bims-micgli Biomed News
on Microglia
Issue of 2026–07–12
77 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. FcγR- and CD9-dependent synapse-engulfing microglia in the thalamus drive cognitive impairment following cortical brain damage in mice.
  2. Antibodies sculpt adult brain circuits.
  3. Metabolic and epigenetic regulation of microglia memory in neurological disorders.
  4. The Wiskott-Aldrich Syndrome protein (WASp) contribution to microglial phagocytic function and neurodevelopmental support.
  5. Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.
  6. ACE2 deficiency alters brain RAS signaling to induce pro-inflammatory microglial remodeling and Worsen Parkinson's disease pathology.
  7. Tertiary lymphoid structures in neuroinflammation coordinate neuroimmune homeostasis and pathological progression.
  8. Astrocyte-to-microglia purinergic signaling mediates synaptic shielding and promotes neuronal activity.
  9. Senescent cells accumulate lipid droplets.
  10. Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.
  11. Protocol for evaluating microglial phagocytosis in situ in mouse hippocampal slices.
  12. Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
  13. Spinal cord microglia exhibit a dysfunctional response to myelin damage.
  14. Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection.
  15. Glial Cysteine Cathepsins: From Homeostasis to Neurodegeneration.
  16. Functional deficits in immortalized microglial cell lines limit their utility for modeling neuroinflammation.
  17. Glycosylation in Alzheimer's disease.
  18. Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.
  19. Inflammatory alterations mediate tau-associated neurodegeneration.
  20. Exhausted CD8+ T cell subsets differ a TAD.
  21. Age-associated neuronal micronuclei formation and transfer to microglia.
  22. IL-10 and β-endorphin: A paradoxical loop of microglial clearance in Alzheimer's disease.
  23. Microglial synaptic pruning in early Alzheimer's disease: emerging roles of the IL-1β-NLRP3 axis.
  24. Targeting IL-33 in Precision Neuroimmunology: Cellular Mechanisms and Therapeutic Strategies for CNS Disorders.
  25. TDP-43 dysfunction facilitates the pathological conversion of tau.
  26. ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.
  27. Calcium signaling in human and mouse microglia exhibit differential susceptibility to phytocannabinoids.
  28. Joint trajectories of brain atrophy, white matter hyperintensities and cognition quantify brain maintenance.
  29. Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.
  30. Reshaping the immune landscape: next-generation microglia-targeted therapies for Alzheimer's disease.
  31. Neutrophil extracellular traps exacerbate blood-brain barrier disruption in neuromyelitis optica spectrum disorder.
  32. Unveiling the Functional Role of KIF21B in Microglia Inflammatory Response.
  33. Glia orchestrate neural circuit development.
  34. Dense CRISPR Mapping of the WAVE Complex Identifies Pharmacological Modulators of AD-Linked Myeloid Migration.
  35. Microglial DNA G-quadruplex accumulation is associated with altered autophagy-related responses and aggravated ischemic brain injury.
  36. Matrix metalloprotease-9 modulates microglial/macrophage responses in murine brain demyelination.
  37. Gangliosides in the 21st century: therapeutic prospects for the brain and spine.
  38. Activity-dependent lipid droplet biogenesis and turnover regulate synaptic integrity.
  39. Integrating morphology and gene expression of neural cells in unpaired single-cell data using GeoAdvAE.
  40. Grey matter degeneration during multiple sclerosis is linked to activation of neuronal necroptosis by oxidized phosphatidylcholines.
  41. Circadian screening of neutrophils identifies therapeutic targets in multiple sclerosis.
  42. C1q and immunoglobulins mediate activity-dependent synapse loss in the adult brain.
  43. Neuropathic pain through the perspective of microglia-neuron interactions: a translational review for clinicians.
  44. Microglial P2ry12 in the Basolateral Amygdala Underlies Neuropathic Pain-Induced Anxiety.
  45. Microglia-mediated synaptic pruning in neural circuit remodeling: multidimensional control in homeostasis and neuropathology.
  46. Microglia derived from human induced pluripotent stem cells are regulated by osteopontin, an endogenous extracellular matrix protein maintaining immune homeostasis.
  47. CSF1R inhibition following antibody mediated demyelination has limited impact on remyelination.
  48. Corrigendum to "Chrysin reprograms microglial metabolism and function via targeting SYK to alleviate the symptoms of Alzheimer's disease" [J. Ethnopharmacol. (2026) 122056].
  49. Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.
  50. Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
  51. Correction: SIRT2 Inhibition promotes microglia LC3-associated phagocytosis via NRF2/CD36 after the experimental subarachnoid hemorrhage.
  52. Ontological Analysis of Brain Proteostasis Highlights the Sex-Dependent Trajectory of ApoE Isoform-Specific Regulation.
  53. Reconstituting central nervous system niche cues partially restores homeostatic-like features in cultured murine primary microglia.
  54. Addendum: In situ architecture of the human prohibitin complex.
  55. Antibiotics promote susceptibility to C. difficile infection through a CCR5-dependent immune response.
  56. Uremic toxins promote renal fatty acid synthesis and fibrosis via activating aryl hydrocarbon receptor.
  57. Modular brain networks shape amyloid-driven tau spread and cognitive decline.
  58. Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
  59. High-throughput whole-brain scattering imaging resolves amyloid plaques through clearing-assisted contrast modulation.
  60. Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8+ T cell responses and promoting tertiary lymphoid structure formation.
  61. The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.
  62. The NORAD -pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes.
  63. Chronic intermittent hypoxia impairs glymphatic function in male mice through ENT-dependent adenosine dysregulation.
  64. Clarity in clearance pathways.
  65. Mesothelial Plasticity Specifies a Pleural Immune Circuit that Orchestrates Lung Regeneration.
  66. Notch Signaling Reprograms Glial Lipid Metabolism to Promote Hypoxia Resistance.
  67. Zinc as a phase-specific therapeutic target in hypoglycemia-induced brain injury.
  68. Author Correction: A route for cerebrospinal fluid flow through leptomeningeal arterial-venous overlaps enables macromolecule and fluid shunting.
  69. Optimized Midbrain Organoid Transplantation Restores Dopaminergic Nigrostriatal Pathway and Motor Function in Parkinson's Disease Mouse Model.
  70. Histone chaperone HIRA regulates adiponectin expression and obesity-associated adipose expansion by facilitating Pol II pause release.
  71. Age-associated niche remodeling drives dental pulp progenitor dysfunction and fibrosis.
  72. Bridging veins govern discrepancy of CSF efflux into dura mater in mice.
  73. Reduced Soluble Ubiquilin2 in Amyotrophic Lateral Sclerosis Carrying Ubiquilin2 (P494L) Mutation: Clinicopathological and Biochemical Evidence From an Autopsy Case.
  74. Glutamate carboxypeptidase II activation in astrocytes mediates glymphatic impairment and cognitive vulnerability in the aging brain following surgery.
  75. Virtual memory CD8⁺ T cells in aging: heterogeneity, bystander protection, inflammatory potential, and inhibitory regulation.
  76. Tau-ing and fro-ing: the tanycytic shuttle in neurodegeneration.
  77. Thymus-derived myeloid programs track microglial tolerance states across human cohorts.
  1. Nat Commun. 2026 Jul 09.
    FcγR- and CD9-dependent synapse-engulfing microglia in the thalamus drive cognitive impairment following cortical brain damage in mice.
    Ken Matoba, Takahiro Kochi, Oluwaseun Fatoba, Md Sorwer Alam Parvez, Inssaf Berkiks, Yassin R Mreyoud, Harrison Strong, Jana H Badrani, Hency Patel, Yoshiko Nagaoka-Kamata, Masakazu Kamata, Hiroshi Tsujioka, Toshihide Yamashita, David K Crossman, Minae Niwa, Shin-Ichi Kano.
      Chronic neuroinflammation gives rise to diverse microglial states across the brain, yet how region-specific microglial remodeling contributes to cognitive dysfunction remains unclear. Here we report that synapse-engulfing microglia in the thalamus drive cognitive impairment after cortical brain damage in mice, primarily studied in females. Region-specific manipulations of microglia during the chronic phase show that reactive microglial changes in the thalamus, but not in the hippocampus, impair recognition memory. Single-cell RNA sequencing reveals an enrichment of synapse-engulfing CD9hi microglia in the thalamus. Antibody-based CD9 blockade in the thalamus, as well as microglia-selective CD9 disruption, rescues thalamic synaptic loss, restores neuronal activity, and improves recognition memory. Further analysis shows that the blood-brain barrier disruption and subsequent γ-immunoglobulin (IgG) extravasation facilitate the generation of CD9hi microglia in an Fcγ receptor III-dependent manner. These findings demonstrate that the induction of synapse-engulfing CD9hi microglia in the thalamus by IgG/FcγRIII signaling drives recognition memory deficits following cortical damage.
    DOI:  https://doi.org/10.1038/s41467-026-74904-1
  2. Science. 2026 Jul 09. 393(6807): 143-144
    Antibodies sculpt adult brain circuits.
    Lauritz Miarka, Marco Prinz.
      Immune cells target hyperactive neurons to eliminate synaptic connections.
    DOI:  https://doi.org/10.1126/science.aei8076
  3. J Leukoc Biol. 2026 Jul 03. pii: qiag085. [Epub ahead of print]118(7):
    Metabolic and epigenetic regulation of microglia memory in neurological disorders.
    Xiaoya Wang, Yunpeng Jia, Xinyi Yan, Youwei Wang.
      As tissue-resident innate immune cells of the central nervous system, microglia are capable of acquiring innate immune memory-a persistent state of functional reprogramming triggered by prior stimuli. This memory typically manifests as 3 distinct phenotypes: trained immunity, immune tolerance, and immune exhaustion. In this review, we synthesize current knowledge on the metabolic and epigenetic mechanisms that govern these 3 forms of microglial innate immune memory. We further summarize and discuss how each phenotype is induced in microglia and its respective pathophysiological roles in neurological disorders. Owing to their slow turnover and unique tissue-resident characteristics, microglia sustain long-lasting memory states that can profoundly influence the trajectory of neuroinflammation and neurodegeneration. Finally, we highlight the bidirectional effects of microglial immune memory on disease progression, discuss emerging therapeutic strategies aimed at modulating these memory states, and outline key translational challenges that remain to be addressed.
    Keywords:  epigenetic reprogramming; innate immune memory; microglia; neurodegenerative diseases; neuroinflammation
    DOI:  https://doi.org/10.1093/jleuko/qiag085
  4. J Neuroinflammation. 2026 Jul 07.
    The Wiskott-Aldrich Syndrome protein (WASp) contribution to microglial phagocytic function and neurodevelopmental support.
    Serena Seminara, Aurora Bianchi, Davide Comolli, Marco Spreafico, Wenjie Liao, Hemanta Sarmah, Grazia Iannello, Barbara Corneo, Gianluigi Forloni, Elisa R Zanier, Massimiliano De Paola, Alessandro Fantin, Stefano Fumagalli.
      Myeloid progenitor cells colonize the brain during embryogenesis and differentiate in microglia. Microglia shape neuronal wiring during development and maintain brain homeostasis in adulthood, both actions requiring intact cytoskeletal functionality. The Wiskott-Aldrich syndrome protein (WASp) mediates cytoskeletal dynamics of peripheral myeloid cells, suggesting a similar role in microglia. To investigate WASp's role in microglia, we impaired WASp function in human induced pluripotent stem cells-derived microglia (iMicro) and zebrafish embryos.WASp colocalized with the actin cytoskeleton at membrane ruffles in phagocytic iMicro and appeared required for their phagocytic function. When co-cultured with neuronal cells, the support of iMicro with defective WASp function to neuronal wiring was impaired. Similarly, zebrafish embryos exposed to WASp inhibition showed brain accumulation of uncleared apoptotic bodies, reduced brain colonization of myeloid cells, and impaired sensorimotor response to mechanical stimuli.These findings identify WASp as a regulator of microglial phagocytosis and cytoskeletal dynamics, with implication in neuronal wiring during neurodevelopment.
    Keywords:  Microglia; Neurodevelopment; Primary immunodeficiency; Wiskott-Aldrich Syndrome protein (WASp)
    DOI:  https://doi.org/10.1186/s12974-026-03948-3
  5. Nat Neurosci. 2026 Jul 08.
    Microglial TDP-43 mediates myelin refinement and represses Tyrobp cryptic exon inclusion in mice.
    Anne-Claire Compagnion, Andranik Ivanov, Anil Rana, Felipe Espinoza, Thomas Sandmann, Fanny S Martineau, Katia Monsorno, Roberta Facchinetti, Alessandro Matera, Lionel Rougé, Fernando González Ibáñez, Clarissa Catale, Matteo Bizzotto, Sonia Garel, Michela Matteoli, Yutaro Kashiwagi, Ryuta Koyama, Christian Haass, Marie-Eve Tremblay, Dieter Beule, Ileana Jelescu, Valerio Zerbi, Gilbert Di Paolo, Rosa C Paolicelli.
      TDP-43 proteinopathy is a hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis and frontotemporal dementia where mislocalization of TDP-43 has been observed in neurons and glial cells. However, the role of TDP-43 in microglia and the consequences of its loss of function remain unexplored. Combining magnetic resonance imaging, and confocal, and electron microscopy, we uncovered structural changes and myelin abnormalities in the early postnatal brain of mice lacking microglial TDP-43. Spatial transcriptomics further revealed an enriched interferon-responsive signature associated with oligodendrocyte dysfunction. Early depletion of microglial TDP-43 led to motor deficits in adult mice. Mechanistically, knocking out TDP-43 impaired microglial ability to engulf and degrade myelin. It also led to cryptic exon inclusion in the Tyrobp mRNA, resulting in truncated DAP12 protein, thus causing defective TREM2 signaling. Our findings reveal a role for TDP-43 in regulating the TREM2-DAP12 axis in mice, highlighting a previously unrecognized mechanism through which TDP-43 controls microglial function.
    DOI:  https://doi.org/10.1038/s41593-026-02348-3
  6. Neuroscience. 2026 Jul 08. pii: S0306-4522(26)00438-0. [Epub ahead of print]611 277-297
    ACE2 deficiency alters brain RAS signaling to induce pro-inflammatory microglial remodeling and Worsen Parkinson's disease pathology.
    Tingting Liu, Yuheng Ren, Juntang Lin, Jianshe Wei.
       BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation and dopaminergic neuron loss. Resident central nervous system (CNS) microglia dynamically switch between pro- and anti-inflammatory states under pathological stress. While cerebral renin-angiotensin system (RAS) participates in PD progression, the molecular connection linking brain RAS to microglial inflammatory remodeling remains undetermined.
    METHODS: We combined multi-omics mining of public GEO PD datasets with multiple in vitro and in vivo experiments, including CRISPR-generated ACE2-knockout BV2 microglia, MPTP-treated wild-type and Ace2+/- heterozygous mice, alongside western blot, immunohistochemistry and immunofluorescence, to unravel RAS-mediated microglial regulation in PD.
    RESULTS: MPTP robustly triggers pro-inflammatory polarization of midbrain microglia. GSEA analysis of immune-related differential genes revealed enrichment in neuroinflammation, mitochondrial metabolism and antigen presentation pathways. We identified functional hub miRNAs and seven AGTR1-centered hub genes with tight ACE2-AGTR1 interaction. ACE2 deletion disturbs cerebral RAS balance, elevating Ang II and AGTR1 levels. Hyperactivated AGTR1 sequentially activates JAK1-STAT3-ERK, JNK-MAPK, PI3K-AKT-mTOR, Sirt1-FoxO1 and TLR4-Myd88 inflammatory axes, shifting microglia toward a pro-inflammatory phenotype and elevating neuronal injury markers. These data confirm ACE2 deficiency exacerbates PD pathology mainly via overactivated AGTR1 signaling.
    CONCLUSION: Disrupted brain RAS homeostasis induces pro-inflammatory microglial remodeling and worsens PD neurodegeneration. This study reveals novel pathogenic mechanisms and identifies promising therapeutic targets for PD treatment.
    Keywords:  Angiotensin-converting enzyme 2; Immune; Inflammation; Microglia; Parkinson’s disease
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.07.008
  7. J Neuroinflammation. 2026 Jul 10.
    Tertiary lymphoid structures in neuroinflammation coordinate neuroimmune homeostasis and pathological progression.
    Yan Zhang, Peishen Han, Xiaoling Zhang.
      The central nervous system (CNS) has long been considered immune privilege due to the blood-brain barrier, lack of traditional lymphatic drainage, and unique immune microenvironment. However, recent neuroimmunology research has demonstrated that the CNS maintains continuous communication with the peripheral immune system via meningeal lymphatic vessels, lymphoid systems, and border-associated macrophages. This paradigm shift has brought tertiary lymphoid structures (TLSs), ectopic lymphoid aggregates induced by chronic inflammation, infection, or tumors, into focus as key players in neuroimmune interactions. TLSs exert a dual effect in neuroinflammation. In infectious diseases like viral encephalitis, they promote local antibody production and T cell responses, aiding pathogen clearance. In contrast, in multiple sclerosis, autoimmune encephalitis, Alzheimer's disease, and Parkinson's disease, TLSs may sustain chronic inflammation, drive autoantibody production, and accelerate neurodegeneration. This review systematically summarizes the composition, induction mechanisms, and functional heterogeneity of TLSs across neurological diseases. We discuss their protective versus pathogenic roles in neuroinflammation and highlight their diagnostic value and therapeutic potential, aiming to provide new insights for precision intervention in neuroimmunological disorders.
    Keywords:  Disease progression; Neuroimmune homeostasis; Neuroimmune interaction; Neuroinflammation; Tertiary lymphoid structures
    DOI:  https://doi.org/10.1186/s12974-026-03961-6
  8. bioRxiv. 2026 Jul 05. pii: 2026.07.05.735345. [Epub ahead of print]
    Astrocyte-to-microglia purinergic signaling mediates synaptic shielding and promotes neuronal activity.
    Koichiro Haruwaka, Juan Liu, Yue Liang, Shinya Matsumoto, Dimitrios Kleidonas, Wu Shi, Shunyi Zhao, Yong U Liu, Anthony D Umpierre, Zhongcong Xie, Miao Jing, Long-Jun Wu.
      How glial cells sense and regulate neuronal hypoactivity remains poorly understood. Using in vivo imaging in anesthetized, sleeping, and behaving mice, we identified a glial purinergic signaling mechanism that converts neuronal hypoactivity into local circuit regulation. Cortical hypoactivity increased spatially confined ATP release through astrocytic pannexin-1 hemichannels, which were structurally enriched near perisomatic parvalbumin-positive boutons. Local ATP release directed microglial process movement and stabilized bulbous endings through microglial P2Y12 signaling, accompanied by localized Ca²⁺ activity in microglial processes. Disruption of astrocytic pannexin-1 or microglial P2Y12 impaired bulbous-ending stabilization and abolished rebound increases in neuronal activity during emergence from anesthesia. Similar ATP release and bulbous-ending formation were observed during chemogenetic neuronal silencing or natural sleep in freely behaving mice. These findings identify astrocyte-to-microglia purinergic signaling as a mechanism that converts neuronal hypoactivity into synapse-selective microglial regulation of circuit activity.
    DOI:  https://doi.org/10.64898/2026.07.05.735345
  9. Aging (Albany NY). 2026 Jul 01. 18(1): 768-786
    Senescent cells accumulate lipid droplets.
    Noa Rachmian-Cooper, Riva Shmulevich, Hagay Akiva, Sarka Pokorna, Bareket Dassa, Ulysse Cherqui, Sergey Malitsky, Maxim Itkin, Binyamin Amichai Kliger, Inna Goliand, Tomer Meir Salame, Valery Krizhanovsky.
      Senescent cells (SnCs) are growth-arrested yet remain metabolically active and undergo extensive reprogramming to support their survival and the Senescence-Associated Secretory Phenotype (SASP). SnCs undergo key metabolic changes, including increased glycolysis, altered mitochondrial function and dysregulated lipid metabolism. While these metabolic changes are increasingly recognized, a comprehensive understanding of how they contribute to the pathophysiological effects of SnCs is still lacking. Here, through metabolic profiling, we identified elevated levels of glycolytic metabolites in SnCs, which coincided with an increased presence of lipid metabolites, specifically triacylglycerol derivatives, the precursors of lipid droplets (LDs). We show that SnCs accumulate LDs in a classical primary human fibroblast model, and that senescent microglia upregulate LDs markers in a mouse model of Alzheimer's disease (AD), where they play a pathological role. Single-nucleus analysis of brains from AD patients further revealed an elevated levels of LDs markers in senescent brain cells, including microglia. Previous studies implicated both lipid droplet-containing microglia and senescent microglia in AD pathology. Our findings provide evidence that these may represent the same cell population, in which the co-occurrence of LDs accumulation and the senescent state jointly contribute to their disease-promoting properties.
    Keywords:  Alzheimer’s disease; aging; lipid droplets; metabolism; senescence
    DOI:  https://doi.org/10.18632/aging.206390
  10. Cell. 2026 Jul 09. pii: S0092-8674(26)00655-0. [Epub ahead of print]189(14): 4193-4224
    Recent advances in Alzheimer's disease: From molecular mechanisms to therapeutic strategies.
    Michelle D Rudman, Jason D Ulrich, David M Holtzman.
      Alzheimer's disease (AD) remains the leading cause of dementia worldwide and an escalating global health crisis. The hallmark amyloid plaques and neurofibrillary tangles (NFT) are now known to be accompanied by a complex array of pathologies that culminate in neurodegeneration and cognitive decline. New disease-modifying therapies for AD can now slow cognitive decline through the removal of amyloid plaques from the brain, but treatments to stop or prevent cognitive impairment remain elusive. In this review, we summarize the most recent updates in AD research on pathologic disease mechanisms and therapeutic strategies, highlighting advancements in apolipoprotein E (APOE) biology, neuroimmunology, biomarker discovery, and initial experience with new disease-modifying therapies. These important discoveries are revolutionizing AD diagnosis and treatment and provide hope for a future where AD is not only treatable but also preventable.
    DOI:  https://doi.org/10.1016/j.cell.2026.06.006
  11. STAR Protoc. 2026 Jul 10. pii: S2666-1667(26)00349-7. [Epub ahead of print]7(3): 104696
    Protocol for evaluating microglial phagocytosis in situ in mouse hippocampal slices.
    Summer G Paulson, Fritz W Lischka, Jeremy D Rotty.
      Microglia are the primary phagocytes of the central nervous system (CNS). Here, we present a protocol for microinjecting opsonized particles into mouse hippocampal slices followed by two-photon time-lapse microscopy. We describe steps for preparing components, removing the brain, creating coronal slices, and incubating samples. We then detail procedures for analyzing microglial morphology and cell process dynamics with microinjected particles. We also provide several common potential problems encountered during the protocol alongside troubleshooting strategies to counter them. For complete details on the use and execution of this protocol, please refer to Paulson et al.1.
    Keywords:  Cell Biology; Microscopy; Neuroscience
    DOI:  https://doi.org/10.1016/j.xpro.2026.104696
  12. Neurosci Bull. 2026 Jul 07.
    Dysfunctional Mitochondria in Microglia Drive Cognitive Aging and Neurodegeneration via cGAS-STING.
    Guanqin Ma, Erlin Wang, Xiaoxu Yan, Xiang-Xiong Xu, Xiaohong Li, Xueling Ma, Wan-Hua Yang, Jianxiong Zeng, Xiaochun Xie.
      Mitochondrial dysfunction induces metabolic dysregulation in immune cells that is etiologically associated with age-related brain disorders. However, how dysfunctional mitochondria in microglia-the brain-resident immune cells-initially affect neurological function remains incompletely understood. Here, we demonstrate that dysfunctional mitochondria in microglia, induced by the conditional knockout of mitochondrial transcription factor A, act as triggers of metabolic dysregulation, cognitive aging, and neurodegeneration in adult mice. Notably, this metabolic disturbance induces a microglial transition to states associated with neuroinflammatory activation and neurodegenerative disease, thereby triggering multiple layers of pathological cascade reactions among other brain cell types and shaping a neuroinflammaging state at single-cell resolution. Mechanistically, mitochondrial dysfunction activates the innate immune cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway, which mediates immune sensing of cytosolic DNA in microglia and contributes to inflammaging. We further present evidence that combined treatment aimed at restoring metabolic homeostasis and inhibiting neuroinflammatory cGAS-STING partially rescues age-related neurological dysfunction in mice. Collectively, our findings reveal a link between mitochondrial dysfunction in microglia and cognitive aging, underscoring the significance of tightly regulated metabolism in age-associated neurological diseases.
    Keywords:  Microglia; Mitochondrial dysregulation; Neurodegeneration; Neuroinflammaging; cGAS–STING
    DOI:  https://doi.org/10.1007/s12264-026-01657-8
  13. J Neuroimmunol. 2026 Jul 02. pii: S0165-5728(26)00171-2. [Epub ahead of print]419 579022
    Spinal cord microglia exhibit a dysfunctional response to myelin damage.
    Matthew C Zupan, Jack M Petersen, Addison C Stover, Corbin A Fairchild, Nishama De Silva Mohotti, Meredith D Hartley.
      Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) that affects both the brain and spinal cord, although the brain has historically received greater attention. In the inducible, oligodendrocyte-specific knockout model of Myrf, which results in white matter damage to both the brain and spinal cord, our laboratory previously demonstrated that the brain undergoes remyelination following white matter damage, whereas the spinal cord has limited remyelination. We also observed that brain microglia display a much stronger activation than spinal cord microglia. Microglia regulate remyelination by clearing myelin debris, processing resulting lipids, and modulating the inflammation response. Therefore, we hypothesized that microglia are involved in limiting spinal cord remyelination in this model, either by having a limited phagocytosis response or by causing neuroinflammation. To test our hypothesis, we characterized microglial phenotypes during demyelination in both brain and spinal cord in the Myrf demyelination model. The brain exhibited an earlier microglial activation response and showed a higher percentage of microglia expressing phagocytic markers, suggesting a primed state for responding to damage. In contrast, spinal cord microglia showed a delayed increase in cells expressing phagocytic markers, sustained inflammation, and a predominately ameboid morphology during demyelination. Together, these findings in the Myrf demyelination model indicate that brain microglia mount a timely and coordinated response to demyelination that supports remyelination, whereas spinal cord microglia adopt a dysfunctional phenotype that likely contributes to reduced myelin repair.
    Keywords:  Brain; Demyelination; Inflammation; Microglia; Phagocytosis; Spinal cord
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.579022
  14. bioRxiv. 2026 Jul 03. pii: 2026.07.02.736124. [Epub ahead of print]
    Humanized tauopathy chimeras uncover microglial and lncRNA strategies for neuroprotection.
    Wenhui Qu, Li Fan, Minwoo Wendy Jang, Pearly Ye, Ethan Cordes, Abulimiti Aikedan, Wen Hu, Ravi Kumar Nagiri, Man Ying Wong, Wenjie Luo, Mathew Blurton-Jones, Hagen U Tilgner, Anna Orr, Shiaoching Gong, Li Gan.
      Human genetics implicates innate immunity as a key modifier of tau toxicity, yet human-specific neuroimmune mechanisms remain difficult to test in vivo. Here, we developed HuMiNAX, the first humanized iPSC-based neuroimmune xenograft model of tau-associated neurodegeneration, enabling human microglia to interact with human neurons and astrocytes in the adult mouse brain. In HuMiNAX, tau seeding induced aggregation only in mutation-carrying human neural grafts, causing neuron loss and inflammatory activation of human microglia. Progranulin-overexpressing human microglia dampened tau-associated inflammation, preserved neurons, and restored neuronal gene-expression and RNA-splicing programs, supporting microglial control of neuronal resilience. CRISPRi knockdown of the human-specific lncRNA HNRNPK-AS1 also protected neurons in HuMiNAX. These findings establish HuMiNAX as a human neuroimmune model of tauopathy and identify microglial and RNA-mediated strategies of neuronal resilience.
    DOI:  https://doi.org/10.64898/2026.07.02.736124
  15. Cell Mol Neurobiol. 2026 Jul 09.
    Glial Cysteine Cathepsins: From Homeostasis to Neurodegeneration.
    Anja Suhadolc, Selena Horvat, Janko Kos, Anja Pišlar.
      Glial cells, namely microglia, astrocytes, and oligodendrocytes, play crucial roles in maintaining homeostasis in the central nervous system and orchestrating responses to injury, infection, and disease. Among the molecular regulators of glial function, cysteine cathepsins have emerged as key modulators of both physiological and pathological processes. These lysosomal peptidases are traditionally known for their housekeeping roles in protein degradation; however, accumulating evidence highlights their broader involvement in antigen presentation, microglial and astrocyte reactivity, inflammatory signalling, apoptosis, and myelination. Under normal conditions, cysteine cathepsins support essential functions in the central nervous system, including immune surveillance and tissue remodelling. Conversely, their dysregulation, characterized by overexpression, increased enzymatic activity, or mislocalization, can promote neuroinflammation and neurodegeneration, contributing to the pathogenesis of disorders such as Alzheimer's disease and multiple sclerosis. This review provides a comprehensive synthesis specifically focused on the diverse roles of cysteine cathepsins across major glial cell types, systematically summarizing current knowledge in microglia, astrocytes, and oligodendrocytes. We emphasize their cell type-specific, context-dependent, protective, and deleterious functions. Furthermore, we discuss mechanistic links between cysteine cathepsin activity and neurodegenerative processes and evaluate the therapeutic potential and current limitations of selectively targeting glial cysteine cathepsins. A deeper understanding of the context-dependent dual roles of these enzymes in brain physiology and pathology is critical for designing targeted interventions that could mitigate neuroinflammation and neurodegeneration.
    Keywords:  Cysteine cathepsins; Glial cells; Neurodegeneration; Neuroinflammation; Therapeutic targets
    DOI:  https://doi.org/10.1007/s10571-026-01776-w
  16. Brain Res. 2026 Jul 08. pii: S0006-8993(26)00322-7. [Epub ahead of print] 150462
    Functional deficits in immortalized microglial cell lines limit their utility for modeling neuroinflammation.
    Xiaoyan Xiong, Qilong Wu, Xuecheng Qiu, Suning Ping.
       BACKGROUND: Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in brain development and disease. Although primary microglia serve as the gold standard for in vitro investigations, their limited proliferative capacity has driven the widespread use of immortalized cell lines, with the BV2 cell line being the most prominent. However, accumulating evidence demonstrates that BV2 cells display profound functional discrepancies relative to primary microglia.
    AIM: To generate optimized lentivirus-mediated human telomerase reverse transcriptase (hTERT)-immortalized microglial cell lines, and to compare their functional similarity to primary microglia against the BV2 cell line.
    METHOD: We established two murine microglial cell lines (CM-A1, CM-A3) via lentiviral hTERT transduction. Cellular characteristics including CD11b expression, cell morphology, phagocytic activity, and inflammatory gene transcriptional responses to lipopolysaccharide (LPS) were comprehensively evaluated.
    RESULTS: CM-A1 and CM-A3 exhibited higher CD11b surface expression and basal phagocytic capacity relative to BV2 cells. Nevertheless, all immortalized cell lines presented notable functional defects, including reduced CD11b surface abundance, blunted morphological transformation following LPS stimulation, loss of LPS-triggered phagocytic upregulation, and dampened induction of pro-inflammatory genes.
    CONCLUSIONS: These findings reveal that both hTERT-immortalized microglial lines and BV2 fail to recapitulate critical dynamic functional responses observed in primary microglia, highlighting the importance of cautious model selection in neuroimmunological research.
    Keywords:  BV-2; Microglia; Neuroinflammation; Phagocytosis; hTERT
    DOI:  https://doi.org/10.1016/j.brainres.2026.150462
  17. Nat Neurosci. 2026 Jul;29(7): 1528
    Glycosylation in Alzheimer's disease.
    Shari Wiseman.
      
    DOI:  https://doi.org/10.1038/s41593-026-02373-2
  18. J Neuroinflammation. 2026 Jul 07.
    Cortistatin as a modulator of inflammatory and mitochondrial dysfunction in Huntington´s disease.
    Pilar González-García, Ignacio Serrano-Martínez, Eliana Barriocanal-Casado, Alejandro Cuenca-Martagón, Pablo Vargas-Rodríguez, Norma Adán, Irene Forte-Lago, Juan Carlos Morales, Patricia Gomez-Suaga, Júlia Bonet-Freixinet, Silvia Ginés, Luis C López, Elena González-Rey.
       BACKGROUND: Huntington's disease (HD) is an inherited, fatal neurodegenerative disorder caused by expanded CAG repeats in the Huntingtin gene, leading to progressive motor, cognitive and psychiatric impairment. Despite its monogenic origin, HD pathogenesis is multifactorial, with convergent contributions from mitochondrial dysfunction, oxidative stress, synaptic failure, and chronic neuroinflammation, which drive neuronal vulnerability and degeneration, particularly within the striatum. Current clinical management remains exclusively symptomatic and fails to halt disease progression, highlighting a critical unmet need for strategies targeting fundamental pathogenic mechanisms. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory properties and has recently been implicated in the regulation of mitochondrial function. Notably, cortistatin deficiency is associated with exacerbated systemic and central inflammation, suggesting that impaired cortistatin signaling may contribute to neurodegeneration. However, its role in HD pathophysiology remains unexplored.
    METHODS: We performed a comprehensive reanalysis of publicly available transcriptomic datasets from HD patients to assess cortistatin expression, followed by validation in experimental HD models. Wild-type and cortistatin-deficient mice treated with 3-nitropropionic acid served as pharmacological HD models, enabling evaluation of cortistatin-dependent disease severity. Behavioral assessments, glial and oxidative markers, and immune factors were evaluated to determine neurological dysfunction and inflammatory responses. Complementary in vitro studies were conducted in striatal neurons expressing mutant huntingtin to examine mitochondrial integrity, inflammatory signaling, metabolic function, and mitochondria-endoplasmic reticulum interactions.
    RESULTS: Cortistatin expression was significantly reduced in postmortem HD human brains and across experimental HD models. Cortistatin deficiency exacerbated motor deficits, neuropathological alterations, inflammatory activation, and neuronal vulnerability in HD context. At the cellular level, reduced cortistatin expression was accompanied by amplified inflammatory signaling, disrupted mitochondrial integrity, impaired mitochondria-endoplasmic reticulum interactions, and increased oxidative stress. Conversely, exogenous cortistatin administration attenuated inflammatory mediator production, preserved mitochondrial structure, and improved redox balance in mutant huntingtin-expressing striatal neurons.
    CONCLUSIONS: Our findings identify cortistatin deficiency as a previously unrecognized contributor to HD pathogenesis and establish cortistatin as a key modulator of neuroinflammation and mitochondrial homeostasis. These results support cortistatin-based strategies as a promising disease-modifying therapeutic avenue for HD and related neurodegenerative disorders characterized by inflammatory activation and mitochondrial impairment.
    Keywords:  Cortistatin; Huntingtin; Huntington’s disease; Mitochondria; Neurodegenerative diseases.; Neuroinflammation; Oxidative stress
    DOI:  https://doi.org/10.1186/s12974-026-03947-4
  19. Brain Commun. 2026 ;8(4): fcag242
    Inflammatory alterations mediate tau-associated neurodegeneration.
    Patrick J Lao, Seonjoo Lee, Daniel Talmasov, Dina Dass, Ndubisi Chikwem, Aubrey Johnson, Anna Smith, Diana Guzman, Amarachukwu Okafor, Hannah Houlihan, Lauren Heuer, Thairi Sanchez, Andrea Maldonado, Catherine Palacios, Samantha Rossano, Howard Andrews, Christiane Reitz, William C Kreisl, James M Noble, Yasir H Qureshi, Scott A Small.
      Microglia monitor and respond to the brain's microenvironment to maintain homeostasis. However, in Alzheimer's disease and related dementias, chronically pro-inflammatory microglia may contribute to pathology. We hypothesized that inflammatory alterations, measured as microglia density via 18 kDa translocator PET, would be elevated with a topography similar to tau, be most strongly associated with tau compared to amyloid and neurodegeneration, and mediate pathways among amyloid, tau and neurodegeneration. Participants (21 cognitively unimpaired, 25 cognitively impaired) from the Longitudinal Imaging of Microglial Activation in Different Clinical Variants of Alzheimer's Disease study underwent baseline amyloid PET (Florbetaben standard uptake value ratio), tau PET (MK6240 standard uptake value ratio), 18 kDa translocator PET (ER176 standard uptake value ratio) and structural MRI (grey matter volume). Biomarkers were quantified in 13 a priori regions of interest. Cognitive assessments and consensus diagnoses were performed at the Columbia Alzheimer's Disease Research Center with biomarker information when available to define cognitive impairment. We evaluated cross-sectional regional colocalization of microglia density and amyloid, tau and neurodegeneration biomarker elevations in cognitively impaired individuals compared to amyloid-negative cognitively unimpaired individuals, microglia density associations with amyloid, tau and neurodegeneration biomarkers and microglia density mediation pathways among amyloid, tau and neurodegeneration. Exploratory analyses were stratified by amyloid positivity. Across all cognitively impaired individuals with different underlying brain microenvironments to which microglia are sensitive, higher microglia density colocalized with greater tau (10 regions) more often than with amyloid (8 regions) and neurodegeneration (4 regions), was associated with greater tau (β = 0.29-0.67 in cingulate, lingual and parietal regions) and neurodegeneration (β = -3.6 to -0.14 in limbic and medial temporal regions), and mediated tau-associated neurodegeneration (β = -0.44 to -0.26 in limbic, temporal and parietal regions). In the context of amyloid-positivity, microglia may also mediate amyloid-associated tau (β = 0.24-0.25 in parietal regions) and tau spreading (β = 0.09-0.12 across progressive Braak stage regions), whereas amyloid may not be necessary for tau-associated neurodegeneration, particularly in limbic regions (β = -0.46 to -0.37 in amyloid-negative individuals with cognitive impairment alone). Glia may represent a promising target for intervening on tau-associated neurodegeneration across individuals with cognitive impairment.
    Keywords:  TSPO PET; amyloid; microglia; neurodegeneration; tau
    DOI:  https://doi.org/10.1093/braincomms/fcag242
  20. Nat Immunol. 2026 Jul 06.
    Exhausted CD8+ T cell subsets differ a TAD.
    Maegan K Murphy, Takeshi Egawa.
      
    DOI:  https://doi.org/10.1038/s41590-026-02583-7
  21. Front Aging Neurosci. 2026 ;18 1787252
    Age-associated neuronal micronuclei formation and transfer to microglia.
    Chihiro Maeda, Yusuke Kishi, Ikuko Takeda, Masafumi Muratani, Hiroaki Wake, Fuminori Tsuruta.
      Microglia, the resident immune cells of the central nervous system, dynamically respond to signals from their microenvironment, including adjacent neurons. Among these signals, nuclear contents released from damaged neurons have been implicated in triggering inflammatory microglial responses. Recently, we found that micronuclei (MNs) derived from neurons during the early postnatal stage act as intercellular mediators that alter the microglial characteristics. However, it remains unclear whether a similar mechanism occurs in the aging brain. In this study, we report that neuronal MNs are formed and transferred to microglia during aging. The neuronal nuclear envelope became fragile with aging and forms MNs in association with nuclear envelope invagination. Subsequently, neuronal MNs were taken up by adjacent microglia. In contrast to the developmental stage, microglia incorporating MNs exhibited extended processes during the aged stage. We also identified several candidate genes whose expression patterns were altered in microglia following MN incorporation. These findings suggest that MN incorporation alters the characteristics and functions of microglia in the aging brain. Our data propose an unrecognized neuron-to-microglia communication in the aged brain mediated by MN propagation.
    Keywords:  extracellular matrix; microglia; micronuclei (MN); neuron; nuclear envelope
    DOI:  https://doi.org/10.3389/fnagi.2026.1787252
  22. Rev Invest Clin. 2026 Jul 10. pii: S0034-8376(26)00016-1. [Epub ahead of print]78(4): 100049
    IL-10 and β-endorphin: A paradoxical loop of microglial clearance in Alzheimer's disease.
    Sana Esmaeeli.
      
    DOI:  https://doi.org/10.1016/j.ric.2026.100049
  23. Inflammopharmacology. 2026 Jul 11.
    Microglial synaptic pruning in early Alzheimer's disease: emerging roles of the IL-1β-NLRP3 axis.
    Arjun Singh Kaushik, Nitin Singh.
      Alzheimer's disease is a progressive neurodegenerative disorder characterized by early synaptic dysfunction that precedes overt neuronal loss and cognitive decline. While amyloid-β and tau pathologies have long dominated disease models, growing evidence highlights neuroinflammation as a critical driver of early pathological changes. In particular, microglia-mediated inflammatory signaling has emerged as a key regulator of synaptic integrity. This review focuses on the interleukin-1β (IL-1β)-NLRP3 inflammasome axis as a central mechanism linking innate immune activation to aberrant synaptic pruning in early Alzheimer's disease. Activation of the NLRP3 inflammasome in microglia by amyloid-β and related danger signals leads to caspase-1-dependent maturation and release of IL-1β. Elevated IL-1β amplifies inflammatory signaling, alters microglial phenotype, and promotes complement-mediated tagging of synapses, resulting in excessive elimination of functional synaptic connections. Experimental evidence from in vitro systems, transgenic mouse models, and pharmacological inhibition studies supports a causal role for this axis in synapse loss, impaired synaptic plasticity, and cognitive deficits. Importantly, these inflammatory and synaptic alterations occur at early disease stages, underscoring their relevance to disease initiation rather than late-stage neurodegeneration. The review further discusses the impact of IL-1β-NLRP3 signaling on neuronal network function, hippocampal plasticity, and cognitive performance, as well as its translational implications. Therapeutic strategies targeting inflammasome activation or IL-1β signaling show promise in preserving synaptic function in preclinical models. Overall, the IL-1β-NLRP3-synapse axis represents a compelling framework for understanding early Alzheimer's disease pathology and offers a rational target for early intervention strategies to slow disease progression.
    Keywords:  Alzheimer’s disease; IL-1β; Microglia; NLRP3 inflammasome; Neuroinflammation; Synaptic pruning
    DOI:  https://doi.org/10.1007/s10787-026-02335-x
  24. J Neuroimmune Pharmacol. 2026 Jul 10. pii: 34. [Epub ahead of print]21(1):
    Targeting IL-33 in Precision Neuroimmunology: Cellular Mechanisms and Therapeutic Strategies for CNS Disorders.
    Lili Li, Shuting Wang, Lian Duan, Luyu Zhang, Hongmu Yan, Yue Zhu, Luyang Tao, Yuan Gao.
      Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, has emerged as a pivotal regulator of neuroimmune interactions in the central nervous system (CNS). Acting through its receptor ST2, IL-33 orchestrates diverse immune responses by modulating microglial polarization, shaping T cell differentiation, activating type 2 innate lymphoid cells (ILC2s), and engaging mast cell-macrophage regulatory circuits. Across distinct neurological disorders, including epilepsy, stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), cerebral malaria, and glioma, IL-33 exerts both protective and pathogenic effects in a context-dependent manner. In epilepsy, IL-33 modulates neuroinflammation and neuronal excitability; in stroke, it attenuates acute neurovascular injury while influencing post-stroke remodeling; in AD, it enhances amyloid-β clearance and mitigates chronic neuroinflammation; in MS, it regulates autoimmune demyelination via T cell and innate immune pathways. These shared yet disease-specific mechanisms underscore IL-33's central role in neuroimmune homeostasis and its potential as a precision therapeutic target. Future research integrating multi-disease models, temporal disease staging, and single-cell multi-omics will be essential to define the conditions under which IL-33 modulation yields maximal therapeutic benefit.
    Keywords:  Central nervous system disorders; IL-33/ST2 signaling; Neuroimmune crosstalk; Neuroinflammation; Therapeutic strategies
    DOI:  https://doi.org/10.1007/s11481-026-10302-0
  25. Mol Neurodegener. 2026 Jul 04.
    TDP-43 dysfunction facilitates the pathological conversion of tau.
    Meghraj S Baghel, Grace D Burns, Margarita Tsapatsis, Aswathy Peethambaran Mallika, Anna Lourdes F Cruz, Tianyu Cao, Xiaoke K Chen, Isabel De La Rosa, Shaelyn R Marx, Yingzhi Ye, Shuying Sun, Tong Li, Jonathan P Ling, Philip C Wong.
      TDP-43 proteinopathy coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer's Disease (AD) and AD related dementia (ADRD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. Loss of TDP-43 splicing repression occurring during the early stage of neurodegenerative disease suggests that such loss could facilitate the pathological conversion of tau. Here, we report that TDP-43 loss-of-function (LOF) in forebrain neurons (Tau4R; CaMKII-CreER; Tardbpf/f mice) exacerbates tauopathy-dependent brain atrophy is associated with vulnerable neurons sensitive to caspase 3-dependent cleavage of endogenous tau. We demonstrate that TDP-43 LOF in human iPSC-derived cortical neurons promotes TDP-43 dependent cryptic splicing which precedes caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER; Tardbpf/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed correlates with caspase 3-dependent tau cleavage, accelerated tauopathy and the loss of vulnerable neurons deficient in TDP-43. Together, these results strongly support the view that TDP-43 dysfunction exacerbates tauopathy-dependent brain atrophy by promoting caspase 3-dependent endoproteolysis of tau, disclosing novel mechanistic insights and therapeutic targets for human tauopathies harboring the co-pathology of TDP-43.
    Keywords:  ADRD; Alzheimer’s disease; Caspase; Co-pathology; FTD; Mouse model; Neurodegeneration; TDP-43; Tau; Tauopathy; Vulnerable neuron
    DOI:  https://doi.org/10.1186/s13024-026-00968-8
  26. Mol Neurodegener. 2026 Jul 07.
    ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.
    Michael R Strickland, David M Holtzman.
      Apolipoprotein E (ApoE) is highly expressed in the central nervous system (CNS) where it plays a critical role in lipid homeostasis and in the etiology of Alzheimer's disease (AD) and related diseases. ApoE associates with lipids to form discoidal and spherical lipoproteins that carry lipid and protein cargo throughout the brain. In this review, we focus on the significance of ApoE as a lipoprotein and how this impacts the function of ApoE in homeostasis and disease. In the CNS, ApoE is primarily secreted by astrocytes, though other cells, including microglia, secrete ApoE under certain conditions. ApoE lipoproteins (LpE) secreted by different cell types carry unique lipids and proteins which alter its function. The lipidation state of ApoE alters its conformation and binding to different receptors and, consequently, its ultimate impact on AD pathology. Most dramatically, nonlipidated ApoE has minimal binding to the low density lipoprotein receptor (LDLR), while lipidation of ApoE restores high affinity binding to LDLR. Furthermore, the degree of ApoE lipidation also impacts ApoE receptor binding through changes in protein conformation and stoichiometry of ApoE molecules per lipoprotein. The lipidation state of ApoE also alters its interaction with amyloid-β and tau, the proteins involved in forming amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD. LpE also carry lipids and proteins that alter the function of ApoE. Understanding how the lipid and protein content of LpE interacts with the conformational changes that occur with lipidation and maturation are essential to mechanistically understanding the role of ApoE in homeostasis and disease pathogenesis. In this review, we highlight the current understanding of LpE biology in the CNS and delineate important areas of future research.
    Keywords:  Alzheimer’s disease; Apolipoprotein; Apolipoprotein E; Central nervous system; Lipoprotein
    DOI:  https://doi.org/10.1186/s13024-026-00970-0
  27. Cell Commun Signal. 2026 Jul 09.
    Calcium signaling in human and mouse microglia exhibit differential susceptibility to phytocannabinoids.
    Ivana Pilchova, Andrea Fleig, Reinhold Penner.
       BACKGROUND: Neurological disorders affect over 40% of the global population and are driven in part by microglia-mediated neuroinflammation that depends on calcium (Ca²⁺) signaling. Cannabis-derived compounds (CBx) modulate microglial activation and cytokine release, however, the impact of understudied CBx on Ca2+ signaling pathways controlling inflammatory responses remains largely unknown.
    METHODS: Here, we systematically examined the effects of over 22 CBx on key microglial Ca2+ signaling pathways. Using pharmacological modulators, live-cell Ca2+ imaging, immunofluorescence, and cytokine and nitric oxide assays, we characterized store-operated Ca2+ entry (SOCE) and purinergic signaling dynamics, inflammatory responses, and CBx effects in human (HMC3) and mouse (BV2) microglia under resting and activated conditions.
    RESULTS: We found that microglial SOCE in both mouse and human cell line models were potently inhibited by the same three, minor, acidic CBx - CBGA, CBGVA, CBDVA. In BV2, at least seven CBx (CBD, CBG, CBDVA, CBDA, CBGA, CBDV, CBNM) inhibited LPS-induced proinflammatory secretion of nitric oxide (NO) and TNF-α. Despite the profound SOCE inhibition in HMC3, CBx failed to inhibit downstream proinflammatory cytokine release in TNF-α - or IL-1β-activated cells. We found major differences in Ca2+ signaling between the models, including purinergic pathways, where HMC3 cells appear to express a more limited purinome with more subdued signaling responses. Purinergic Ca2+ responses to ATP in BV2, especially the delayed phase, was suppressed by at least eight CBx, and most prominently by CBDVA, CBGVA and CBGA. We observed partial, indirect involvement of P2X4, P2 X7, and P2Y13 purinoceptors and propose additional Ca2+ signaling targets mediating the anti-inflammatory properties of CBx. Additionally, we documented the pro-inflammatory potential of CBCA and CBNA that is likely facilitated by their ability to mobilize intracellular Ca2+ levels in both, human and mouse microglia.
    CONCLUSIONS: These findings provide a comprehensive qualitative and quantitative assessment of how individual CBx influence main Ca2+ signaling pathways in microglia and identify novel anti-inflammatory candidates with therapeutic potential for targeting microglial activation.
    Keywords:  Calcium signaling; Cannabinoids; Microglia; Neuroinflammation; Purinergic receptors; Store-operated calcium entry
    DOI:  https://doi.org/10.1186/s12964-026-03031-7
  28. Nat Commun. 2026 07 04. pii: 5846. [Epub ahead of print]17(1):
    Joint trajectories of brain atrophy, white matter hyperintensities and cognition quantify brain maintenance.
    Inga Menze, Jose Bernal, Rogier A Kievit, Kumar Parijat Tripathi, Timo Kaleck, Renat Yakupov, Slawek Altenstein, Claudia Bartels, Katharina Buerger, Michaela Butryn, Peter Dechent, Michael Ewers, Klaus Fliessbach, Ingo Frommann, Maria Gemenetzi, Wenzel Glanz, Daria Gref, Julian Hellmann-Regen, Stefan Hetzer, Enise I Incesoy, Daniel Janowitz, Ingo Kiliman, Luca Kleineidam, Marie Theres Kronmüller, Christoph Laske, Debora Melo van Lent, Falk Lüsebrink, Robert Perneczky, Oliver Peters, Lukas Preis, Josef Priller, Boris-Stephan Rauchmann, Ayda Rostamzadeh, Sandra Roeske, Klaus Scheffler, Björn-Hendrik Schott, Anja Schneider, Sebastian Sodenkamp, Annika Spottke, Eike Jakob Spruth, Melina Stark, Stefan Teipel, Michael Wagner, Jens Wiltfang, Frank Jessen, Alfredo Ramirez, Stefanie Schreiber, Emrah Düzel, Gabriel Ziegler.
      Brain maintenance - the preservation of brain structure or function relevant to cognitive performance - remains challenging to quantify. Here, we propose a domain-general brain maintenance index derived by jointly modelling the longitudinal co-evolution of ageing-related atrophy (via medial temporal lobe to ventricle ratio, MTLV-ratio), white matter hyperintensities (WMH), and global cognition assessed by the preclinical Alzheimer's cognitive composite (PACC5) using latent growth curve modelling. We demonstrate its utility in 543 cognitively unimpaired older adults from the DELCODE cohort, followed annually over four years. We show that changes in MTLV-ratio and WMH additively predict cognitive change. We further show that higher neuroticism, depressive symptoms, lower openness, and faster biological ageing are related to unfavourable domain-specific trajectories and poorer brain maintenance. Our findings highlight the combined relevance of WMH and ageing-related atrophy dynamics for brain maintenance. Maintaining cerebrovascular and mental health alongside cognitive engagement could promote brain maintenance, delay cognitive decline and dementia.
    DOI:  https://doi.org/10.1038/s41467-026-74957-2
  29. Basic Clin Pharmacol Toxicol. 2026 Aug;139(2): e70273
    Chemokines in Alzheimer's Disease: Early Defence, Late Damage and the Impact of Sex and Infection.
    Blanca I Aldana, Kristine Freude.
      Chemokines constitute a versatile signalling network maintaining homeostasis and glia-neuron communication in the healthy brain but become progressively dysregulated during aging and Alzheimer's disease (AD). This review examines how chemokine systems transition from tightly regulated homeostatic signals to drivers of chronic neuroinflammation in AD. We describe the major chemokine families (CC, CXC, CX3C) and their dominant central nervous system (CNS) receptors (CCR2, CXCR3, CX3CR1), which activate canonical inflammatory pathways including NF-κB, JAK/STAT and PI3K-AKT. In AD, chemokine dysregulation occurs in a coordinated manner across multiple functional modules, including recruitment-associated (CCL2, CXCL1), interferon-inducible (CXCL10), loss-of-restraint (CX3CL1) and vascular-associated chemokines. These alterations shift the network from regulated immune communication to self-sustaining inflammatory circuits perpetuating chronic neuroinflammation. These networks reprogram microglia and astrocytes into disease-associated phenotypes, amplify peripheral immune cell infiltration and destabilise synaptic function. Biological sex profoundly influences neuroinflammatory trajectories, with females exhibiting enhanced microglial senescence and interferon signalling, while males show accelerated complement activation. Viral pathogens, particularly neurotropic viruses (HSV-1, HHV-6, VZV) and SARS-CoV-2, actively reprogram chemokine networks, linking infection to amyloid-β accumulation, tau pathology and neurodegeneration. Therapeutically, chemokine axes represent precision targets requiring stage-matched, sex-stratified interventions rather than broad anti-inflammatory approaches. Understanding chemokine network dynamics offers mechanistic insights into AD pathogenesis and could provide pointers for therapeutic strategies.
    Keywords:  chemokine networks; glial reprogramming; sex differences; viral pathogens
    DOI:  https://doi.org/10.1111/bcpt.70273
  30. Biol Res. 2026 Jul 10.
    Reshaping the immune landscape: next-generation microglia-targeted therapies for Alzheimer's disease.
    Jun Wu, Jueying Zhao, Shen Chen, Fangyi Xu.
       BACKGROUND: Alzheimer's disease (AD) is a significant global health challenge characterized as a multifactorial neurodegenerative disorder, involving amyloid-β (Aβ) and Tau aggregation, neuroinflammation and progressive neuronal injury. While Amyloid-targeted therapies have achieved a breakthrough in prevention of Aβ aggregation, the strategies face notable limitations in achieving curative outcomes and management of amyloid-independent central nervous system (CNS) dysfunction. Consequently, targeting microglia, the central immune cells of the brain, has emerged as a promising strategy to enhance the specificity and efficacy of AD interventions.
    MAIN BODY: Accumulating evidence indicates microglial dysfunction is not a passive immune bystander of AD, but serves as a critical mechanistic nexus linking Aβ accumulation and AD symptomatic phenotype. This review critically examines the "next generation" of microglial therapeutics, moving beyond broad immunosuppression to precision phenotype modulation. We highlight breakthrough strategies in recent years including immune reconstitution, metabolic reprogramming, nanomaterial-mediated drug delivery, and the revolutionary potential of iPSC-derived microglia replacement. By elucidating the rationale underlying the specific strategies based on microglial biofunction and potential molecular mechanism in AD pathology, we provide an overview of current development of clinical trials and cutting-edge modalities aimed at restoring microglial homeostasis, affording an opportunity to alter the AD trajectory.
    CONCLUSION: This review aims to delineate the path from bench to bedside and propose promising pathways to overcome current bottlenecks in AD drug development.
    Keywords:  Alzheimer’s disease; Cell-based therapies; EV-based therapies; Immuno-targeted therapies; Metabolism-targeted therapies; Microglia
    DOI:  https://doi.org/10.1186/s40659-026-00716-8
  31. J Neuroinflammation. 2026 Jul 09.
    Neutrophil extracellular traps exacerbate blood-brain barrier disruption in neuromyelitis optica spectrum disorder.
    Xue Ma, Yao Wang, Xin Chen, Zonghao Pan, Yi Li, Kaixi Ren, Daidi Zhao, Hongzeng Li, Jun Guo.
      Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by recurrent optic neuritis and myelitis. Blood-brain barrier (BBB) disruption is a key pathological feature of NMOSD, but the role of neutrophil extracellular traps (NETs) in this process remains poorly defined. Serum proteomic profiling in patients with acute NMOSD revealed enrichment of the NET formation pathway. Neutrophils from these patients showed an increased propensity for NETosis, accompanied by elevated myeloperoxidase-DNA complexes, neutrophil elastase-DNA complexes, and cell-free DNA in serum, as well as increased neutrophil elastase-DNA complex levels in cerebrospinal fluid. In a murine NMOSD model, neutrophil depletion, peptidylarginine deiminase 4 inhibition (Cl-amidine), and NET degradation (DNase I) each attenuated astrocyte loss, demyelination, neuroinflammation, and BBB disruption. In vitro, patient-derived NETs downregulated tight junction proteins in bEnd.3 endothelial cells through mechanisms associated with myeloperoxidase and neutrophil elastase, while c-Jun N-terminal kinase inhibition mitigated NET-induced endothelial barrier disruption. Together, these findings suggest that aberrant NETosis may contribute to BBB disruption in acute NMOSD and support further investigation of NET-associated pathways as potential therapeutic targets.
    Keywords:  Blood-brain barrier disruption; C-Jun N-terminal kinase signaling; Neuromyelitis optica spectrum disorder; Neutrophil extracellular traps; Tight junction proteins
    DOI:  https://doi.org/10.1186/s12974-026-03959-0
  32. Glia. 2026 Sep;74(9): e70198
    Unveiling the Functional Role of KIF21B in Microglia Inflammatory Response.
    Danny Ganchala, Alvaro Bautista-Abad, Daniel Pinto-Benito, Julia Simon-Areces, Daniela Grassi, Francesco Paolo Ulloa Severino, Maria-Angeles Arevalo.
      Microglia are brain immune cells that maintain homeostasis and respond to injury, changing cell morphology to drive inflammation, migration, and phagocytosis. This study examined the role of the kinesin KIF21B in microglial activation, demonstrating for the first time its expression in microglial cells in two in vivo neuroinflammatory models: TBI (focal inflammation) and LPS administration (diffuse inflammation). While TBI provoked a significant increase in KIF21B/Iba1 colocalization in the tissue around the lesion exclusively in females, LPS administration did not alter KIF21B expression in either sex. Given the importance of cytoskeleton remodeling for microglial migration and phagocytosis, this work investigates whether KIF21B contributes to these actions. Downregulating KIF21B in primary cultured mouse microglia had sex-specific effects. In females, KIF21B silencing reduced both migratory capacity and phagocytosis of E. coli-coated spheres and neuronal debris. In males, it exacerbated migration and selectively increased neuronal debris phagocytosis, while E. coli-coated sphere uptake remained unaffected. These functional differences were accompanied by sex-dependent morphological alterations, quantified through area, circularity, Feret's diameter, and perimeter: KIF21B silencing blocked the transition to amoeboid morphology in females while inducing hyperpolarized elongation in males. Finally, LPS treatment increased KIF21B colocalization with microtubules and reduced its colocalization with F-actin in females, while neither interaction was significantly altered in males. Overall, the findings suggest that KIF21B regulates microglial function in a sex-dependent manner through its effects on cytoskeletal organization.
    Keywords:  KIF21B; microglia; neuroinflammation; phagocytosis; sex differences
    DOI:  https://doi.org/10.1002/glia.70198
  33. Dev Cell. 2026 Jul 08. pii: S1534-5807(26)00232-7. [Epub ahead of print]61(7): 1407-1430
    Glia orchestrate neural circuit development.
    Kristina Sakers, Patrick W Sheehan, Wendy Xin, Dorothy P Schafer, Cagla Eroglu.
      Over the past ∼25 years, our understanding of neural circuit development in the central nervous system has shifted. Once considered passive supporters, glial cells, namely, astrocytes, oligodendrocyte lineage cells, and microglia, are increasingly recognized as active regulators of developmental circuit formation and maturation. In this review, we synthesize evidence for the multifaceted functions by which glial cells instruct neuronal circuit establishment and maturation across developmental stages and in both vertebrate and invertebrate nervous systems. We describe the programs deployed to guide successive phases of synapse formation, refinement, plasticity, and stabilization in a circuit- and experience-dependent manner. We also highlight how an extensive glia-glia communication repertoire provides another critical layer of control over development. In summary, glia cooperatively shape circuit development by instructing, stabilizing, or eliminating specific wiring programs. Disruption of this coordinated logic, beyond dysfunction of any single glial or neuronal process, underlies vulnerability to neurodevelopmental and neuropsychiatric disease.
    Keywords:  astrocyte; critical period; glia; microglia; oligodendrocyte; plasticity; synapse
    DOI:  https://doi.org/10.1016/j.devcel.2026.06.008
  34. bioRxiv. 2026 Jul 03. pii: 2026.06.30.735672. [Epub ahead of print]
    Dense CRISPR Mapping of the WAVE Complex Identifies Pharmacological Modulators of AD-Linked Myeloid Migration.
    Jason C Ngo, Yice Xu, Marta Olah, Falak Sher.
      Although genetic risk for Alzheimer's disease (AD) strongly converges on microglial pathways, the druggable functional protein regions that control disease-relevant microglial behaviors remain largely unknown. Here, we applied dense CRISPR-Cas9 mutagenesis and CRISPRtile-based functional mapping to the WAVE regulatory complex (WRC), a central regulator of actin remodeling and cell migration. In a pooled CCL2-directed migration assay in human THP-1 myeloid cells, perturbation of NCKAP1L , CYFIP1 , and BRK1 impaired migration and revealed divergent effects among WRC paralogs. Residue-level analysis mapped discrete migration-associated functional regions within CYFIP1 and NCKAP1L, including a CYFIP1 regulatory hotspot and a prioritized NCKAP1L region nominated for pharmacological targeting. Human single-nucleus datasets identified NCKAP1L as a microglia-enriched WRC component expressed across diverse microglial states. Machine-learning-guided compound prediction nominated Montelukast sodium and Piperacetazine, which we experimentally validated as negative and positive modulators of chemokine-directed migration, respectively. These findings establish WRC-dependent migration as a pharmacologically tunable myeloid process relevant to AD.
    DOI:  https://doi.org/10.64898/2026.06.30.735672
  35. Int Immunopharmacol. 2026 Jul 09. pii: S1567-5769(26)00957-4. [Epub ahead of print]186 117111
    Microglial DNA G-quadruplex accumulation is associated with altered autophagy-related responses and aggravated ischemic brain injury.
    Rijin Lin, JiaXin Wan, Mengyan Fan, Yiming Ma, Liang Chen, XiaoWen Zhang, Jiamei Zhang, Huixiang Liu, Nan Zhang, Li Zhong, Jie Zhang, Sheng Guan, Jing Li.
      Ischemic stroke creates a hypoxic and nutrient-deprived microenvironment that rapidly activates microglia, a central driver of post-ischemic inflammation and a key determinant of secondary tissue damage and neurological recovery. G-quadruplex (G4) structures are non-canonical nucleic acid conformations that can reshape stress responses in diverse settings, yet whether microglial DNA G4 relates to ischemic pathology remains unknown. Here, using a transient middle cerebral artery occlusion (tMCAO) mouse model and an oxygen-glucose deprivation/reoxygenation (OGD/R) primary microglia model, we examined how DNA G4 dynamics relate to microglial stress responses and post-ischemic outcomes. We found that cerebral ischemia induced a dynamic accumulation of microglial DNA G4 signal, accompanied by transient changes in autophagy-related markers. Pharmacological stabilization of G4 with pyridostatin (Pds) was associated with increased mTOR phosphorylation under ischemic stress, increased inhibitory ULK1 phosphorylation, and alterations in autophagy-related proteins, including a reduced LC3-II/LC3-I ratio, p62 accumulation, and downregulation of Beclin-1. In parallel, Pds treatment was associated with increased overall cellular stress under ischemic conditions. Under the prophylactic in vivo paradigm, Pds-treated mice showed larger infarct burden and worse neurological deficits. Importantly, the mTOR inhibitor rapamycin partially reversed Pds-associated autophagy-related changes and partially improved tissue and functional outcomes, although it did not fully normalize the broader stress-associated alterations. Collectively, our findings suggest that a pre-existing G4-stabilized state is associated with altered mTOR-ULK1/autophagy-related responses and aggravated ischemic outcomes, highlighting the G4-mTOR-autophagy-related axis as a potential contributor to post-ischemic microglial stress responses.
    Keywords:  Autophagy; G-quadruplex; Ischemic stroke; Microglia; mTOR
    DOI:  https://doi.org/10.1016/j.intimp.2026.117111
  36. Acta Neuropathol Commun. 2026 Jul 10.
    Matrix metalloprotease-9 modulates microglial/macrophage responses in murine brain demyelination.
    Eline Bernaerts, Amber De Visscher, Sam Vanherle, Marie Rutten, Fran Prenen, Nele Berghmans, Jana Van Broeckhoven, Hanne Meers, Mirre De Bondt, Febe Boudry, Sofie Knoops, Tania Mitera, Lien De Somer, Jeroen Bogie, Patrick Matthys, Jennifer Vandooren.
      Multiple sclerosis (MS) is a chronic autoimmune disorder, in which the immune system targets the protective myelin sheath surrounding axons in the brain, spinal cord and optic nerve, leading to demyelination and ultimately neurodegeneration. Promoting remyelination to delay or halt disease progression remains a major therapeutic challenge in MS research. Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of MS. Elevated levels of MMP-9 have been detected in cerebrospinal fluid (CSF), serum and demyelinating lesions of MS patients, where MMP-9 contributes to myelin breakdown, epitope generation, and leukocyte infiltration. In the in vivo experimental autoimmune encephalomyelitis and lysophosphatidylcholine (LPC) murine MS models, Mmp9-/- mice exhibited delayed resolution of disease symptoms, suggesting a role for MMP-9 in remyelination. In this study, we investigated the role of MMP-9 in demyelination and remyelination, using two complementary models: LPC-induced demyelination in ex vivo brain slices and cuprizone (CPZ)-induced demyelination in vivo. In LPC-treated slices, MMP-9 deficiency impaired remyelination via microglia/macrophage-mediated mechanisms. Consistently, Mmp9-/- mice displayed increased numbers of activated microglia/macrophages in the corpus callosum following CPZ intoxication, with modest persistence during remyelination compared to WT mice. Naïve Mmp9-/- microglia/macrophages also showed enhanced myelin debris phagocytosis compared to WT cells. However, MMP-9 deficiency had minimal impact on demyelination or remyelination in the CPZ model. Proteomic analysis of CSF revealed differential expression of inflammatory mediators, including decreased levels of CCL2 and CXCL9, whereas CCL20 was increased in Mmp9-/- CPZ-treated mice. Collectively, these findings indicate that MMP-9 does not directly regulate demyelination and remyelination in the CPZ-induced demyelination model, but increases microglial abundance, highlighting its indirect role in CNS demyelination.
    Keywords:  Cuprizone-induced demyelination model; Inflammation; Lysophosphatidylcholine model; MMP-9; Microglia; Proteolysis; Resolution
    DOI:  https://doi.org/10.1186/s40478-026-02371-2
  37. Front Neurol. 2026 ;17 1795901
    Gangliosides in the 21st century: therapeutic prospects for the brain and spine.
    Pierre J Magistretti, Charles Finsterwald, Yutaka Itokazu, Simonetta Sipione, Fred H Geisler, Tarcisio Barros Filho.
      Gangliosides are sialylated glycosphingolipids highly enriched in the central nervous system, where they regulate membrane signaling, metabolism, neurogenesis, and immune responses. This Review integrates recent advances across distinct experimental and clinical domains. First, recent studies demonstrate that the monosialoganglioside GM1 enhances astrocyte-neuron metabolic coupling via the astrocyte-neuron lactate shuttle, thereby supporting neuronal bioenergetics and resilience. Complementary mechanistic work shows that specific gangliosides regulate adult neurogenesis through developmentally controlled epigenetic and transcriptional programs. In Huntington's disease models, preclinical evidence indicates that GM1 and related gangliosides attenuate microglia-mediated inflammatory responses and promote proteostasis through extracellular vesicle-dependent clearance of misfolded proteins. Finally, clinical evidence from acute spinal cord injury demonstrates that GM1 administration accelerates neurological recovery, underscoring its translational relevance. Together, these findings position gangliosides as multi-target modulators of neural repair and inflammation, and highlight their potential for therapeutic development.
    Keywords:  GM1; Huntington (disease); acute spinal cord injury (ASCI); astrocyte; extracellular vesicles; microglia; neurodegenenerative diseases
    DOI:  https://doi.org/10.3389/fneur.2026.1795901
  38. bioRxiv. 2026 Jun 29. pii: 2026.06.25.734633. [Epub ahead of print]
    Activity-dependent lipid droplet biogenesis and turnover regulate synaptic integrity.
    Eleni Katafygiotou, Ada Squires, Anne Liang, Holden Hadfield, João A Paulo, Walid Idi, Steven P Gygi, Joongkyu Park, Jeeyun Chung.
      Lipid droplets (LDs) are conserved organelles that buffer lipid storage and stress, yet their dynamics and functions in neurons remain largely unknown. Here, we report activity-dependent dynamics of neuronal LDs, visualized by a novel, genetically encoded LD reporter (termed LipiDew), in both cultured neurons and mouse motor cortex. Using LipiDew, we found that various paradigms of neuronal activation induced predominant and transient formation of LDs in neurites. Disruption of autophagic LD degradation (lipophagy) resulted in abnormal lipid accumulation in dendritic spines and shafts, promoted recruitment of synaptic scaffolding proteins to LDs, and altered intracellular calcium kinetics in neurons. In addition, mice with neuron-specific genetic impairment of lipophagy showed motor function defects. Together, these findings identify activity-dependent LD formation and lipophagic clearance in neuronal compartments as a crucial regulatory mechanism of synaptic integrity and neuronal function.
    DOI:  https://doi.org/10.64898/2026.06.25.734633
  39. bioRxiv. 2026 Jun 30. pii: 2025.11.19.689368. [Epub ahead of print]
    Integrating morphology and gene expression of neural cells in unpaired single-cell data using GeoAdvAE.
    Jinqiu Turbo Du, Tom Chartrand, Suman Jayadev, Katherine E Prater, Kevin Z Lin.
       Background: Cellular morphological transitions are observed across many diseases, yet their functional role remains unclear because few technologies profile form and function in the same cell. Linking single-cell morphology to transcriptomics is difficult: the two modalities share no feature correspondence and are typically measured in different cells.
    Methods: We present GeoAdvAE, a geometry-aware adversarial autoencoder for diagonal (unpaired) integration of single-cell morphology and single-cell RNA sequencing. GeoAdvAE couples modality-specific variational autoencoders with a Gromov-Wasserstein regularizer and an adversarial discriminator to embed unpaired morphologies and transcriptomes into a shared latent space that preserves both reconstruction fidelity and cross-modal geometry.
    Results: Using patch-seq neurons with joint morphology-RNA measurements as ground truth, GeoAdvAE attains the best cross-modal cell-type matching accuracy among diagonal integration methods, outperforming optimal-transport, latent-alignment, and adversarial baselines. Applied to 98 CAJAL-quantified microglial morphologies and 31,948 single-cell transcriptomes from the 5xFAD Alzheimer's disease model, GeoAdvAE recovers a one-dimensional axis that aligns the two modalities. Integrated-gradient attribution highlights transcriptomic shifts (DNA repair in ramified microglia; cell killing in amoeboid microglia), nominates gene markers ( Ms4a6b ; Ftl1 / Fth1 ), and reveals disease-associated microglia signatures that are decoupled from morphology.
    Conclusions: GeoAd-vAE provides a scalable and interpretable approach to connecting cellular "form" and "function" when joint profiling of morphology and transcriptomics is impractical. Our method is publicly available at https://github.com/turbodu222/GeoAdVAE .
    DOI:  https://doi.org/10.1101/2025.11.19.689368
  40. Res Sq. 2026 Jul 03. pii: rs.3.rs-10050556. [Epub ahead of print]
    Grey matter degeneration during multiple sclerosis is linked to activation of neuronal necroptosis by oxidized phosphatidylcholines.
    Yifei Dong, Ruoqi Yu, Qurat Ul Ain, Gaili Yan, Jian Park, Rachel Dignean, Stephanie Zandee, Wendy Klement, Sandra Larouche, Chao Zheng, Justin Botterill, Alexandre Prat, Dorian McGavern.
      Oxidized phosphatidylcholines (OxPCs) are biomarkers of oxidative stress found in grey matter (GM) lesions during multiple sclerosis (MS), yet their distinct role in GM neurodegeneration remains undefined. Here we report that stereotaxic OxPC deposition in the mouse spinal cord GM induces age dependent neuroinflammation and neurodegeneration. Microglia are the predominant macrophages responding to OxPC induced GM lesions and help to mitigate acute neurodegeneration. Neuronal necroptosis activation in mouse GM lesions and neuronal upregulation of OxPCs and necroptosis activation in MS GM lesions suggest OxPC induced necroptosis promote GM degeneration during MS. In support, necroptosis inhibition ameliorates OxPC induced GM neuron loss. Finally, iron(ii)-containing heme deposition in the GM induces both OxPC formation and neuronal necroptosis activation, suggesting an endogenous upstream mechanism for generating neurotoxic OxPCs. These results highlight a plausible link between heme deposition, lipid peroxidation, and neuronal loss, and that necroptosis inhibition could help prevent GM neurodegeneration during MS.
    DOI:  https://doi.org/10.21203/rs.3.rs-10050556/v1
  41. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2536812123
    Circadian screening of neutrophils identifies therapeutic targets in multiple sclerosis.
    Francesco De Virgiliis, Coline Barnoud, Wenyan He, Qun Zeng, Robert Pick, Tianyue Sun, Stéphane Jemelin, Valeria Maria Oliva, Tiphaine Furlan, Carmen Picon-Muñoz, Doron Merkler, Christoph Scheiermann.
      Circadian rhythms are intrinsic time-keeping mechanisms that play a critical role in tuning immunity. Here, we investigated the impact of circadian rhythms on the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS). We demonstrate that circulating neutrophils in blood significantly increase early in EAE, prior to symptoms onset. Importantly, we found that these cells infiltrate the central nervous system (CNS) in a time-of-day (ToD)-dependent manner, with increased infiltration at the onset of the behavioral active phase of the mice (evening). Transcriptomic analysis of CNS-infiltrating neutrophils revealed distinct ToD-dependent gene expression profiles, which identified Formyl peptide receptor 2 (FPR2) as a potential therapeutic candidate, since pharmacological inhibition of FPR2 led to reduced EAE disease severity. Furthermore, combinatorial treatment with a drug that targets VLA-4 (used in clinical practice under the trade name Natalizumab to treat MS) led to additive effects, substantially reducing EAE symptoms. Together, these findings highlight the importance of circadian immune cell dynamics during EAE development and provide a characterization of the circadian immune landscape in an animal model of MS, identifying potential targets for MS therapies.
    Keywords:  circadian rhythm; multiple sclerosis; neutrophil
    DOI:  https://doi.org/10.1073/pnas.2536812123
  42. Science. 2026 Jul 09. 393(6807): eadv1219
    C1q and immunoglobulins mediate activity-dependent synapse loss in the adult brain.
    Gerard Crowley, Minjung Kim, Nathanael O'Neill, Emir Turkes, Fateme Ghasemi, Luca Giudice, Sebastiaan De Schepper, Benjy J Y Tan, Benito Maffei, Laís S S Ferreira, Julie Rebejac, Javier Rueda-Carrasco, Margarita Toneva, John Christian Fajardo, Judy Z Ge, Zhengyue Grace Yang, Paula Korhonen, Phillip Muckett, Damaris Bennett, Camille Paoletti, Tammie T M Sow, David A Posner, Annerieke Sierksma, Dimitra Sokolova, Viktoras Konstantellos, Leen Ali, Kiavash Movahedi, Andrew F MacAskill, Victor L J Tybulewicz, Tarja Malm, Gabriele Lignani, Menna R Clatworthy, Soyon Hong.
      Complement component 1q (C1q), the initiator of the classical complement cascade, mediates synaptic elimination in development and disease, yet the triggers for its deposition on synapses remain unclear. Using in vivo chemogenetics, we demonstrate that neuronal hyperactivity induces region-specific, C1q-dependent synapse loss in the adult hippocampus. Suppressing perforant pathway hyperactivity in a mouse model of Alzheimer's disease reduced local amyloid-β amounts and C1q deposition and partially rescued synapse loss. Combining spatial transcriptomics, live cell tracking, and super-resolution microscopy, we identified association of antibody-secreting B-lineage cells in the adult hippocampus with activity-dependent, C1q-mediated synapse loss under physiological conditions. Together, these findings link neuronal hyperactivity to C1q-mediated synapse loss in the adult brain and implicate immunoglobulins as players in this process.
    DOI:  https://doi.org/10.1126/science.adv1219
  43. Reg Anesth Pain Med. 2026 Jul 08. pii: rapm-2026-107844. [Epub ahead of print]
    Neuropathic pain through the perspective of microglia-neuron interactions: a translational review for clinicians.
    Lingyi Zhang, Jessica Yu, Xiaobing Yu, Zhonghui Guan, Po-Yi Paul Su.
       BACKGROUND/IMPORTANCE: Neuropathic pain affects up to 10% of the population and is often refractory to current treatments. Growing evidence implicates neuroimmune interactions, particularly microglia, in the pathophysiology, but their role is underappreciated in clinical practice.
    OBJECTIVE: To summarize current evidence for microglial contributions to neuropathic pain, emphasizing microglia-neuron interactions and translational implications for clinicians.
    EVIDENCE REVIEW: This narrative review synthesizes preclinical and emerging human data (postmortem histopathology, glial-signal positron emission tomography (PET) imaging, dorsal root ganglion transcriptomics) to examine microglial contributions to pain initiation, maintenance and resolution, sex differences and therapeutic implications.
    FINDINGS: Preclinical evidence demonstrates that microglia are necessary and sufficient for pain initiation. Nerve injury engages central sensitization through colony-stimulating factor 1 (CSF1)-CSF1 receptor (CSF1R), purinergic receptors, damage-associated molecular pattern/Toll-like receptor signaling, cytokine cascades (TNFα, IL-1β, IL-6), prostaglandin E₂, extracellular matrix and synaptic remodeling and brain-derived neurotrophic factor-tropomyosin receptor kinase B-mediated disinhibition. Microglia also contribute to pain resolution via pro-resolving mediators and stimulator of interferon genes (STING)/interferon signaling. Sex differences are prominent: microglial mechanisms predominate in males, whereas T-cell-mediated pathways prevail in females. Human postmortem and glial-signal imaging studies support glial involvement in chronic pain but lack direct validation of specific microglial targets.
    CONCLUSIONS: Microglia coordinate pain initiation and resolution via conserved, drug-addressable pathways. Three translational implications emerge: (1) neuroimmune interventions are most effective early, given that microglia drive initiation more than maintenance; (2) sex-stratified trial designs are warranted given divergent microglial versus T-cell mechanisms by sex and (3) CSF1R-PET imaging may enable mechanism-based patient selection. These implications require prospective clinical validation.
    Keywords:  Analgesia; CHRONIC PAIN; EDUCATION
    DOI:  https://doi.org/10.1136/rapm-2026-107844
  44. Glia. 2026 Sep;74(9): e70196
    Microglial P2ry12 in the Basolateral Amygdala Underlies Neuropathic Pain-Induced Anxiety.
    Xiaohui Yang, Li Chen, Qiuxiao Shi, Hanmin Liu, Yuying Tang.
      Anxiety is a common clinical comorbidity of neuropathic pain. The basolateral amygdala (BLA) is critically involved in both pain and anxiety processing. Microglia have emerged as key regulators of neuronal plasticity, and disruption of homeostatic neuron-microglia crosstalk can precipitate neuropsychiatric disorders. Although microglia are abundant in the BLA, their specific role in modulating neuronal plasticity underlying pain-induced anxiety remains poorly understood. Here, we demonstrate that spared nerve injury (SNI) induces anxiety-like behaviors in mice, accompanied by neuronal hyperexcitability and increased spine density in the BLA. These changes correlated with increased density of hyper-ramified microglia, along with upregulated P2ry12 expression and enhanced microglial BDNF production. Importantly, microglial P2ry12 knockdown significantly attenuated both process hyper-ramification and BDNF overexpression in the BLA. Furthermore, either microglial depletion with clodronate or microglial P2ry12 knockdown in the BLA reversed neuronal hyperexcitability and spine overgrowth, and alleviated pain and anxiety-like behaviors in SNI mice. Meanwhile, clodronate mildly suppressed neuronal excitability and dendritic spine density in the BLA of control mice, whereas P2ry12 knockdown had no detectable impact on these neuronal measures. Together, these findings support a role for microglia in maintaining physiological neuronal excitability and spine density. Highly-ramified microglia and their increased P2ry12 expression underlie the enhanced neuronal excitability and spine density in the BLA, thereby promoting comorbidity of pain and anxiety.
    Keywords:  P2ry12; anxiety; excitability; microglia; pain; spine
    DOI:  https://doi.org/10.1002/glia.70196
  45. BMC Med. 2026 Jul 08.
    Microglia-mediated synaptic pruning in neural circuit remodeling: multidimensional control in homeostasis and neuropathology.
    Zheng Liu, Wu-Lan Ao, Ai-Di Luo, Si-Qi Guan, Ji Wang, Chang-Yin Yu, Zu-Cai Xu, Ping Xu, Hao Huang.
       BACKGROUND: Microglia, the resident immune cells of the central nervous system, are key regulators of synaptic plasticity and neural circuit homeostasis.
    MAIN BODY: This review summarizes the mechanisms by which microglia shape synaptic structure and function, including dynamic synaptic interactions, selective pruning, epigenetic regulation, extracellular matrix remodeling, metabolic adaptation, and communication with other glial cells. Under physiological conditions, these processes support circuit refinement, synaptic stability, and cognition, which are modulated by circadian rhythms and the microbiota-gut-brain axis. In Alzheimer's disease, schizophrenia, and related disorders, microglial dysfunction can shift synaptic pruning from a controlled homeostatic process to pathological synapse loss. Excessive complement-mediated pruning, disrupted excitation-inhibition balance, neuroinflammation, and metabolic dysregulation may jointly impair synaptic integrity and circuit function.
    CONCLUSION: This review highlights microglial heterogeneity, state transitions, and targeted modulation as important directions for understanding synaptic remodeling and developing therapeutic strategies for neurological diseases.
    Keywords:  Circadian rhythm; Excitation/inhibition balance; Metabolic reprogramming; Microbiota-gut-brain axis; Microglia; Neurodegenerative diseases; Synaptic plasticity; Synaptic pruning
    DOI:  https://doi.org/10.1186/s12916-026-05016-2
  46. Front Neurosci. 2026 ;20 1785992
    Microglia derived from human induced pluripotent stem cells are regulated by osteopontin, an endogenous extracellular matrix protein maintaining immune homeostasis.
    Daniel Navin Olschewski, Anna Maria Koenig, Helena Mira Nerone, Elena Gross, Tomo Šarić, Sabine Ulrike Vay, Michael Schroeter, Gereon R Fink, Maria Adele Rueger.
       Introduction: Microglia are brain-resident immune cells responsible for maintaining homeostasis, coordinating responses to injury and disease, and mediating regeneration. Upon activation, they undergo dynamic changes in morphology, gene expression, and function, reflecting the nature and context of the stimuli encountered. Although pharmacological modulation of microglia holds great promise for treating various neurological disorders, its development is hampered by a major translational roadblock: Human microglial cell lines commonly used in preclinical studies, as well as primary rodent microglia, substantially limit the translatability of results. Here, we aimed to generate microglia from human induced pluripotent stem cells (hiPSCs) and to demonstrate their physiological responsiveness to the brain-endogenous, context-relevant ligand osteopontin (OPN).
    Materials and methods: Microglia generated from two healthy hiPSC lines were stimulated with OPN, lipopolysaccharide (LPS), or their combination for 24 h and subsequently analyzed. Microglial identity and the expression of the phagocytic cell marker cluster of differentiation 68 (CD68) were determined by immunocytochemistry. Cell viability was assessed by propidium iodide (PI)/Hoechst staining, morphological activation was evaluated using Sholl analysis, and inflammatory gene expression changes were assessed by RT-qPCR.
    Results: hiPSC-derived microglia acquired a native central nervous system (CNS)-specific immunophenotype, expressing the microglia-specific markers ionized calcium-binding adapter molecule 1 (IBA1), transmembrane protein 119 (TMEM119), PU.1, and Spalt-like transcription factor 1 (SALL1), while remaining negative for Myb and membrane-spanning 4-domains, subfamily A, member 7 (MS4A7) at the protein level. Exposure to LPS led hiPSC-derived microglia to adopt a rounded, process-retracted shape and to increase CD68 protein intensity, a surrogate marker of lysosomal and phagocytic activity, while downregulating the anti-inflammatory marker cluster of differentiation 206 (CD206) at the transcriptional level. OPN induced a distinct microglial functional state characterized by intermediate morphology, increased CD68 intensity, and reduced homeostatic gene expression, without eliciting robust inflammatory gene expression. Intriguingly, OPN prevented LPS-induced microglial cell death, and when hiPSC-derived microglia exposed to LPS were additionally treated with OPN, the morphological effects of LPS were reversed.
    Conclusion: OPN induced a distinct early response profile in hiPSC-derived microglia, characterized by intermediate morphological remodeling, increased CD68 intensity, and reduced homeostatic gene expression, without overt pro-inflammatory gene expression. These findings support the role of OPN as a physiological priming signal in microglia and highlight hiPSC-derived microglia as a model for studying regulators of microglial modulation.
    Keywords:  iPSC (induced pluripotent stem cell); in vitro model culture system; microglia; neuroinflammation; osteopontin
    DOI:  https://doi.org/10.3389/fnins.2026.1785992
  47. Acta Neuropathol Commun. 2026 Jul 09.
    CSF1R inhibition following antibody mediated demyelination has limited impact on remyelination.
    Lisa C Golden, Graham C Peet, Rebecca E Rodriguez, Nicholas J Jahahn, Gregory P Owens, Jeffrey L Bennett, Wendy B Macklin.
      Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system. B cell depleting treatments are effective MS therapies, and while antibodies may serve as a biomarker, little is known about how they participate in MS pathology. Using a proteolipid protein 1 complex-specific (PLP1c) recombinant antibody cloned from cerebrospinal fluid plasmablasts of MS patients, we studied the development and resolution of antibody-mediated demyelinating lesions in vivo in mice. Demyelination was complement-dependent and resolved over four weeks. Because of the previously described impact of microglia on remyelination, we targeted microglia depletion with CSF1R inhibition to test their role in this model. Despite a significant reduction in total microglia following CSF1R inhibition, microglia or macrophage density was high in recovering lesions. Premyelinating oligodendrocyte populations were altered without impacting gross lesion recovery. Future work will determine if PLP1c-binding antibodies are representative of other MS-derived antibodies, and how pathogenic MS autoantibodies may contribute to the variability of MS lesion remyelination.
    Keywords:  Complement; Demyelination; Immunoglobulin; Microglia; Multiple sclerosis; PLP1; Remyelination
    DOI:  https://doi.org/10.1186/s40478-026-02370-3
  48. J Ethnopharmacol. 2026 Jul 08. pii: S0378-8741(26)01023-8. [Epub ahead of print] 122169
    Corrigendum to "Chrysin reprograms microglial metabolism and function via targeting SYK to alleviate the symptoms of Alzheimer's disease" [J. Ethnopharmacol. (2026) 122056].
    Lixi Li, Yanjia Gu, Xinyue Luo, Jinyu Wang, Ying Jia, Tingxu Yan.
      
    DOI:  https://doi.org/10.1016/j.jep.2026.122169
  49. Brain. 2026 Jul 06. pii: awag234. [Epub ahead of print]
    Fus-depleted oligodendrocytes reduce neuronal damage and Alzheimer's disease progression in the AppNL-G-F mouse.
    Te-Hsuan Tung, Sudhagar Babu, Xiangting Tang, Alec L Sciutto, Micah Romer, Prathima Racha, Rong Xu, Victoria Fiesler, Adrita Saha, Teresa Thai, Takashi Saito, Takaomi C Saido, Yongxin Zhao, Judith B Grinspan, Hansruedi Mathys, Takashi D Y Kozai, Franca Cambi.
      Alzheimer's Disease (AD) is an age-dependent neurodegenerative disorder and represents the most common type of dementia, increasing in incidence at an alarming rate in the aging population. The hallmarks of the disease are amyloid plaque accumulation, microglia and astrocyte activation, and loss of presynaptic structure leading to cognitive decline. Recently, oligodendrocyte (OL) and myelin abnormalities have emerged as important contributors to the pathogenesis of AD. In normal brain homeostatic conditions, OL maintain neuronal health through myelin axon interactions and by supplying neurotrophic and metabolic support. How strengthening OL function may support neuronal health in AD neurodegeneration remains to be fully characterized and represents a gap in knowledge and a missed therapeutic opportunity. This study sought to examine how myelin and OL may improve neuronal deficits associated with AD. We have generated a novel mouse model (AD/cKO) by crossing the AppNL-G-F mouse, an established AD model, which carries three human AD mutations in the mouse App gene, with the FusOLcKO whose OL depleted of Fus (Fused in Sarcoma) produce thicker myelin associated with greater cholesterol biosynthesis. We evaluated spatial memory function with standardized cognitive testing. We evaluated microglia density and state, astrocytic activation and toxic phenotype, myelin density, cholesterol content, amyloid plaque burden, presynaptic structures, and neuronal hypoxic and oxidative damage in the hippocampus and cortex. We characterized the transcriptome of AD/cKO hippocampal OL compared to AD by using single-cell transcriptomic studies. Spatial working memory was fully preserved in the aged AD/cKO mouse relative to the AD mouse. This outcome was associated with reduced neuronal oxidative damage, preserved presynaptic structures at the amyloid plaque niches, and a shift in microglia state at the niches in both hippocampus and cortex. In contrast, amyloid plaque burden and microglia density were decreased in the hippocampus but not in cortex, uncoupling the neuronal and microglia effects from the amyloid burden. Fus dependent myelin increase was present in both hippocampus and cortex. Single-cell transcriptomics of AD/cKO hippocampal OL revealed upregulation of energy metabolism and antioxidant genes, suggesting a role of OL enhanced energy metabolism in mediating protection of neurons and affecting microglia state in AD pathology. This work provides new insight into how oligodendrocytes may protect neurons in AD, communicate with other glial cellular players, and point to potential targets for disease intervention aimed at slowing AD progression.
    Keywords:  lipid metabolism; microglia; mitochondria; neuroinflammation; neuroprotection; transcriptomics
    DOI:  https://doi.org/10.1093/brain/awag234
  50. Protein Sci. 2026 Aug;35(8): e70703
    Mitochondrial membrane remodeling in stress adaptation: Lipid control of organelle quality.
    Lena J Reichert, F-Nora Vögtle, Carlotta Peselj.
      Mitochondria respond to proteotoxic stress through the mitochondrial unfolded protein response, traditionally viewed as a transcriptional program that restores proteostasis by inducing chaperones and proteases. Emerging evidence indicates that mitochondrial membrane remodeling constitutes an additional adaptive component of this response. Regulated changes in mitochondrial lipid composition, particularly involving the signature phospholipid cardiolipin, support mitochondrial function during stress by stabilizing protein import machineries, promoting mitochondrial protein biogenesis, and facilitating recovery from dysfunction. In addition, stress originating in other organelles, especially the endoplasmic reticulum, reshapes mitochondrial membranes through altered lipid biosynthesis, inter-organelle lipid trafficking, and stress signaling pathways. These findings suggest that mitochondrial membrane remodeling represents a regulatory layer of organelle quality control integrated within interconnected stress response networks and may provide new opportunities to enhance mitochondrial resilience in disease.
    Keywords:  ER–mitochondria crosstalk; cardiolipin; mitochondrial membrane remodeling; mitochondrial protein biogenesis; mitochondrial unfolded protein response (UPRmt); organelle stress signaling
    DOI:  https://doi.org/10.1002/pro.70703
  51. J Neuroinflammation. 2026 Jul 07. pii: 231. [Epub ahead of print]23(1):
    Correction: SIRT2 Inhibition promotes microglia LC3-associated phagocytosis via NRF2/CD36 after the experimental subarachnoid hemorrhage.
    Bin Sheng, Xiangxin Chen, Tao Tao, Jiaqing Sun, Wei Li, Lingyun Wu, Zheng Peng, Xiaojian Li, Zhengxu Zhou, Qian Yu, Yeping Ling, Prativa Sherchan, Jerry J Flores, Jiping Tang, Lei Huang, Chunhua Hang, John H Zhang.
      
    DOI:  https://doi.org/10.1186/s12974-026-03943-8
  52. bioRxiv. 2026 Jun 30. pii: 2026.06.29.735293. [Epub ahead of print]
    Ontological Analysis of Brain Proteostasis Highlights the Sex-Dependent Trajectory of ApoE Isoform-Specific Regulation.
    Ariel Denos, Benjamin Jones, Noah Moran, Ethan Smith, Katie Brown, Noah Earls, Rebecca Burlette, Christian Garrard, Elise Clark, Esteban Coleman, Jared Elison, Jason Wells, Jossue Matute, Joshua Brown, Martin Sorensen, Mitchell Poulson, Nazanin Paymard, Coleman Nielsen, Dennis Tolley, Eleni Vickers, Wejdene Daouahi, John C Price.
      Apolipoprotein E (ApoE) is the strongest genetic predictor of Alzheimers disease (AD) risk, with ApoE4 increasing and ApoE2 decreasing risk relative to ApoE3. Using a global LC-MS proteomic approach, we integrated protein abundance and kinetics in Human-APOE knock-in mice for young (3-month) and aged (18-month) cohorts to quantify the changes in steady-state proteostasis. By mapping 6,052 identified proteins and 3,986 associated turnover rates into ontological groups, we observed that vesicle trafficking and mitochondrial dysregulation occur as early as 3 months in ApoE4 mice accompanied by hyperactive metabolism that eventually reduces with age. In contrast, young and old ApoE2 mice retain similar signatures to ApoE3 mice in metabolic, mitochondrial, cellular regulation, and membrane trafficking ontologies. We found that females had more isoform-induced ontological changes relative to ApoE3, providing insight into sex-dependent vulnerabilities. Our global proteomic approach for ApoE proteostasis crucially unifies independent literature observations while providing turnover kinetics to uncover the underlying mechanism behind abundance changes. Data are available via ProteomeXchange with identifier PXD079261.
    DOI:  https://doi.org/10.64898/2026.06.29.735293
  53. Sci Rep. 2026 Jul 07. pii: 20998. [Epub ahead of print]16(1):
    Reconstituting central nervous system niche cues partially restores homeostatic-like features in cultured murine primary microglia.
    Victoria Ilse, Susan Barendrecht, Julia Hahndorf, Stefanie Geissler, Benjamin Hietel, Daniel-Christoph Wagner, Martin S Staege, Holger Cynis.
      Microglia rapidly lose their homeostatic phenotype after isolation, limiting the interpretability of in vitro studies. We systematically evaluated culture conditions that reconstitute central nervous system (CNS) niche inputs to better preserve microglial homeostatic features. Neonatal mouse microglia were isolated by fluorescence-activated cell sorting, Percoll gradients, or a shaking protocol and cultured with defined cytokines (TGF-β1, IL-34, CX3CL1), extracellular matrix (collagen IV), and metabolic support (cholesterol, insulin-transferrin-selenium) under serum-free or serum-containing conditions. RT-qPCR revealed rapid downregulation of seven homeostatic transcripts (Tmem119, P2ry12, Cx3cr1, Hexb, Fcrl2, Olfml3, Tgfbr1) within 24 h across isolation methods, with further decline for a subset over 7 days. A cytokine cocktail partially restored homeostatic gene expression, with collagen IV and cholesterol further enhancing selected transcripts. Serum-free conditions favored ramified, surveillant-like microglia, whereas serum promoted amoeboid, activated-like cells, and adding defined factors preserved ramification while improving transcriptional recovery. Transcriptomic analyses demonstrated that optimized conditions shifted global expression profiles toward neonatal ex vivo microglia, upregulated most microglia-specific homeostatic genes, and downregulated inflammatory effectors. These data define a scalable, serum-free, collagen IV-based culture system with defined CNS cues that partially preserves key aspects of microglial homeostatic transcriptional and morphological features compared with conventional serum-containing culture, providing more physiologically relevant conditions for mechanistic and disease-relevant studies.
    Keywords:  CNS niche cytokines (hTGF-β1, hIL-34, hCX3CL1); Culture shock; Homeostatic gene signatures; Primary microglia
    DOI:  https://doi.org/10.1038/s41598-026-61142-0
  54. Nat Cell Biol. 2026 Jul 06.
    Addendum: In situ architecture of the human prohibitin complex.
    Felix Lange, Michael Ratz, Jan-Niklas Dohrke, Maxence Le Vasseur, Dirk Wenzel, Peter Ilgen, Dietmar Riedel, Stefan Jakobs.
      
    DOI:  https://doi.org/10.1038/s41556-026-02020-9
  55. bioRxiv. 2026 Jun 29. pii: 2026.06.24.734321. [Epub ahead of print]
    Antibiotics promote susceptibility to C. difficile infection through a CCR5-dependent immune response.
    Md Jashim Uddin, Nick R Natale, Farha Naz, Jiayi Tian, Rachel McMillan, Duncan J Hart, Shelby L Schenck, William A Petri.
      Antibiotics (ABXs) represent the current standard of care for treating Clostridioides difficile infection (CDI). Paradoxically, ABX-induced dysbiosis is the primary risk factor for CDI, as disruption of the colonic microbial ecosystem creates an opportunity for C. difficile colonization. Given that ABXs can also alter immune responses, we investigated whether ABXs prime the colonic immune milieu for CDI susceptibility. Here, we implicate ABXs in driving CDI severity through the emergence of pathogenic CCR5-reliant immune populations in the mouse colon. High-throughput immune cell profiling revealed that ABXs shift the colonic immune compartment toward a CCR5-associated type I immunity signature, marked by an expansion of CCR5 + ILC1s and CCR5 + Th1 cells. A partial genetic deletion of CCR5 reversed CDI severity, alleviating colonic inflammation and improving survival. Pharmacological inhibition of the CCL3/4/5-CCR5 circuit also recapitulated these favorable disease outcomes, which we attribute to reduced colonic CCR5 + ILC1, CCR5 + Th1, and CCR5 + CD8 T cell populations during CDI. Together, our findings extend beyond dysbiosis as the canonical CDI risk factor and establish ABX-induced immune imbalance as an underappreciated determinant of CDI susceptibility.
    DOI:  https://doi.org/10.64898/2026.06.24.734321
  56. Nat Commun. 2026 Jul 10.
    Uremic toxins promote renal fatty acid synthesis and fibrosis via activating aryl hydrocarbon receptor.
    Hongyan Xie, Yitao Zhang, Li Lu, Hengjiang Guo, Xi'ang Sun, Ming Ning, Xin Xie, Luxin Li, Yangyang Niu, Jingyao Li, Xin Wang, Lehao Wu, Li Zhou, Wei Zhang, Yingying Zhang, Chen Xu, Limin Lu, Chen Yu.
      Chronic kidney disease (CKD) affect about 10% of adults worldwide, with dyslipidemia being a common feature. Abnormalities in renal lipid metabolism have been strongly implicated in CKD progression; however, the mechanisms by which CKD leads to lipid metabolism disturbances remain underexplored. Here we show that following the accumulation of uremic toxins, the synthesis and deposition of lipids, along with the uremic toxin receptor aryl hydrocarbon receptor (AhR), are upregulated in the kidneys. Tubule-specific AhR knockout in male mice alleviates uremic toxin-induced increases in renal fatty acid (FA) synthesis, lipid accumulation and fibrosis. Immunoprecipitation‒mass spectrometry identifies nuclear receptor subfamily 1 group D member 1 (NR1D1) as an AhR-interacting protein. Co-immunoprecipitation confirms that AhR interacts with NR1D1 and promotes its ubiquitin-mediated degradation. As NR1D1 is an FA synthesis suppressor, its reduction relieves the transcriptional repressing effects on sterol regulatory element-binding protein 1 (SREBP1), thereby enhancing SREBP1/fatty acid synthase (FASN) pathway activity and FA synthesis. In summary, by acting on AhR, the accumulation of uremic toxins may accelerate renal fibrosis via the SREBP1/FASN pathway-mediated increase in FA synthesis.
    DOI:  https://doi.org/10.1038/s41467-026-75114-5
  57. Alzheimers Dement. 2026 Jul;22(7): e71617
    Modular brain networks shape amyloid-driven tau spread and cognitive decline.
    Fabian Hirsch, Lukas Frontzkowski, Anna Steward, Sebastian N Roemer-Cassiano, Davina Biel, Zeyu Zhu, Carla Palleis, Johannes Gnörich, Madleen Klonowski, Günter Höglinger, Matthias Brendel, Nicolai Franzmeier.
       INTRODUCTION: Alzheimer's disease involves trans-synaptic spread of tau pathology from temporal lobe epicenters, driven by amyloid beta (Aβ) deposition. How modular brain network architecture shapes this process and the ensuing cognitive decline remains incompletely understood. We tested whether the efficiency with which tau epicenters access cross-network communication pathways modulates Aβ-driven tau propagation.
    METHODS: We combined baseline/longitudinal amyloid/tau positron emission tomography (PET) data across two independent AD cohorts (N = 490) with multimodal connectomics data. We quantified epicenter broadcast capacity (EBC), capturing whether tau epicenters preferentially access regions supporting cross-network communication or within-network communication.
    RESULTS: Higher EBC was associated with faster Aβ-related global tau accumulation, greater spatial tau spread, and steeper cognitive decline. Effects were driven by stronger epicenter communication with cross-network connectors, whereas preferential within-network routing was associated with relative containment of tau spread.
    DISCUSSION: We identify a mechanism through which epicenter connectivity biases Aβ-driven tau propagation toward brain-wide broadcast or regional containment, helping explain heterogeneity in disease progression.
    Keywords:  graph theory; integration; neurodegeneration; neuroimaging; segregation; tauopathy
    DOI:  https://doi.org/10.1002/alz.71617
  58. Elife. 2026 07 08. pii: RP107745. [Epub ahead of print]14
    Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
    Peter Georgiev, Sheila Johnson, Kiran Kurmi, Song-Hua Hu, SeongJun Han, Dillon Patterson, Thao H Nguyen, Linglin Huang, Dan Liang, Naomi Goldman, Thomas Conway, Hannah Creasey, Jared Rowe, Marcia C Haigis, Arlene H Sharpe.
      Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4+ T cells. We demonstrate that asparagine depletion at different time points after CD4+ T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4+ T cell differentiation reduces cytokine production in multiple CD4+ T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4+ T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.
    Keywords:  autoimmune response/disease; immunology; inflammation; lymphocyte subsets; mouse
    DOI:  https://doi.org/10.7554/eLife.107745
  59. bioRxiv. 2026 Jun 29. pii: 2026.06.28.735093. [Epub ahead of print]
    High-throughput whole-brain scattering imaging resolves amyloid plaques through clearing-assisted contrast modulation.
    Chong Chen, Peilin Gu, Jian Ren.
      Label-free scattering imaging is widely used in pathology because it enables sensitive tissue assessment without exogenous contrast agents. Yet its limited optical penetration has prevented scattering-based methods from being applied to whole-organ pathology mapping. Here we present clearing-assisted scattering tomography (CAST), a high-throughput, label-free whole-brain mesoscope enabled by selective lipid clearance for scattering enhancement (SELiC). SELiC modulates endogenous refractive-index heterogeneity in cleared tissue, providing whole-brain optical penetration while retaining strong scattering contrast from amyloid plaques and white-matter fibre bundles. CAST enables volumetric imaging of intact mouse brains and brain-wide mapping of amyloid plaque pathology across anatomical regions. This platform establishes a scalable route for label-free, system-level analysis of amyloid pathology and tissue architecture in Alzheimer's disease (AD) models.
    DOI:  https://doi.org/10.64898/2026.06.28.735093
  60. Nat Commun. 2026 Jul 07. pii: 5681. [Epub ahead of print]17(1):
    Anti-PD-1 plus anti-CTLA-4 blockade overcomes immune exclusion in NSCLC brain metastases by enhancing CD8+ T cell responses and promoting tertiary lymphoid structure formation.
    Kazutaka Hosoya, Hiroaki Ozasa, Takahiro Tsuji, Masahiro Oi, Yusuke Shima, Keiichiro Suminaga, Kentaro Hashimoto, Hiroshi Yoshida, Tomoko Funazo, Hitomi Ajimizu, Takashi Nomizo, Hironori Yoshida, Hiroyuki Katsuragawa, Kentaro Tsuji, Noritaka Sano, Shigeki Takada, Yohei Mineharu, Shigeto Nishikawa, Toshi Menju, Akihiko Yoshizawa, Yoshiki Arakawa, Hiroaki Wake, Toyohiro Hirai.
      Brain metastases (BrMs) in non-small cell lung cancer (NSCLC) respond poorly to anti-PD-1 monotherapy, but the underlying immune resistance remains incompletely defined. Here we integrate clinical outcome analyses, paired human tissue profiling and syngeneic mouse models to characterize the BrM immune microenvironment. Clinical analyses suggest improved intracranial disease control with nivolumab plus ipilimumab compared with nivolumab alone. Paired human specimens show that BrMs contain fewer cytotoxic T lymphocytes (CTLs) and tertiary lymphoid structures (TLSs) than primary tumors, defining an immune-excluded phenotype. A syngeneic BrM model recapitulates this phenotype and resists anti-PD-1 monotherapy, whereas combined anti-PD-1 and anti-CTLA-4 blockade suppresses tumor growth and prolongs survival. Single-cell RNA sequencing, flow cytometry and immunofluorescence show increased CTL infiltration and effector function after combination therapy. CD8+ T cell depletion abrogates therapeutic benefit, and combination therapy expands T follicular helper-like cells and induces TLS-like structures. These findings manifest increased adaptive immune response of dual checkpoint blockade in NSCLC BrMs.
    DOI:  https://doi.org/10.1038/s41467-026-74782-7
  61. Neurochem Res. 2026 Jul 07. pii: 209. [Epub ahead of print]51(4):
    The Protective Effects of Small-Molecule Compound 0242 Against LPS-Induced Neuroinflammation and in P301S Tau Transgenic Mice.
    Xinyuan Suo, Peifeng Wan, Jie Yu, Xinyu Zhu, Chenggang Tian, Shuyu Li, Guangqiang Sun, Hongchun Liu, Simin Liu, Meiyu Geng, Jingwei Tian, Weibo Yang, Yu Zhang.
      Neuroinflammation and tau pathology are central drivers of Alzheimer's disease (AD) progression, necessitating multi-target therapeutic strategies. Here, we evaluated the efficacy and mechanisms of 0242, a novel small-molecule derivative optimized from the berberine scaffold. In lipopolysaccharide (LPS)-stimulated BV-2 microglia, 0242 treatment significantly inhibited cell activation and nitric oxide release without cytotoxicity, while downregulating the mRNA levels of pro-inflammatory cytokines IL-1β and TNF-α. Transcriptomic profiling revealed that 0242 modulated LPS-induced inflammatory gene signatures by enriched core signaling cascades, including NF-κB, TLR, and JAK-STAT and upregulating cytoprotective genes such as ceruloplasmin (Cp) and Bcl2a1b. In vivo, oral administration of 0242 attenuated hippocampal astrocyte and microglial activation in an LPS-induced acute neuroinflammatory mouse model. Furthermore, in female P301S tau transgenic mice, 0242 treatment significantly improved spontaneous locomotor activity and recognition memory. Histological and biochemical analyses confirmed that 0242 suppressed hippocampal glial activation and reduced total tau protein levels in the prefrontal cortex. Collectively, these findings suggest that 0242 may exert potent anti-neuroinflammatory effects by modulating multiple immune signaling cascades and uniquely alleviates tau pathology in AD.
    Keywords:  0242; Alzheimer’s disease; Neuroinflammation
    DOI:  https://doi.org/10.1007/s11064-026-04834-3
  62. bioRxiv. 2026 Jul 03. pii: 2026.06.30.735697. [Epub ahead of print]
    The NORAD -pumilio regulatory axis links lncRNA dysregulation to tau propagation-associated phenotypes.
    Dominantly Inherited Alzheimer Network
      Long non-coding RNAs (lncRNAs) are increasingly implicated in neurodegenerative disease, yet their roles in tauopathy remain poorly understood. Here, we defined the lncRNA landscape across iPSC-derived neurons, astrocytes, and microglia harboring the frontotemporal dementia-associated MAPT IVS10+16 mutation and investigated how lncRNA dysregulation interfaces with tau pathology. Transcriptomic analyses revealed extensive cell-type specific lncRNA expression changes, with neurons exhibiting the greatest degree of mutation-associated remodeling. Comparative analyses with MAPT IVS10+16 patient brain tissue identified NORAD and MIR22HG as lncRNAs significantly dysregulated across all three cell types and human brains. NORAD was also altered in Alzheimer's disease and Parkinson's disease brains, suggesting a broader role in neurodegenerative disease. Mechanistically, NORAD -associated protein networks converged on pathways related to RNA regulation, cytoskeletal organization, proteostasis, and tau interaction networks. Given the established role of NORAD in regulating PUM1 and PUM2 RNA-binding (pumilio) proteins, we examined the NORAD -pumilio axis and identified enrichment of pumilio-associated pathways linked to autophagy, endocytosis, proteostasis, and cytoskeletal regulation. NORAD depletion reduced tau seeding and uptake, whereas functional depletion of PUM1 or PUM2 increased both processes, supporting an antagonistic relationship between NORAD and pumilio signaling in modulation of tau aggregation. Together, these findings identify widespread lncRNA dysregulation across neural cell types in the setting of a MAPT mutation and nominate the NORAD -pumilio axis as a regulatory pathway linking RNA homeostasis and tau propagation biology.
    DOI:  https://doi.org/10.64898/2026.06.30.735697
  63. Sleep. 2026 Jul 07. pii: zsag182. [Epub ahead of print]
    Chronic intermittent hypoxia impairs glymphatic function in male mice through ENT-dependent adenosine dysregulation.
    Chenlei Peng, Xiaoting Sun, Ziyi Zhang, Manli Jia, Jiayi Jin, Yan He, Wu Zheng, Jiangfan Chen, Xuzhao Zhou, Xiaohong Cai.
      Chronic intermittent hypoxia (CIH), a defining feature of obstructive sleep apnea, is strongly associated with cognitive impairment and increased risk of neurodegenerative disease, yet the underlying mechanisms linking hypoxic stress to disrupted brain homeostasis remain poorly defined. Impaired glymphatic clearance has been reported in patients with obstructive sleep apnea, but whether and how intermittent hypoxia directly alters glymphatic function is unknown. Here, we investigated the effects of acute and chronic intermittent hypoxia on cerebrospinal fluid-interstitial fluid exchange in male mice and examined the molecular mechanisms governing these effects. Using tracer-based influx and efflux assays, in vivo two-photon imaging, behavioral testing, and genetic and pharmacological manipulation, we show that intermittent hypoxia exerts a duration-dependent, biphasic effect on glymphatic function. Acute exposure transiently enhanced glymphatic influx and efflux, whereas prolonged CIH progressively impaired glymphatic transport, disrupted perivascular aquaporin-4 (AQP4) polarization, reduced vascular pulsatility, and impaired spatial working memory. CIH was associated with reduced extracellular adenosine levels, suppression of cerebral energy metabolism, and altered expression of equilibrative nucleoside transporters (ENTs). Genetic ablation of AQP4 abolished CIH-induced glymphatic impairment, confirming its essential role in hypoxia-induced glymphatic dysfunction. Importantly, pharmacological inhibition or genetic deletion of ENT1 and deletion of ENT2 restored adenosine availability, normalized AQP4 polarization and vascular dynamics, and rescued glymphatic dysfunction and cognitive deficits under CIH. These findings identify ENT-dependent dysregulation of adenosine signaling as a key mechanism by which chronic intermittent hypoxia compromises glymphatic clearance, providing mechanistic insight into how sleep-disordered breathing disrupts brain waste removal and cognitive function.
    Keywords:  Adenosine signaling; Aquaporin-4; Chronic intermittent hypoxia; Glymphatic; Obstructive sleep apnea
    DOI:  https://doi.org/10.1093/sleep/zsag182
  64. Nat Neurosci. 2026 Jul;29(7): 1528
    Clarity in clearance pathways.
    Leonie Welberg.
      
    DOI:  https://doi.org/10.1038/s41593-026-02371-4
  65. bioRxiv. 2026 Jun 29. pii: 2026.06.26.734883. [Epub ahead of print]
    Mesothelial Plasticity Specifies a Pleural Immune Circuit that Orchestrates Lung Regeneration.
    Le Xu, Kevin H Chen, Barsha Dash, Bingpeng Yao, Rongbo Li, Xingan Wang, Zihe Zhou, Vincent Yu, Rebecca Salamon, Pushpinder S Bawa, Minzhe Guo, Zea Borok, Darrell N Kotton, Oliver Eickelberg, Marta Bueno, Xin Sun.
      Following injury, predisposition towards regenerative repair and away from degenerative remodeling is central to organismal health, yet the upstream determinants that instruct this fate choice remain poorly understood. Here, we identify mesothelial cell plasticity as a central determinant between regeneration and degeneration by comparing mouse models of pneumonectomy (PNX) versus chronic lung allograft dysfunction (CLAD). While mesothelial cells expand in both settings, following PNX, these cells undergo differentiation through multiple transitional states, culminating in an inflammatory population that orchestrates monocyte recruitment and subsequent tissue regeneration. In contrast, in CLAD, mesothelial cells enrich in an extracellular matrix-enriched state that lacks pro-regenerative signaling capacity. Using single cell epigenomic profiling and in vivo genetics, we define a mesothelium-specific TWIST1-CCL2 axis that governs mesothelium plasticity and signaling, monocyte recruitment and lung regrowth. Together, these findings demonstrate that context-dependent reprogramming of a pleural population, known to protect organs, can be leveraged to drive regeneration.
    DOI:  https://doi.org/10.64898/2026.06.26.734883
  66. bioRxiv. 2026 Jun 29. pii: 2026.06.26.734874. [Epub ahead of print]
    Notch Signaling Reprograms Glial Lipid Metabolism to Promote Hypoxia Resistance.
    Yajuan Li, Qin Shuo, Anna Wang, Charlene Miciano, Allen Wang, Dan Zhou, Gabriel G Haddad, Lingyan Shi.
      Hypoxia poses a major threat to the developing nervous system, where high metabolic demand is required to support brain growth, glial and neuronal maturation, and function. Although glial cells are essential for maintaining neural homeostasis under stress, how specific glial subtypes remodel metabolism to promote hypoxia tolerance remains poorly understood. Here, we identify a Notch-dependent lipid metabolic program in excitatory amino acid transporter 1 (Eaat1)-positive glia that supports hypoxia adaptation in the developing Drosophila larval brain. Using stimulated Raman scattering (SRS) microscopy combined with deuterium-labeled metabolic probes, we visualized substrate-specific metabolic activity in vivo at subcellular resolution. In control, non-adapted flies, we found that acute hypoxia markedly increased de novo lipogenesis in Eaat1-positive glia. In flies adapted to chronic hypoxia, Eaat1-positive glia exhibited a pre-programmed metabolic shift, characterized by reduced glucose-derived lipogenesis and enhanced acetate-derived lipid synthesis. Constitutive activation of Notch signaling in Eaat1-positive glia was sufficient to phenocopy this acetate-favored lipogenic state, suggesting that Notch promotes metabolic plasticity under oxygen-limited conditions. To define the transcriptional programs associated with this response, we performed single-nucleus RNA sequencing (snRNA-seq) of the developing Drosophila central nervous system and mapped Eaat-1expressing cell populations across hypoxia and Notch activation. Notch activation reshaped hypoxia-associated transcriptional responses and counteracted metabolic suppression caused by low oxygen. Together, our findings identify Eaat1-positiveglia as a metabolically adaptive glial population and reveal a conserved Notch-regulated mechanism that rewires lipid metabolism to support hypoxia tolerance in the developing brain. These results provide insight into glial metabolic strategies that may be relevant to hypoxia-associated neurological conditions, including neonatal hypoxic-ischemic brain injury and ischemic stroke.
    DOI:  https://doi.org/10.64898/2026.06.26.734874
  67. Neurotherapeutics. 2026 Jul 09. pii: S1878-7479(26)00132-7. [Epub ahead of print]23(4): e00962
    Zinc as a phase-specific therapeutic target in hypoglycemia-induced brain injury.
    Dong Gyun Ko, Hyun Wook Yang, Hyun Ho Jeong, Min Kyu Park, Bo Young Choi, Seok Joon Won, Raymond A Swanson, Sang Won Suh.
      Hypoglycemia remains a major cause of neurological morbidity. However, effective targeted therapies for affected brain regions remain lacking. Although excitotoxicity and energy failure have long been implicated, emerging evidence has identified dysregulated zinc signaling as a central mediator of neuronal vulnerability and recovery. During acute glucose deprivation, synapse-released zinc accumulates intracellularly, impairing mitochondrial function, activating nicotinamide adenine dinucleotide phosphate oxidase, amplifying oxidative stress, and triggering poly (ADP-ribose) polymerase-dependent cell death pathways. Notably, neuronal injury is markedly exacerbated during glucose reperfusion, when zinc-reactive oxygen species coupling drives metabolic collapse. During the recovery phase, zinc contributes to neurogenesis, synaptic remodeling, and circuit repair, underscoring its phase-dependent duality. Here, we synthesize mechanistic and translational evidence supporting zinc as a dynamic regulator of neuronal fate in hypoglycemia-induced brain injury. We propose that zinc functions as a metabolic switch linking acute oxidative injury to subsequent regenerative processes. Importantly, this framework suggests a precision-timed therapeutic strategy involving acute zinc chelation or inhibition of zinc-coupled oxidative pathways during injury, followed by controlled restoration of zinc-dependent signaling during recovery. By redefining hypoglycemic brain injury through phase-specific zinc modulation, we identify new therapeutic opportunities relevant not only to hypoglycemia but also to broader metabolic and ischemic brain disorders.
    Keywords:  Excitotoxicity; Glucose deprivation and reperfusion; Hypoglycemia; Neuron death; Zinc
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00962
  68. Nat Neurosci. 2026 Jul 06.
    Author Correction: A route for cerebrospinal fluid flow through leptomeningeal arterial-venous overlaps enables macromolecule and fluid shunting.
    Benjamin A Plog, Kyungdeok Kim, Daan Verhaege, Min Woo Kim, Zachary Papadopoulos, Krikor Dikranian, Taitea Dykstra, Jay Cao, Richard J Perrin, Katherine E Schwetye, Jonathan Kipnis, Antoine Drieu.
      
    DOI:  https://doi.org/10.1038/s41593-026-02385-y
  69. Neurosci Bull. 2026 Jul 06.
    Optimized Midbrain Organoid Transplantation Restores Dopaminergic Nigrostriatal Pathway and Motor Function in Parkinson's Disease Mouse Model.
    Lin-Bo Chen, Xin-Yu She, Xi Jiang, Peng-Jian Wu, Chang-Qing Zheng, Jun Yao.
      Parkinson's disease (PD) is characterized by the progressive degeneration of midbrain dopaminergic (DA) neurons, leading to disruption of the nigrostriatal pathway and motor deficits. Here, we present an optimized protocol for generating human midbrain organoids (hMOs) suitable for homotopic transplantation, through sequential modifications. Homotopic transplantation of these optimized hMOs into the substantia nigra (SN) of 6-hydroxydopamine (6-OHDA)-lesioned PD mice resulted in significant graft survival, with a majority of grafted cells expressing the A9-specific neuronal marker GIRK2. The grafts reconstituted the nigrostriatal pathway, as confirmed by restored DA fiber density, elevated striatal dopamine levels, and retrograde AAV tracing. These structural improvements were accompanied by notable behavioral recovery, including reduced apomorphine-induced rotations, enhanced rotarod performance, and restored limb symmetry in cylinder tests. Our findings demonstrate that optimized hMOs, when transplanted into their native niche, can reestablish functional circuitry and alleviate motor deficits, providing an efficient and clinically relevant strategy for PD therapy.
    Keywords:  Homotopic transplantation; Human midbrain organoids (hMOs); Induced pluripotent stem cells (iPSCs); Parkinson’s disease (PD)
    DOI:  https://doi.org/10.1007/s12264-026-01669-4
  70. Proc Natl Acad Sci U S A. 2026 Jul 14. 123(28): e2603875123
    Histone chaperone HIRA regulates adiponectin expression and obesity-associated adipose expansion by facilitating Pol II pause release.
    Danyang Wan, Ji-Eun Lee, Young-Kwon Park, Guojia Xie, Susanna Maisto, Christabelle Agyapong, Keiko Ozato, Oksana Gavrilova, Kai Ge.
      Adipose tissue is essential for maintaining glucose and lipid homeostasis in mammals. However, epigenomic mechanisms underlying adipose tissue function remain largely unclear. Here, we identify the histone chaperone HIRA as an epigenomic regulator of adipose tissue function. Adipose tissue-specific knockout of Hira in mice impairs insulin sensitivity and restrains adipose tissue expansion during high-fat diet-induced obesity. Mechanistically, HIRA is required for the expression of Adipoq, encoding the adipokine adiponectin, and lipid metabolism genes in adipose tissue. Genomic mapping reveals that HIRA binds to promoters and enhancers of Adipoq and lipid metabolism genes in adipocytes. Acute HIRA depletion using the dTAG system, followed by nascent RNA-Seq and ChIP-Seq, demonstrates that while HIRA is largely dispensable for enhancer activation and coactivator binding, it promotes transcription of target genes by facilitating RNA polymerase II pause release and subsequent elongation likely independently of H3.3 deposition. Our findings uncover a mechanism by which HIRA regulates transcription and establish HIRA's critical role in insulin sensitivity and lipid metabolism, providing a potential therapeutic target for obesity and insulin resistance.
    Keywords:  adipocyte metabolism; adiponectin; adipose expansion; histone chaperone HIRA; transcriptional regulation
    DOI:  https://doi.org/10.1073/pnas.2603875123
  71. Commun Biol. 2026 Jul 07.
    Age-associated niche remodeling drives dental pulp progenitor dysfunction and fibrosis.
    Xiaoyi Yu, Tianmeng Sun, Mengyu Xu, Tianyuan Zhao, Huanyu Luo, Qing Zhong, Cangwei Liu, Zhengwen An.
      Dental pulp homeostasis and regeneration rely on specialized mesenchymal populations, yet aging promotes fibrotic remodeling and functional decline. Here, using the continuously growing mouse incisor as an experimentally tractable model, we integrate single-cell RNA sequencing, spatial transcriptomics, lineage tracing, and functional assays to investigate age-associated pulp remodeling. We identify a distinct Lypd1+ fibroblast progenitor population that is particularly vulnerable to age-associated dysfunction. Lineage tracing and trajectory analysis show that these cells originate from the Sfrp2hi stem cell pool, while functional studies of MACS-isolated human LYPD1+ cells provide supportive evidence for a related progenitor-like state. Notably, early aging preferentially affects Lypd1+ progenitors, rather than Sfrp2hi stem cells, promoting fibrotic conversion through aberrant upregulation of 11β-HSD2, which enhances aldosterone-mediated mineralocorticoid receptor (MR)-associated signals. Additionally, aging promotes the accumulation of Ccl4+ macrophages that establish a pro-inflammatory niche, where macrophage-derived PDGFB induces 11β-HSD2 via the P38 MAPK signaling. In vivo inhibition of the PDGF/P38/11β-HSD2 axis attenuates age-related pulp fibrosis. Together, our findings indicate that age-associated pulp fibrosis in this model is driven, at least in part, by niche-mediated metabolic reprogramming of progenitor cells rather than intrinsic stem cell exhaustion, highlighting corticosteroid metabolism as a potential therapeutic target for fibrotic degeneration in aging dental pulp.
    DOI:  https://doi.org/10.1038/s42003-026-10632-y
  72. J Exp Med. 2026 Aug 03. pii: e20252556. [Epub ahead of print]223(8):
    Bridging veins govern discrepancy of CSF efflux into dura mater in mice.
    Lingli Yan, Senthil Kumaran Satyanarayanan, Di Huang, Yanzhu Qin, Di Wu, Jianheng Lai, Dajiang Qin, Huanxing Su.
      Meningeal lymphatic vessels within the dura provide a route for cerebrospinal fluid (CSF) outflow, but how CSF crosses the arachnoid barrier, particularly toward basal dural compartments, remains unclear. Using in vivo CSF tracer infusion and ultrastructural analysis in mice, we show that bridging vein-associated arachnoid cuff exit (ACE) domains provide specialized routes for CSF movement from the SAS into the dura. These ACE-associated structures are abundant in the basal than dorsal meninges, supporting preferential CSF efflux toward basal meningeal lymphatics. In contrast, spinal meninges lack comparable ACE structures, and spinal CSF exits along the nerve root arachnoid sleeves rather than entering the spinal dura. Depletion of parenchymal border macrophages stalls tracer movement, leading to retention within the subarachnoid and dural compartments, revealing their regulatory role in arachnoid-bypassing CSF drainage. These findings establish a compartmentalized CSF outflow model, in which basal bridging vein-associated ACE structures serve as major dural exit portals, with dorsal limitation and spinal exclusion.
    DOI:  https://doi.org/10.1084/jem.20252556
  73. Neuropathol Appl Neurobiol. 2026 Aug;52(4): e70091
    Reduced Soluble Ubiquilin2 in Amyotrophic Lateral Sclerosis Carrying Ubiquilin2 (P494L) Mutation: Clinicopathological and Biochemical Evidence From an Autopsy Case.
    Tadashi Adachi, Toshiya Nakano, Kentaro Yoshida, Yuki Suzuki, Mayuko Sakuwa, Masato Hasegawa, Alfi Raudatil Jannah, Norikazu Hara, Akinori Miyashita, Takeshi Ikeuchi, Ritsuko Hanajima.
      We report the clinicopathological and biochemical findings of ALS associated with a UBQLN2 P494L mutation. Autopsy revealed widespread TDP-43 pathology and UBQLN2-positive inclusions. Immunoblot analysis demonstrated a marked reduction of soluble UBQLN2, supporting functional UBQLN2 insufficiency as a pathogenic mechanism underlying TDP-43 aggregation.
    Keywords:  TDP‐43; Ubiquilin2; amyotrophic lateral sclerosis; immunoblotting; intranuclear inclusion
    DOI:  https://doi.org/10.1111/nan.70091
  74. Alzheimers Dement. 2026 Jul;22(7): e71666
    Glutamate carboxypeptidase II activation in astrocytes mediates glymphatic impairment and cognitive vulnerability in the aging brain following surgery.
    Yuto Hasegawa, Hiroki Kawai, Robyn Wiseman, Gianluca Ursini, Hannah Alton, Feiyi Xiong, Sohan Gummadi, Naomi Mao, Kyle Mailhot, Yannan Li, Xiaolei Zhu, Tomoyo Sawada, Barbara Slusher, Atsushi Kamiya.
       INTRODUCTION: Perioperative neurocognitive disorder is a common and debilitating complication in the elderly, yet its cellular and molecular mechanisms in the aging brain remain poorly understood.
    METHODS: Using aged mice, we examined the impact of abdominal surgery on cognition, glymphatic activity, and astrocyte function. Sex-dependent mechanisms were investigated by integrating single-cell RNA sequencing with astrocyte-specific genetic and pharmacological manipulation.
    RESULTS: Abdominal surgery induced male-specific deficits in recognition and spatial memory, reduced hippocampal glymphatic influx, and glutamate accumulation in aged mice. These changes were associated with male-specific upregulation of glutamate signaling in a distinct astrocyte subpopulation, enhanced astrocytic glutamate carboxypeptidase II (GCPII) activity, and loss of aquaporin-4 (AQP4) polarization. Astrocyte-specific GCPII knockdown rescued cognitive deficits and hippocampal glymphatic influx, consistent with pharmacological GCPII inhibition ameliorating glutamate levels, AQP4 polarization, and cognitive performance.
    DISCUSSION: These findings identify astrocytic GCPII-mediated glutamate dysregulation as a mechanism contributing to sex-specific postoperative cognitive vulnerability in aging.
    Keywords:  aging; astrocytes; glutamate carboxypeptidase II; glymphatic system; perioperative neurocognitive disorder; sex differences
    DOI:  https://doi.org/10.1002/alz.71666
  75. Immun Ageing. 2026 Jul 10.
    Virtual memory CD8⁺ T cells in aging: heterogeneity, bystander protection, inflammatory potential, and inhibitory regulation.
    Archit Kumar, Raymond Yung.
      Aging reshapes the CD8⁺ T cell compartment through contraction of the naïve pool and expansion of memory-phenotype populations, including the progressive accumulation of antigen-inexperienced virtual memory (VM) CD8⁺ T cells. VM CD8⁺ T cells arise in the absence of foreign antigen priming and acquire a memory-like phenotype. In aged hosts, VM CD8⁺ T cells constitute a substantial fraction of the antigen-inexperienced memory-phenotype CD8⁺ T cell pool, and their differentiation is shaped by self-reactivity, homeostatic cytokines, and transcriptional programs linked to IL-15 and EOMES. During aging, VM CD8⁺ T cells accumulate numerically, display altered proliferative responses, retain sensitivity to homeostatic and inflammatory cytokines, and can preserve effector function during infection. These features suggest that VM CD8⁺ T cells may partially compensate for the age-associated loss of naïve CD8⁺ T cells by providing rapid effector-like responses. At the same time, aged VM CD8⁺ T cells appear to comprise heterogeneous subsets, including populations with cytotoxic and inflammatory potential. Emerging evidence suggests that inhibitory receptors may mark distinct VM states during aging, although their functional significance and potential regulatory role remain to be established.
    Keywords:  Aging; CD8+ T cells; Granzymes; Inflammation; Memory T cells; Virtual memory T cells
    DOI:  https://doi.org/10.1186/s12979-026-00582-8
  76. J Prev Alzheimers Dis. 2026 Jul 04. pii: S2274-5807(26)00167-6. [Epub ahead of print]13(8): 100643
    Tau-ing and fro-ing: the tanycytic shuttle in neurodegeneration.
    Vincent Prévot, Markus Schwaninger, Ruben Nogueiras, S Rasika.
      After more than a century since Alzheimer's disease (AD) was described and decades of research into β-amyloid and Tau proteins, mechanisms underlying pathogenic protein clearance from brain remain poorly understood. Recent research identifies tanycytes-specialized hypothalamic cells lining the third ventricle-as a previously unrecognized clearance system for brain Tau. These cells actively transport Tau from cerebrospinal fluid to blood via pituitary portal circulation but are dramatically fragmented in AD brains. Single-nucleus RNA sequencing reveals altered stress and transport gene expression in AD tanycytes, while functional studies show disrupted tanycytic transport reduces Tau efflux and exacerbates pathology. Beyond protein clearance, tanycytes maintain critical metabolic and neuroendocrine pathways influencing cognition. Their unique blood-brain interface position makes them attractive therapeutic targets. As transcriptomic evidence suggests tanycytes are hotspots for age-related changes, their dysfunction may herald "tanycytopathies" underlying multiple neurodegenerative disorders.
    Keywords:  Brain clearance mechanisms; TAU efflux; Tanycytes; Tanycytopathies
    DOI:  https://doi.org/10.1016/j.tjpad.2026.100643
  77. Neurochem Int. 2026 Jul 07. pii: S0197-0186(26)00112-9. [Epub ahead of print] 106221
    Thymus-derived myeloid programs track microglial tolerance states across human cohorts.
    Sanwal Ahmad Zafar, Wei Qin, Liu Chengliang, Areeba Ali Khan, Muhammad Salman Faisal.
       INTRODUCTION: Microglial functional positioning varies across individuals and disease contexts, yet conserved biological axes supporting reproducible cross-cohort inference remain poorly defined. Intrathymic T cell development offers a paradigm in which chemokines, extracellular matrix (ECM)/adhesion factors, and axon guidance cues jointly govern immune cell migration and selection. We asked whether thymus-derived transcriptional programs provide a transferable basis for quantifying microglial tolerance-like positioning across independent human cohorts.
    METHODS: We applied consensus non-negative matrix factorization to Tabula Sapiens thymus single-cell transcriptomes to derive eight Myeloid Education Signatures (MES); under formal enrichment testing, two were significantly enriched for ECM/adhesion biology and the rest were treated as data-driven programs without a dominant axis. MES scores were projected into four independent microglia cohorts (SEA-AD, Olah, Tuddenham, multiple sclerosis; >100 donors) and related to a donor-level tolerance score (homeostatic minus activation gene-set activity). Glucocorticoid receptor (GR) activity, calibrated from an external perturbation dataset, was evaluated as a moderator. Cross-cohort synthesis used random-effects meta-analysis with sensitivity analyses and multiple testing control.
    RESULTS: Seven of eight MES modules were inversely associated with tolerance positioning; the eighth (MES08, defined by CCL2/CXCL2 chemokine genes) showed the most heterogeneous coupling across cohorts. The association strengthened monotonically with microglial purity in three of four cohorts, was recapitulated in Visium spatial transcriptomics, and was robust to covariate adjustment, housekeeping-gene removal, and leave-one-dataset-out sensitivity. This coupling was preferential to thymus-derived modules: modules built identically from six other tissues (blood, spleen, liver, lung, bone marrow, lymph node) coupled 1.2 to 2.9 fold less strongly, across module-number and feature-selection choices. Under a formal per-module interaction model, GR activity did not moderate the association, a well-powered null reproduced with a canonical GR panel and an external cohort. Irisin pathway (five-gene FNDC5/PPARGC1A module) associations were modest and largely non-significant after correction.
    CONCLUSIONS: Thymus-derived myeloid programs constitute a transferable, tissue-preferential axis inversely coupled to microglial tolerance-like positioning, without detectable glucocorticoid moderation.
    Keywords:  Alzheimer’s disease; innate immune tolerance; microglia; myeloid education signatures; single-cell transcriptomics; thymus
    DOI:  https://doi.org/10.1016/j.neuint.2026.106221
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