified translocation, suggesting oncofusions arise by PAX3/7 DNA-binding domain fusing to interactome members. As loss of common interactome proteins impaired oncogenic activity we screened the interactome for shared vulnerabilities. This identified thymidylate synthase as preferentially required for FP-RMS growth. Accordingly, the antifolate pralatrexate suppressed growth across all seven oncofusions, in multiple human FP-RMS cell lines, and a patient-derived xenograft. These findings demonstrate that divergent FP-RMS oncofusions are functionally fungible through a shared interactome that defines common vulnerabilities.
    DOI:  https://doi.org/10.1038/s41467-026-73749-y
  83. Cell Death Differ. 2026 May 27.
    Mitochondrial calcium uptake drives organelle remodeling to promote inflammasome-dependent cytokine release.
    Gaia Gherardi, Francesca Spinelli, Miriana Sbrissa, Martina Quagliata, Roberto Luisetto, Anna Scanu, Elena Vezzoli, Michela Carraro, Alva M Casey, Tiago F Branco, Naotada Ishihara, Andrea Mattarei, Stefano Masiero, Michael P Murphy, Paolo Bernardi, Carlo Tacchetti, Luca Scorrano, Anna Raffaello, Rosario Rizzuto.
      Mitochondrial Ca2+ uptake shapes cellular signaling by modulating metabolism, cell death and cytosolic Ca2+ dynamics, yet its pathological and therapeutic relevance remains undefined. Here, we show that Ca2+ entry through the mitochondrial Ca2+ uniporter (MCU) is required for mitochondrial fragmentation and subsequent NLRP3 inflammasome-mediated IL-1β release in lipopolysaccharide-primed, stimulated macrophages. This fragmentation occurs independently of the mitochondrial permeability transition pore but depends on activation of the organelle fission machinery. In an inflammatory disease model, MCU deficiency attenuated IL-1β secretion and reduced monosodium urate (MSU) crystal-induced joint inflammation in vivo. Collectively, our findings establish mitochondrial Ca2+ uptake as a key upstream signal that promotes organelle fragmentation to license inflammasome activation, positioning MCU as a potential therapeutic target in inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41418-026-01769-8
  84. Sci Adv. 2026 May 29. 12(22): eaee4242
    Mechanisms of ligand recognition and channel opening for P2X2 receptors in lipid nanodiscs.
    Surbhi Dhingra, Maia Moog, Kenton J Swartz.
      Extracellular adenosine 5'-triphosphate (ATP) activates P2X receptor channels (P2XRs) that serve important roles in the immune and nervous systems. Available structures of P2XRs in detergents reveal that ATP binding to the extracellular domain leads to severing of subunit interfaces within transmembrane regions as the pore opens. Here we report cryo-electron microscopy structures of the human P2X2R in lipid nanodiscs in an apo closed state, with ATP4-, Mg-ATP2-, and suramin bound. We find that a unique Arg residue interacts with the γ-PO4 of ATP4- in P2X2R and underlies the requirement of this subtype for ATP4-. Channel opening and desensitization occur when ATP4- binds, whereas the channel remains closed when Mg-ATP2- binds. A continuous belt of partially resolved lipids in the outer leaflet stabilizes the closed state, and the presence of lipids prevents the severing of subunit interfaces as the channel opens. These findings establish key mechanistic principles of gating for P2X2R in a membrane-like environment, providing a framework for future mechanistic studies and therapeutic development.
    DOI:  https://doi.org/10.1126/sciadv.aee4242
  85. Glia. 2026 Jul;74(7): e70164
    Specific Deletion of Interleukin-1 Beta in Microglia Improves Acute Outcome and Modulates Neurogenesis After Ischemic Stroke.
    Alba Grayston, Margarida Baptista, Kelly Wemyss, Ruby Taylor, Grace Cullen, Syeda S Jafree, Nadim Luka, Joshua R Cox, Joanne E Konkel, David Brough, Stuart M Allan, Emmanuel Pinteaux.
      Interleukin-1 (IL-1) signaling is a major driver of post-ischemic neuroinflammation, yet the cell- and isoform-specific roles of the two major IL-1 receptor type 1 agonists, IL-1α and IL-1β, remain incompletely defined in the context of stroke. Microglia rapidly express IL-1α after cerebral ischemia, whereas IL-1β expression is delayed and restricted to a small subset of microglia and infiltrating immune cells. Here, we investigated for the first time the specific contribution of microglial-derived IL-1β to acute injury and post-stroke neurorepair after transient middle cerebral artery occlusion in male and female mice, through microglial-specific tamoxifen-inducible Cre-loxP-mediated recombination. Deletion of microglial IL-1β improved acute neurological outcomes, reduced neutrophil accumulation in the ischemic brain, and dampened systemic inflammatory cytokines. These effects were most evident during the acute phase and in females in mice. In contrast, long-term functional recovery was largely unaffected. However, microglial IL-1β deletion differentially regulated post-stroke neurogenesis, enhancing subventricular zone neurogenic responses and ectopic neuroblast migration while limiting hippocampal neurogenesis. Together, these findings identify microglial IL-1β as a key amplifier of early inflammatory injury after stroke, exerting region-specific effects on neurogenic niches, and highlight distinct, non-redundant roles for microglial IL-1 isoforms in ischemic brain injury and repair.
    Keywords:  interleukin‐1 beta; ischemic stroke; microglia
    DOI:  https://doi.org/10.1002/glia.70164
  86. Inflammation. 2026 May 26.
    The CEBPB-AP-1 (JunB/Fos) Axis Drives Neuroinflammation and Microglial Dysfunction Via TNF Signaling in Ischemic Stroke.
    Kun Liang, Shuangshuang Lu, Weihao Shi, Weijian Fan, Yijun Huang, Jianwei Chen, Lei Zhu.
      Ischemic stroke triggers a strong neuroinflammatory response, with microglia playing dual roles in both exacerbating tissue damage and promoting repair. The molecular mechanisms regulating microglial activation and polarization remain inadequately defined. In this study, we demonstrate that the transcription factor CEBPB is a key upstream regulator of the AP-1 (JunB-Fos) complex, driving pro-inflammatory transcriptional programs in microglia following transient focal cerebral ischemia (tFCI). Transcriptomic profiling of microglia from tFCI mice revealed significant gene expression changes, particularly enrichment in inflammatory, immune, and cytokine production pathways, and identified Cebpb, Junb, Fos, and Tnf as key hub genes. Mechanistically, CEBPB is upregulated in post-ischemic microglia and directly binds to the Fos promoter to activate AP-1, inducing downstream inflammatory mediators, including IL-1β and TNF-α. Inhibition of AP-1 with the selective inhibitor T-5224 shifted microglia from a pro-inflammatory to an anti-inflammatory phenotype in vitro, decreasing pro-inflammatory cytokine production and enhancing anti-inflammatory mediator release. In vivo, T-5224 treatment in tFCI mice suppressed neuroinflammation, reduced neuronal apoptosis in the striatum and cortex, promoted a restorative microglial phenotype, and improved long-term sensorimotor and cognitive function. These findings establish the CEBPB/AP-1 axis as a critical driver of neuroinflammation in ischemic stroke and highlight it as a promising therapeutic target.
    Keywords:  AP-1; CEBPB; Ischemic stroke; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1007/s10753-026-02525-3
  87. Sci Adv. 2026 May 29. 12(22): eaec1416
    Lymph node-targeted DNA engages TBK1/IFN-I-driven innate immunity to induce potent T cell responses and durable memory in mice and NHPs.
    Martin P Steinbuck, Lochana M Seenappa, Wei Zhan, Erica Palmer, Mimi M Jung, Aniela Jakubowski, Xavier Cabana-Puig, Lisa K McNeil, Christopher M Haqq, Katherine A Fitzgerald, Peter C DeMuth.
      Adjuvants are immunoactivators capable of shaping the magnitude and quality of antigen-specific immune responses induced by subunit immunization. Presently, there is an acute need for effective adjuvants that safely induce durable and balanced humoral and cellular responses. Here, we engineered a class of Amphiphile (AMP)-modified, immunostimulatory DNA adjuvants designed for targeted delivery to lymph nodes and enhanced stimulation of TANK-binding kinase 1 (TBK1)-mediated danger-sensing pathways to generate strong adaptive immunity and long-term memory with potent recall potential. AMP-DNA adjuvants induced robust interferon type-I (IFN-I)-driven inflammatory environments in mouse and nonhuman primate (NHP) lymph nodes, leading to significantly enhanced cytokine secretion by polyfunctional CD8+ and CD4+ T cells in multiple tissues, as well as strongly elevated T helper cell 1 (TH1)-associated and neutralizing antibody responses, in the absence of systemic toxicity. These results demonstrate that AMP modification enables lymph node-targeted DNA adjuvants to potently activate IFN-I signaling to generate substantial cellular and humoral responses crucial for vaccine efficacy.
    DOI:  https://doi.org/10.1126/sciadv.aec1416
  88. Mult Scler Relat Disord. 2026 May 23. pii: S2211-0348(26)00299-3. [Epub ahead of print]111 107263
    Serum FAM19A5 elevation in NMOSD: astrocytic injury or reactive gliosis?
    Okan Sökmen.
      
    Keywords:  Astrocytic injury; Astroglial remodeling; Biomarker; FAM19A5; Neuromyelitis optica spectrum disorder; Reactive gliosis
    DOI:  https://doi.org/10.1016/j.msard.2026.107263
  89. bioRxiv. 2026 May 12. pii: 2026.05.11.724371. [Epub ahead of print]
    Microglia-derived extracellular vesicles attenuate acute a-synuclein induced astrocyte inflammation.
    Matthew P Nelson, Daisy Dong, Kathleen A Maguire-Zeiss.
      Aggregates of misfolded α-synuclein (Syn) and neuroinflammation are pathological features of Parkinson's disease (PD). These, misfolded conformations of Syn promote cytokine and chemokine signaling in the surrounding microenvironment by triggering activation of glial cells through pattern recognition receptors. Microglia and astrocytes act as innate mediators of the neuroimmune response in the brain by regulating inflammatory signaling via paracrine and autocrine forms of cell communication. Extracellular vesicles (EVs) represent a form of glial cell to cell communication that can regulate the glial neuroimmune responses depending on the phenotype of the donor cell. Research has shown that the contents of EVs can be altered via pharmacologically altering the donor cell which offers a potential avenue for the regulation of inflammation. As such, we analyzed enriched mouse cortical primary astrocytes and characterized their response to Syn exposure in the absence and presence of microglia-derived EVs. Using trans-resveratrol, a naturally occurring polyphenol implicated for its anti-inflammatory properties, as our pharmacological agent to generate an anti-inflammatory microglial-derived EV phenotype we found that EVs derived from resveratrol-treated microglia decreased the production of proinflammatory molecules in enriched astrocytes exposed to Syn. Sequencing of EV miRNAs revealed two miRNAs (miR-5099 and miR-115) with significant up-regulation in resveratrol EVs compared to control EVs. Astrocytes transfected with corresponding miRNA mimics prior to Syn exposure showed a dramatic decrease in inflammatory biomarker production. These findings show that microglia-derived EVs and their specific miRNA cargo can attenuate Syn-directed inflammation in astrocytes and may serve as a novel therapeutic for proteinopathies like PD.
    DOI:  https://doi.org/10.64898/2026.05.11.724371
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