bims-micgli Biomed News
on Microglia
Issue of 2026–02–15
fifty-one papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Functional border-associated macrophages limit Alzheimer's Disease progression.
  2. Amyloid β-Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology.
  3. TREM2 and APOE are dispensable for microglial clearance of dying neurons revealed by in vivo imaging.
  4. Levetiracetam prevents Aβ production through SV2a-dependent modulation of APP processing in Alzheimer's disease models.
  5. VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.
  6. Inhibition of TGF-β signaling in microglia stimulates hippocampal adult neurogenesis and reduces anxiety-like behavior in adult mice.
  7. Differential downstream signaling in microglia lacking Alzheimer's-related TREM2 or its adaptor TYROBP/DAP12.
  8. Microglia TFEB activation attenuates Alzheimer's disease pathology by enhancing autophagy-lysosomal function.
  9. TSC-associated microglial hyperactivity: enhanced calcium signaling, metabolism, and phagocytosis.
  10. Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice.
  11. Microglia at the Forefront: New Insights From the Glial Club South Cone Meeting 2025.
  12. Amyloid β Instigates Cardiac Neurotrophic Signaling Impairment, Driving Alzheimer's Associated Heart Disease.
  13. Greater locus coeruleus vulnerability in atypical clinicopathologic forms of Alzheimer's disease.
  14. Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.
  15. TREM2 activation suppresses central sensitisation by promoting autophagy in a chronic migraine model with recurrent nitroglycerin stimulation in mice.
  16. Astrocyte-specific deletion of LRRC8A causes neurological dysfunction but not chronic white matter edema.
  17. Coffee linked to slower brain ageing in study of 130,000 people.
  18. Cell type-resolved proteomics reveals intra- and intercellular signaling in Alzheimer's disease.
  19. Neutrophil-microglia interaction drives motor dysfunction in neuromyelitis optica model induced by subarachnoid AQP4-IgG.
  20. Immunometabolism Reframes Alzheimer's Disease: From Systemic Dysmetabolism to Glial Rewiring.
  21. Ketogenic diet dampens excitatory neurotransmission by shrinking synaptic vesicle pools.
  22. MST1 promotes microglial pyroptosis and neuroinflammation in alzheimer's disease by regulating the novel DPP8/NLRP1/Caspase-1/GSDMD-N axis.
  23. Microglia-Derived Extracellular Vesicles from Alzheimer's Disease Patients Carry miRNAs Driving a Neuroinflammatory Response.
  24. Membrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop.
  25. Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis.
  26. Myelin sheaths in the central nervous system can withstand damage and dynamically remodel.
  27. Th17 effector cytokines induce shared and distinct microglial and endothelial cell responses in post-streptococcal encephalitis.
  28. Liver-X-receptor agonism enhances T cell priming and activation to promote anti-tumor immunity.
  29. Alterations in secondary lipids are associated with neuroinflammation in the brain of Neu1-deficient mice.
  30. A 6-year-old boy with left temporal lobe mass.
  31. FKBP5 regulates interferon signaling leading to myeloid cell activation in multiple sclerosis.
  32. Early microglial priming in Alzheimer's disease revealed by ME-seq.
  33. Munc13-1 couples DAG and Ca2+ signaling to dynamic vesicle priming, synaptic short-term plasticity, and posttetanic potentiation.
  34. A Protective Role of Hydrogen Sulfide Donor GYY4137 Through Activated Microglia-induced Anti-inflammatory Cytokines in the Spinal Cord of Diabetic Rats.
  35. Docosahexaenoic acid supplementation aggravates myasthenia gravis through immune dysregulation.
  36. Alterations in cerebrospinal fluid levels of myelin- and oligodendrocyte-related proteins in sporadic Creutzfeldt-Jakob disease.
  37. D178N prion protein mutation endows RML prions with new strain properties that do not mimic human genetic prion diseases.
  38. Spatial transcriptomics reveals brain-wide circadian disruption in an Alzheimer's disease model.
  39. Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
  40. APOE4-driven T cell dysregulation in Alzheimer's disease: single-cell genomics and Mendelian randomization reveal novel therapeutic targets.
  41. Comparative analysis of key phagocytic genes in humans and mice using machine learning integrated with single-cell RNA sequencing.
  42. Human microglia express anti-inflammatory ISG15 in response to Neisseria meningitidis.
  43. Sleep-dependent clearance of brain lipids by peripheral blood cells.
  44. Shedding light on interventions for brain aging.
  45. A neuron type-specific microexon in Ank3/ankyrin-G modulates calcium activity and neuronal excitability.
  46. Microglia makeover: On-demand control panel revamp.
  47. Distinct CSF lipidomic profiles are associated with five proteomic subtypes in patients with Alzheimer's disease.
  48. Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease.
  49. TREM2 Facilitates Myelin Debris Clearance but Exacerbates Chronic Inflammation and Fibrosis After Spinal Cord Injury.
  50. A macrophage-induced subpopulation of mesenchymal cells expressing Fcer1g contributes to wound-induced fibrosis.
  51. Natalizumab exacerbates astrocytopathy in NMOSD via blockade of endothelial VCAM1-astrocytic integrin α4 interaction.
  1. bioRxiv. 2026 Feb 03. pii: 2026.01.31.703045. [Epub ahead of print]
    Functional border-associated macrophages limit Alzheimer's Disease progression.
    Drew Adler, Natália Pinheiro-Rosa, Alon Millet, Zoran Z Gajic, Evan Cheng, Begoña Gamallo-Lana, Yosuke Morizawa, Eric Klann, Wen-Biao Gan, Adam C Mar, Jose H Ledo, Hernandez Moura Silva, Juan J Lafaille.
      Brain-resident macrophages are known to play numerous roles in the progression of Alzheimer's Disease (AD). However, the relative contribution of microglia and border-associated macrophages (BAM) to AD pathogenesis has been difficult to disentangle. We recently identified Maf , a newly described AD GWAS gene, as essential for BAM, but not microglial, survival. By crossing BAM depleted mice with the 5xFAD AD model, we found stark evidence of cerebral amyloid angiopathy (CAA), increased overall β-amyloid burden, accelerated markers of neurodegeneration, and early memory deficits. In the healthy brain, BAM take up more β-amyloid per cell than microglia. However, as disease progresses, both in human AD patient samples and model AD mice, BAM number is reduced, and the remaining BAMs display impaired endocytic capacity, and show signs of metabolic exhaustion at an earlier age than microglia. Thus, strategies to preserve or restore BAM function represents a novel therapeutic avenue for AD and CAA.
    DOI:  https://doi.org/10.64898/2026.01.31.703045
  2. J Neurochem. 2026 Feb;170(2): e70380
    Amyloid β-Cholesterol Interplay: Removal of Cholesterol From the Membranes to Catalyze Aggregation and Amyloid Pathology.
    Rishiram Baral, Ruan van Deventer, Yuri L Lyubchenko.
      The interplay between the cholesterol metabolism and assembly of Aβ42 (the 42-residue form of the amyloid-β peptide) peptides in pathological aggregates is considered one of the major molecular mechanisms in the development of Alzheimer's disease (AD). Numerous in vitro studies led to the finding that high cholesterol levels in membranes accelerate the production of Aβ aggregates. The molecular mechanisms explaining how cholesterol localized inside the membrane bilayer catalyzes the assembly of Aβ aggregates above the membrane remain unknown. We addressed this problem by combining different AFM modalities, including imaging and force spectroscopy, with fluorescence spectroscopy. Our combined studies revealed that Aβ42 was capable of removing cholesterol from the membrane. Importantly, physiologically low concentrations of Aβ42 demonstrate such ability. Extracted cholesterol interacts with Aβ42 and accelerates its on-membrane aggregation, which is a molecular mechanism explaining how cholesterol embedded in the membrane accelerates Aβ42 aggregation. The discovered ability of Aβ42 to remove cholesterol from membranes resulted in three major AD-related events. First, free cholesterol catalyzes the assembly of Aβ42 in aggregates, which is the mechanism by which physiologically important Aβ42 monomers are converted into their pathological form. Second, the release of cholesterol from membranes leads to its accumulation in the brain, which is one of the risk factors associated with disease development and progression. Third, cholesterol depletion decreases membrane stiffness, which can result in deterioration of the function of membrane-bound proteins, such as dendritic spine degeneration and, ultimately, synapse loss, a common pathological feature of AD.
    Keywords:  AFM; Alzheimer's disease; Aβ42; amyloid beta; cholesterol; membranes; protein aggregation
    DOI:  https://doi.org/10.1111/jnc.70380
  3. iScience. 2026 Feb 20. 29(2): 114559
    TREM2 and APOE are dispensable for microglial clearance of dying neurons revealed by in vivo imaging.
    Anupama Rai, Eyiyemisi C Damisah, Robert A Hill, Lei Tong, Jaime Grutzendler.
      TREM2 and APOE are major Alzheimer's disease (AD) risk genes that may influence microglial pathophysiology by affecting their ability to phagocytose cellular debris and protein aggregates. Here, we investigated the impact of TREM2 and APOE on the removal of dying neurons in the live brain by combining a targeted photochemical method for programmed cell death with high-resolution two-photon imaging in adult mice. We show that deletion of either Trem2 or Apoe does not affect the dynamics of microglia engagement with dying neurons or their efficiency in phagocytosing corpses. Notably, microglia encapsulating amyloid deposits phagocytosed nearby dying cells without disengaging from plaques or moving their cell bodies; however, in the absence of TREM2, microglial cell bodies readily migrated toward dying cells, subsequently disengaging from plaques. These findings indicate TREM2 and APOE variants likely confer AD risk through mechanisms independent of impaired neuronal corpse phagocytosis.
    Keywords:  Cell biology; Molecular biology; Neuroscience
    DOI:  https://doi.org/10.1016/j.isci.2025.114559
  4. Sci Transl Med. 2026 Feb 11. 18(836): eadp3984
    Levetiracetam prevents Aβ production through SV2a-dependent modulation of APP processing in Alzheimer's disease models.
    Nalini R Rao, Ivan Santiago-Marrero, Olivia DeGulis, Toshihiro Nomura, Kritika Goyal, SeungEun Lee, Timothy J Hark, Justin C Dynes, Emily X Dexter, Maciej Dulewicz, Junyue Ge, Arun Upadhyay, Eugenio F Fornasiero, Robert Vassar, Jörg Hanrieder, Anis Contractor, Jeffrey N Savas.
      Amyloid-β (Aβ) peptides are a defining feature of Alzheimer's disease (AD). These peptides are produced by the proteolytic processing of the amyloid precursor protein (APP), which can occur through the synaptic vesicle (SV) cycle. However, how amyloidogenic APP processing alters SV composition and presynaptic function is poorly understood. Using App knock-in mouse models of amyloid pathology, we found that proteins with impaired degradation accumulate at presynaptic sites together with Aβ42 in the SV lumen. Levetiracetam (Lev) is a US Food and Drug Administration-approved antiepileptic that targets SVs and has shown therapeutic potential to reduce AD phenotypes through an undefined mechanism. We found that Lev lowers Aβ42 levels by reducing amyloidogenic APP processing in an SV2a-dependent manner. Lev modified SV cycling and increased APP cell surface expression, which promoted its preferential processing through the nonamyloidogenic pathway. Stable isotope labeling combined with mass spectrometry confirmed that Lev prevents Aβ42 production in vivo. In transgenic mice with aggressive amyloid pathology, electrophysiology and immunofluorescence confirmed that Lev restores SV cycling abnormalities and reduces synapse loss. Last, early Aβ pathology in brains from donors with Down syndrome was characterized by elevated presynaptic proteins. Together, these findings highlight the potential to prevent Aβ pathology before irreversible damage occurs.
    DOI:  https://doi.org/10.1126/scitranslmed.adp3984
  5. Sci Adv. 2026 Feb 13. 12(7): eadz5645
    VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's neurons.
    Leonie M Heger, Francesco Gubinelli, Andreas J Huber, Aida Cardona-Alberich, Matteo Rovere, Ulf Matti, Stephan A Müller, Sankarshana R Nagaraja, Lena Jaschkowitz, Martina Schifferer, Wolfgang Wurst, Stefan F Lichtenthaler, Christian Behrends, Sivakumar Sambandan, Lena F Burbulla.
      Parkinson's disease (PD) is characterized by α-synuclein accumulation and dopaminergic neuron degeneration, with dopamine (DA) oxidation emerging as a key pathological driver. However, the mechanisms underlying this neurotoxic process remain unclear. Using PD patient-derived and CRISPR-engineered induced pluripotent stem cell midbrain dopaminergic neurons lacking DJ-1, we identified defective sequestration of cytosolic DA into synaptic vesicles, which culminated in DA oxidation and α-synuclein pathology. In-depth proteomics, state-of-the-art imaging, and ultrasensitive DA probes uncovered that decreased vesicular monoamine transporter 2 (VMAT2) protein and function impaired vesicular DA uptake, resulting in reduced vesicle availability and abnormal vesicle morphology. Furthermore, VMAT2 activity and vesicle endocytosis are processes dependent on adenosine 5'-triphosphate (ATP), which is notably reduced in DJ-1-deficient dopaminergic neurons. ATP supplementation restored vesicular function and alleviated DA-related pathologies in mutant dopaminergic neurons. This study reveals an ATP-sensitive mechanism that regulates DA homeostasis through VMAT2 and vesicle dynamics in midbrain dopaminergic neurons, highlighting enhanced DA sequestration as a promising therapeutic strategy for PD.
    DOI:  https://doi.org/10.1126/sciadv.adz5645
  6. Nat Commun. 2026 Feb 09. 17(1): 1440
    Inhibition of TGF-β signaling in microglia stimulates hippocampal adult neurogenesis and reduces anxiety-like behavior in adult mice.
    Kierra Ware, Joshua Peter, Jake Yazell, Christina Thapa, Aleksandr Taranov, Alicia Bedolla, Claire Distel, Sven Lammich, Regina Feederle, Alice Sülzen, Shane Liddelow, Krishna Roskin, Yu Luo.
      Adult neurogenesis in the subgranular zone (SGZ) has been implicated in cognitive and affective functions. The role of neuroinflammation and reactive microglia in SGZ neurogenesis is not well understood. TGF-β signaling is critical to maintaining microglia homeostasis in the adult brain. To investigate the role of microglia in SGZ neurogenesis, using microglia-specific inducible knockout (iKO) mice for TGF-β1 ligand or receptor (Alk5 or Tgfbr2), here we show that TGF-β-deficient microglia increase adult neurogenesis in the SGZ, accompanied by altered anxiety-like behavior in KO mice. Single-cell RNAseq (ScRNAseq) analysis shows decreased PTEN signaling, and immunohistochemistry shows increased mTOR activity in DCX+ newly born neuroblasts at the SGZ in iKO mice. Inhibition of mTOR signaling by rapamycin reverses the heightened SGZ neurogenesis in iKO mice. This study reveals the role of microglia in regulating hippocampal adult neurogenesis via the PTEN-mTOR pathway and its potential implications for behavioral and affective functions.
    DOI:  https://doi.org/10.1038/s41467-026-68885-4
  7. Mol Neurodegener Adv. 2026 ;2(1): 8
    Differential downstream signaling in microglia lacking Alzheimer's-related TREM2 or its adaptor TYROBP/DAP12.
    Gabriela E Farias Quipildor, Ramona Belfiore, Khaled Althobaiti, Zahra Najarzadeh, Charles Glabe, Benjamin P Readhead, Sam Gandy, Stephen R J Salton, Michelle E Ehrlich.
      Microglia, the primary immune cell in the brain, have multiple activation phenotypes involved in broad functions within the brain, playing roles in neurotoxicity/neuroprotection, release of inflammatory and anti-inflammatory cytokines, and in cell survival, proliferation, and phagocytosis. TREM2 and TYROBP form a transmembrane complex in microglia that modulates intracellular signaling networks, and these proteins are essential regulators of the transition from homeostatic to activated microglia. Recent findings support a TREM2-independent molecular signature that is involved in the early transition of homeostatic to disease-associated microglia (DAM), with the next sequential step of DAM activation from stage 1 to stage 2 being TREM2-dependent. However, the underlying mechanisms determining how TREM2 or TYROBP regulate these downstream phenotypes are largely unknown. We isolated primary microglia from C57BL/6 wild-type (WT) controls, Trem2 knock-out (KO), and Tyrobp KO mice at post-natal day 0-3. Cells were treated with Alzheimer's disease (AD)-relevant stimuli, such as amyloid beta (Aβ) oligomers or fibrils, or 'neuroinflammatory-like' stimuli, such as lipopolysaccharide (LPS). We explored protein and gene expression in the presence or absence of inhibitors of the TREM2/TYROBP downstream signaling pathway. We also performed a high-throughput Olink proteomic analysis of conditioned media from WT, Trem2 KO, and Tyrobp KO stimulated with either LPS or Aβ oligomers or fibrils. Our results show that the absence of either TREM2 or TYROBP is associated with increased basal levels of phosphorylated ERK in primary microglia compared to WT controls. In addition, Trem2 KO and Tyrobp KO cells show a less ramified cell morphology at baseline, as compared to WT microglia. Moreover, stimulating primary microglia with either Aβ oligomers or LPS leads to differential protein and gene expression in cells lacking TREM2 or TYROBP. The dysregulated downstream signal transduction and morphology in the absence of TREM2 or TYROBP suggest their essential roles not only in microglial homeostasis but also in their activation in response to different stimuli.
    Graphical abstract:
    Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-025-00012-x.
    Keywords:  DAP12; Microglia; Signal transduction; TREM2; TYROBP
    DOI:  https://doi.org/10.1186/s44477-025-00012-x
  8. J Neuroinflammation. 2026 Feb 11.
    Microglia TFEB activation attenuates Alzheimer's disease pathology by enhancing autophagy-lysosomal function.
    Yeji Kim, Tae-Young Ha, Oksana Kondaurova, Myung-Shik Lee, Keun-A Chang.
      Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) accumulation, neuroinflammation, synaptic dysfunction, and cognitive decline. Impairment of microglial autophagy-lysosomal pathway (ALP) is increasingly recognized as a key driver of the disease progression. Transcription factor EB (TFEB), a master regulator of ALP, has emerged as a promising therapeutic target; however, its specific role in microglia remains unclear. Here, we aimed to determine the therapeutic effects of microglial TFEB expression in AD pathogenesis. We established a tamoxifen-inducible, microglia-specific TFEB-overexpressing 5xFAD mouse line (5xTFEB) and conducted behavioural testing, histopathology and biochemical analyses, live-cell imaging of Aβ phagocytosis, and bulk RNA sequencing. Differential gene expressions were analysed, and inflammasome activation was evaluated. Microglial TFEB overexpression restored ALP function, promoted phagolysosomal clearance of oligomeric Aβ, and reduced the amyloid burden in the cortex, hippocampus, and entorhinal cortex of the 5xFAD mice. These changes rescued memory deficits in both male and female 5xTFEB mice. Transcriptomic profiling revealed upregulation of ALP and downregulation of inflammatory signalling. Additionally, inflammasome activation was attenuated in 5xTFEB mice. Targeted TFEB activation in microglia reprograms degradative and immune pathways, enhancing Aβ clearance while alleviating neuroinflammation and cognitive impairment in AD. Overall, microglial TFEB modulation is a promising cell-type-specific therapeutic strategy for AD and related neurodegenerative disorders.
    Keywords:  Alzheimer’s disease; Amyloid beta; Autophagy-lysosomal pathway; Microglia; Neuroinflammation; TFEB
    DOI:  https://doi.org/10.1186/s12974-026-03728-z
  9. Acta Neuropathol. 2026 Feb 13. 151(1): 16
    TSC-associated microglial hyperactivity: enhanced calcium signaling, metabolism, and phagocytosis.
    Rozemarijn S Kalf, Mark J Luinenburg, Giulia Dematteis, Mirte Scheper, Jasper J Anink, Giulia Cavallo, Andrea Mattarei, Wim Van Hecke, Angelika Mühlebner, Laura Tapella, James D Mills, Dmitry Lim, Eleonora Aronica.
      Tuberous sclerosis complex (TSC) is a multisystem genetic disorder with prominent neurological manifestations, most notably epilepsy, and is frequently accompanied by a wide range of neuropsychiatric comorbidities. Hyperactivation of the mechanistic target of rapamycin (mTOR) pathway plays a central role in TSC pathology, disrupting both general brain development and specific molecular processes such as metabolism. While much attention has focused on neurons and astrocytes in these TSC-related alterations, the contribution of microglia remains relatively underexplored. In this study, we first analysed the transcriptomic profiles from resected TSC brain tissue and identified evidence of calcium (Ca2+) dysregulation in TSC microglia. In order to investigate the functional consequences, we then examined induced pluripotent stem cell (iPSC) derived microglia-like (iMGL) cells from TSC patients. Our findings reveal that these iMGL cells displayed markedly altered Ca2⁺ signalling, characterized by impaired store-operated calcium entry (SOCE) and an increase in mitochondrial Ca2⁺ uptake. These changes are accompanied by elevated mitochondrial respiratory activity, suggesting a shift in metabolic state. In addition, TSC iMGL cells displayed increased phagocytic activity and an altered inflammatory responsiveness, consistent with a dysregulated microglial activation state. Supporting these functional alterations in iMGL cells, transcriptomic analysis of TSC brain tissue revealed upregulation of several genes associated with lipid metabolism, phagocytosis, and innate immune activation, with partial overlap with stage 2 disease-associated microglia (DAM)-like programs. Together these findings suggest that microglial dysfunction may represent a relevant component of TSC pathophysiology.
    Keywords:  Calcium signalling; Epilepsy; Microglia; Phagocytosis; Tuberous sclerosis complex
    DOI:  https://doi.org/10.1007/s00401-026-02986-8
  10. Res Sq. 2026 Feb 03. pii: rs.3.rs-8603227. [Epub ahead of print]
    Transplantation of Human IPSC-derived Microglia Ameliorates Neuropathology and Circuit Dysfunction in Progranulin-Deficient Mice.
    Hayk Davtyan, Sarah Naguib, Yuliya Voskobiynyk, Jean Paul Chadarevian, Joia K Capocchi, Jeannie L Giacchino, Ghazaleh Eskandari-Sedighi, Vivianna DeNittis, Jeremy B Ford, Ani Agababian, Jasmine Nguyen, Alina L Chadarevian, Madison S Sutherland, Sepideh Kiani Shabestari, Alissa L Nana, Jiasheng Zhang, Salvatore Spina, Man Ying Wong, Lea T Grinberg, William W Seeley, Eric Huang, Claire D Clelland, Shiaoching Gong, Li Fan, Jeanne T Paz, Mathew Blurton-Jones, Li Gan.
      Frontotemporal dementia (FTD) is a major cause of early-onset neurodegeneration characterized by progressive behavioral, emotional, and cognitive decline. Progranulin haploinsufficiency, a leading genetic cause of familial FTD, disrupts lysosomal function, lipid metabolism, autophagy, and neuroimmune signaling across multiple cell types. Increasing evidence indicates that microglia are particularly sensitive to progranulin loss, exhibiting elevated complement activation that contributes to TDP-43 proteinopathy and neuronal dysfunction. Here, we investigate the biological role of restoring progranulin exclusively within microglia by transplanting human induced pluripotent stem cell-derived microglia (iMG) into progranulin ( Grn )-deficient mice. We find that wild-type, but not Grn -deficient, human iMG restore brain-wide progranulin levels, normalize microglial transcriptional states, and ameliorate pathological, functional, and behavioral phenotypes associated with progranulin loss. Because microglia are the only source of progranulin in this system, these findings demonstrate that microglial progranulin is sufficient to restore key aspects of cellular, circuit, and behavioral homeostasis in a progranulin-deficient FTD model. More broadly, this work highlights a central, microglia-intrinsic role for progranulin in maintaining brain function and provides a framework for dissecting microglia-specific mechanisms across FTD and related neurodegenerative disorders.
    DOI:  https://doi.org/10.21203/rs.3.rs-8603227/v1
  11. J Neurochem. 2026 Feb;170(2): e70384
    Microglia at the Forefront: New Insights From the Glial Club South Cone Meeting 2025.
    Guillermo H Giambartolomei, Pablo Iribarren, Laura A Pasquini, Hugo Peluffo.
      Microglia are the primary innate immune cells of the central nervous system and act as dynamic regulators of neural development, homeostasis, and response to injury. This review summarizes key discussions from the Glial Club South Cone Meeting 2025, focusing on (i) mechanisms and regulation of microglial phagocytosis and its dual role in tissue repair and neurodegeneration, (ii) the emerging immunometabolic and neuroprotective functions of the lipid-sensing receptor CD300f in aging and Alzheimer's disease models, and (iii) the context-dependent roles of autophagy in microglial activation, inflammation control and proteostasis. We highlight how phagocytic signaling (IFN, IL-6, "eat-me," "don't-eat-me" cues), immune receptors and epigenetic regulation shape microglial states and function. Translational implications are discussed, including strategies to preserve beneficial microglial functions while limiting detrimental phagoptotic and pro-inflammatory responses. Identifying receptor-specific ligands, clarifying causal roles of phagocytosis in neurodegeneration, and dissecting autophagy-dependent quality-control pathways emerge as priority areas for future research.
    Keywords:  CD300f; autophagy; microglia; neurodegeneration‐aging; neuroinflammation; phagocytosis
    DOI:  https://doi.org/10.1111/jnc.70384
  12. Adv Sci (Weinh). 2026 Feb 10. e11924
    Amyloid β Instigates Cardiac Neurotrophic Signaling Impairment, Driving Alzheimer's Associated Heart Disease.
    Andrea Elia, Rebecca Parodi-Rullan, Rafael Vazquez-Torres, Ashley Carey, Huaqing Zhao, Sabzali Javadov, Silvia Fossati.
      While a link between cardiovascular risk factors and increased Alzheimer's disease (AD) risk has been reported, it remains unclear whether AD pathology has a direct effect on cardiac function and myocardial innervation. AD and amyloidosis are known to impair neuronal function and affect brain neurotrophic factors (NGF and BDNF) expression. Amyloid aggregates and neuro-signaling impairments may also expose AD patients to peripheral nervous system deficits, promoting cardiac disorders. Here, we provide novel understanding of cardiac physiological impairment, amyloid pathology, neurotrophic factors loss, and impoverishment of cardiac neuronal fibers in Tg2576-AD mice hearts, human cardiomyocytes in culture, and human AD post-mortem left ventricular (LV) heart tissue. We reveal that Tg2576 animals exhibit increased myocardial fibrosis, amyloid β (Aβ) deposition, and brain/heart-axis neurotrophic deficiencies, resulting in myocardial denervation and cardiac dysfunction. Aβ oligomers challenge reduces BDNF expression in both human immortalized and iPSC-derived cardiomyocytes, by disrupting TrkB/CREB signaling. Analysis of human LV AD post-mortem tissue confirms cell and animal results. Our findings reveal potential pathways by which Aβ pathology may disrupt cardiac neurotrophic signaling and physiology, identifying a possible link between AD and heart degeneration.
    Keywords:  Alzheimer's disease; brain‐heart axis neuro‐signaling pathway; cardiac dysfunction; human iPSC‐derived cardiomyocytes; human post‐mortem heart
    DOI:  https://doi.org/10.1002/advs.202511924
  13. Alzheimers Dement. 2026 Feb;22(2): e71140
    Greater locus coeruleus vulnerability in atypical clinicopathologic forms of Alzheimer's disease.
    Sara Rose Dunlop, Billie J Matchett, Alexander F Mannsbart, Fadi S Hanna Al-Shaikh, Zhongwei Peng, Darren M Rothberg, Jessica F Tranovich, Ranjan Duara, Idaly Velez Uribe, Joselen Gondrez, Rickey E Carter, Tanis J Ferman, Gregory S Day, Neill R Graff-Radford, Dennis W Dickson, Lea T Grinberg, Melissa E Murray.
       INTRODUCTION: The locus coeruleus (LC) degenerates early in Alzheimer's disease (AD). However, the extent of rostrocaudal degeneration across clinicopathologic heterogeneity remains underexplored in AD.
    METHODS: Using digital pathology, we quantified LC neuronal density and area at three neuroanatomic levels in a large AD series.
    RESULTS: Analysis of neuropathologic AD subtypes revealed greater middle LC vulnerability in hippocampal sparing AD compared to typical and limbic predominant AD. Regression analyses identified distinct predictor variables associated with the degeneration of rostral and middle LC. Age at onset predicted 24% of the variability in rostral LC neuronal density, whereas Braak stage, brain weight, Lewy body disease, and age at onset accounted for 15% of the variability in middle LC. Analyses of clinical presentations revealed lower rostral LC neuronal density in non-amnestic compared to amnestic AD cases.
    DISCUSSION: These insights demonstrate greater LC degeneration in atypical clinicopathologic forms of AD, including hippocampal sparing, young-onset, and non-amnestic presentations.
    Keywords:  LC; atypical AD; co‐pathology; digital pathology; non‐amnestic AD; selective vulnerability; young‐onset AD
    DOI:  https://doi.org/10.1002/alz.71140
  14. bioRxiv. 2026 Jan 27. pii: 2026.01.27.701787. [Epub ahead of print]
    Pathological TDP-43 filaments accumulate at synapses and cause synaptic dysfunction.
    Renren Chen, Imogen Stockwell, Jessica C Pierce, Sew-Yeu Peak-Chew, Melissa Huang, Kathy Newell, Bernardino Ghetti, Michael A Cousin, Ingo H Greger, Benjamin Ryskeldi-Falcon.
      The assembly of TAR DNA-binding protein 43 (TDP-43) into amyloid filaments within neurons is a hallmark of multiple neurodegenerative diseases, including motor neuron diseases (MND), frontotemporal dementias (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). These diseases result from the deterioration and loss of neurons, with synaptic dysfunction and neuronal hyperexcitability being prominent early events. Pathogenic mutations in the TDP-43 gene, TARDBP , that promote filament formation have established a causal role for TDP-43 assembly in neurodegenerative diseases. However, the molecular mechanisms underlying filament accumulation and their contribution to neurodegeneration are poorly understood. TDP-43 filaments can propagate between neurons in a prion-like manner, which may underlie the progressive spread and accumulation of TDP-43 pathology in disease. Here, we studied early stages of TDP-43 filament accumulation following internalisation of patient-derived TDP-43 filaments by mouse and human cortical neurons. Using proximity labelling, we identified molecular environments and putative interactions of TDP-43 filaments. We found that TDP-43 filaments accumulated at synapses, particularly in proximity to the presynaptic active zone, which we confirmed in FTD patient brain sections. Electron cryo-tomography (cryo-ET) directly visualised abundant TDP-43 filaments spanning the presynaptic cytoplasm in situ , which contacted synaptic vesicles and the plasma membrane. Functional measurements revealed that the accumulation of TDP-43 filaments led to presynaptic dysfunction and subsequent neuronal hyperexcitability. These findings suggest that synapses are a major early site of TDP-43 filament accumulation, relevant to their propagation, and directly link TDP-43 filament gain of function to synaptic dysfunction.
    DOI:  https://doi.org/10.64898/2026.01.27.701787
  15. Br J Pharmacol. 2026 Feb 11.
    TREM2 activation suppresses central sensitisation by promoting autophagy in a chronic migraine model with recurrent nitroglycerin stimulation in mice.
    Suifa Hu, Xiamin Liu, Lang Zhang, Sufang Zhong, Zhi Liang, Weixian Zeng, Li Yi, Zhiwen Zeng, Baodong Chen, Rikang Wang.
       BACKGROUND AND PURPOSE: Microglial activation plays a role in driving chronic migraine (CM). Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in brain microglia and impacts neuroinflammation in nervous system diseases. However, its role in CM is unclear. Here, we have investigated the role of microglial TREM2 in the development of CM.
    EXPERIMENTAL APPROACH: We used male mice receiving repeated intraperitoneal nitroglycerin (NTG) injections as a CM model. Mechanical and thermal hypersensitivity were assessed by mechanical withdrawal threshold and thermal withdrawal latency. TREM2 knockout mice (TREM2-/-) and systemically administered TREM2 agonist COG1410 were evaluated for TREM2's role in CM. TREM2, calcitonin gene-related peptide (CGRP) and c-fos expression in the trigeminal nucleus caudalis (TNC) were measured for central sensitisation assessment. Immunohistochemical analyses and western blots measured protein expression in the TNC and BV-2 microglia. Quantitative real-time polymerase chain reaction (qRT-PCR) detected inflammatory factor expression.
    KEY RESULTS: Recurrent NTG injection up-regulated TNC protein levels of TREM2, CGRP and c-fos. TREM2 loss accelerated NTG-induced CM development, increased CGRP and c-fos expression, and inhibited TNC autophagy. Conversely, COG1410 prevented hyperalgesia and reduced CGRP/c-fos expression in the TNC after recurrent NTG administration. In vitro, TREM2 knockdown enhanced the expression of inflammation-related genes and the mTOR/p70s6k pathway activation in lipopolysaccharide (LPS)-stimulated BV-2 microglia, whereas COG1410 significantly inhibited LPS-induced mTOR/p70s6k pathway activation and alleviated inflammatory responses.
    CONCLUSION AND IMPLICATIONS: These data show that TREM2 plays a protective role in CM by modulating microglial activation and autophagy in the TNC via the mTOR/p70s6k pathway.
    Keywords:  TREM2; chronic migraine; hyperalgesia; microglia; nitroglycerin; trigeminal nucleus caudalis
    DOI:  https://doi.org/10.1111/bph.70353
  16. Neurobiol Dis. 2026 Feb 05. pii: S0969-9961(26)00057-4. [Epub ahead of print]220 107313
    Astrocyte-specific deletion of LRRC8A causes neurological dysfunction but not chronic white matter edema.
    Sven Kerst, Leoni Hoogterp, Marjolein Breur, Gemma M van Rooijen-van Leeuwen, Marianna Bugiani, Rajan Sah, Huibert D Mansvelder, Marjo S van der Knaap, Rogier Min.
      Volume-regulated anion channels (VRACs) are central to cell volume homeostasis. They mediate swelling-induced efflux of chloride and organic osmolytes to drive regulatory volume decrease. In the brain, VRACs have been proposed to play a key role in astrocytic volume regulation. Genetic defects in astrocytic VRAC modulating proteins (MLC1, GlialCAM, Aquaporin-4, GPRC5B) cause the leukodystrophy Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by chronic white matter edema and myelin vacuolization. Disrupted VRAC activity in MLC-patient-derived lymphoblasts and primary astrocytes from MLC mice further supports a pathogenic link between defective VRAC activity and MLC. Here, we studied the physiological and pathological consequences of astrocyte-specific removal of the essential VRAC subunit LRRC8A. In contrast to established MLC mouse models, astrocyte specific Lrrc8a knockout mice had normal brain water content, no myelin vacuolization, and preserved expression of MLC-related proteins. At a late age they developed a mildly ataxic gait and displayed increased severity of kainate-induced seizures. Two-photon imaging in acute brain slices revealed that astrocytes lacking LRRC8A show normal volume recovery and chloride dynamics upon high potassium-induced cell swelling. Together, these findings demonstrate that astrocyte LRRC8A is not essential for volume regulation in situ and that its loss alone is insufficient to cause the chronic white matter edema typical of MLC. The mild neurological deficits indicate a physiological role for astrocyte LRRC8A, but MLC pathology likely arises from broader dysregulation of the astrocytic protein complex coordinating ion and water homeostasis.
    Keywords:  Astrocyte; LRRC8A; Leukodystrophy; MLC; VRAC; Volume regulation; White matter edema
    DOI:  https://doi.org/10.1016/j.nbd.2026.107313
  17. Nature. 2026 Feb 09.
    Coffee linked to slower brain ageing in study of 130,000 people.
    Amanda Heidt.
      
    Keywords:  Ageing; Alzheimer's disease; Nutrition; Public health
    DOI:  https://doi.org/10.1038/d41586-026-00409-y
  18. bioRxiv. 2026 Feb 04. pii: 2026.02.02.703357. [Epub ahead of print]
    Cell type-resolved proteomics reveals intra- and intercellular signaling in Alzheimer's disease.
    Xue Zhang, Kaiwen Yu, Him K Shrestha, Ying Zhou, Jiyuan Yang, Zhen Wang, Xiaokang Ren, Ping-Chung Chen, Huan Sun, Danting Liu, Yun Jiao, Jay M Yarbro, Ju Wang, Zhiping Wu, Kiara Harper, Liusheng He, Zuo-Fei Yuan, Xusheng Wang, Anthony A High, Gang Yu, Jiyang Yu, Zhexing Wen, Junmin Peng.
      Alzheimer's disease (AD) arises from pathological interactions among diverse brain cell types, but cell-specific proteomic changes remain underexplored. Here, we present deep proteomic profiling of sorted or proximity-labeled brain cells from AD mouse models (5xFAD and App NL-G-F ) at multiple ages, quantifying 13,411 proteins in microglia (three subtypes), astrocytes, oligodendrocyte precursor cells, and neurons. We identified 3,028 differentially abundant proteins across these cell types, the majority of which were not detected in bulk proteomic datasets, and constructed cell type-specific networks to define functional modules and hub proteins. Comparison with transcriptomic data revealed that ∼30% of proteomic changes are RNA-independent. Further analyses uncovered cross-cell type signaling proteins conserved in human AD brains, such as pleiotrophin (Ptn), which is transcriptionally enriched in astrocytes but accumulates in microglia. Importantly, recombinant PTN directly activates induced microglia-like (iMG) human cells. Thus, these findings provide a comprehensive cell type-resolved proteomic atlas of AD models, highlighting novel intra- and intercellular signaling events.
    Highlights: A high-resolution cell type-resolved proteomic atlas of Alzheimer's disease mouse models∼3,000 cell type-specific protein alterations identified beyond bulk tissue analysesProteomic profiling of microglial subtypes reveals subtype-specific changes in Alzheimer's diseaseAstrocyte-microglia signaling is highlighted and validated through PTN-mediated interactions.
    DOI:  https://doi.org/10.64898/2026.02.02.703357
  19. J Clin Invest. 2026 Feb 10. pii: e199706. [Epub ahead of print]
    Neutrophil-microglia interaction drives motor dysfunction in neuromyelitis optica model induced by subarachnoid AQP4-IgG.
    Fangfang Qi, Vanda A Lennon, Shunyi Zhao, Yong Guo, Husheng Ding, Caiyun Liu, Whitney M Bartley, Tingjun Chen, Claudia F Lucchinetti, Long-Jun Wu.
      Neutrophils and neutrophil extracellular traps (NETs) contribute to early neuromyelitis optica (NMO) histopathology initiated by IgG targeting astrocytic aquaporin-4 water (AQP4) channels. Yet, the mechanisms underlying neutrophil recruitment and their pathogenic roles in disease progression remain unclear. To investigate molecular-cellular events preceding classical complement cascade activation in a mouse NMO model, we continuously infused, via spinal subarachnoid route, a non-complement-activating mouse monoclonal AQP4-IgG. Parenchymal infiltration of netting neutrophils containing C5a ensued with microglial activation and motor impairment, but no blood-brain barrier leakage. Motor impairment and neuronal dysfunction both reversed when AQP4-IgG infusion stopped. Two-photon microscopy and electron-microscopy-based reconstructions revealed physical interaction of infiltrating neutrophils with microglia. Ablation of either peripheral neutrophils or microglia attenuated the motor deficit, highlighting their synergistic pathogenic roles. Of note, mice lacking complement receptor C5aR1 exhibited reduction in neutrophil infiltration, microglial lysosomal activation, neuronal lipid-droplet burden and motor impairment. Pharmacological inhibition of C5aR1 recapitulated this protection. Immunohistochemical analysis of an NMO patient's spinal cord revealed disease-associated microglia surrounding motor neurons in non-destructive lesions. Our study identifies neutrophil-derived C5a signaling through microglial C5aR1 as a key early driver of reversible motor neuron dysfunction in the precytolytic phase of NMO.
    Keywords:  Autoimmune diseases; Autoimmunity; Neuroscience
    DOI:  https://doi.org/10.1172/JCI199706
  20. Cell Mol Neurobiol. 2026 Feb 13.
    Immunometabolism Reframes Alzheimer's Disease: From Systemic Dysmetabolism to Glial Rewiring.
    Duc-Hiep Bach, Thanh Liem Nguyen.
      Alzheimer's disease (AD) is increasingly recognized as a disorder of dysregulated immunometabolism at the neurovascular-glia-neuron interface. Systemic metabolic stressors such as insulin resistance, dyslipidaemia, and obesity converge on brain innate immune cells to reprogram energy pathways and sustain maladaptive inflammation. In microglia, metabolic rewiring across glycolysis-oxidative phosphorylation balance, glutaminolysis, and lipid handling governs trained-immunity programs that dictate amyloid and tau clearance, synaptic maintenance, and neurotoxicity. These processes converge on druggable nodes including AMPK-mTOR signaling, HIF-1α, and tricarboxylic-acid intermediates. Neurovascular fuel delivery is likewise impaired: endothelial GLUT1 loss and mitochondrial stress at the blood-brain barrier accelerate amyloid accumulation and neuronal injury. Lipid metabolism bridges metabolism and inflammation, as APOE4-driven microglial lipid droplets link genetic risk to inflammatory phenotypes. NLRP3 integrates metabolic danger signals into chronic neuroinflammation. Translational momentum now builds around metabolic interventions particularly GLP-1 receptor agonists and SGLT2 inhibitors that modulate glial metabolism, systemic inflammation, and barrier integrity. Converging metabolomic, lipidomic, and extracellular-vesicle biomarkers enable tracking of these pathways in humans, defining an immunometabolic axis of AD and supporting precision-medicine strategies to reprogram metabolism for disease modification.
    Keywords:  Alzheimer’s disease; Blood–brain barrier; Immunometabolism; Metabolic dysfunction; Microglia; Neuroinflammation
    DOI:  https://doi.org/10.1007/s10571-026-01691-0
  21. Cell Rep. 2026 Feb 09. pii: S2211-1247(26)00023-9. [Epub ahead of print]45(2): 116945
    Ketogenic diet dampens excitatory neurotransmission by shrinking synaptic vesicle pools.
    Marion I Stunault, Pan-Yue Deng, Anjali Yadav, Erica M Periandri, Francisca N de Luna Vitorino, Michael B Thomsen, Jasmin Sponagel, Amelia J Barfield, Renzelle J Ponce, Layla Foroughi, Benjamin A Garcia, Gabor Egervari, Vitaly A Klyachko, Ghazaleh Ashrafi.
      Ketogenic diet (KD) is used for the treatment of drug-resistant childhood epilepsy and has been proposed to improve outcomes in neurodegenerative diseases. However, the mechanisms by which KD alters brain circuitry remain unclear. Here, we investigated the impact of KD on hippocampal function through integrative analysis of gene expression and neurotransmission. We found that KD induces extensive transcriptional reprogramming, including altered expression of numerous synaptic genes. Proteomic and genomic profiling revealed significant changes in histone modifications, particularly at promoters of KD-regulated genes. Electrophysiological recordings showed that KD reduces excitatory synaptic gain and short-term plasticity at CA3-CA1 synapses, dampening the summation of excitatory inputs and enhancing the summation of inhibitory inputs. These functional changes were driven, in part, by a reduction in the readily releasable vesicle pool at excitatory synapses under KD. Together, our findings demonstrate that KD drives transcriptional remodeling of hippocampal circuits, leading to synaptic adaptations that may underlie its anti-epileptic and neuroprotective effects.
    Keywords:  CP: metabolism; CP: neuroscience; epilepsy; hippocampus; ketogenic diet; metabolism; synaptic plasticity; synaptic vesicles
    DOI:  https://doi.org/10.1016/j.celrep.2026.116945
  22. J Neuroinflammation. 2026 Feb 13.
    MST1 promotes microglial pyroptosis and neuroinflammation in alzheimer's disease by regulating the novel DPP8/NLRP1/Caspase-1/GSDMD-N axis.
    Dongqing Cui, Shuangwu Liu, Yanxia Liu, Shuqi Luo, Yurui Sheng, Shuaiyong Zhang, Pengfei Lin.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) induced disruption of brain homeostasis, leading to neuronal damage and cognitive impairment. Increasing evidence confirms that microglia-driven neuroinflammation serves as a core mechanism driving the progression of AD. Mammalian Ste20-like kinase 1 (MST1) plays a crucial regulatory role in apoptosis, immune inflammation, and oxidative stress. Our team's previous research revealed that MST1 regulates mitochondrial oxidative stress in neurons, contributing to the pathogenesis of AD. Here, we show that MST1 is activated as p-MST1 in the peripheral blood of AD patients, the serum of 5xFAD mice, and the hippocampal and cortical brain tissues of 5xFAD mice, an effect which was associated with microglial pyroptosis under chronic inflammatory stimulation. Knocking down MST1 in hippocampal and cortical tissues of 5xFAD mice improved cognitive deficits, reduced p-tau protein levels, and alleviated neurodegeneration and neuroinflammatory responses. Concurrently, MST1 knockdown suppressed abnormal microglial activation, decreased inflammatory cytokine release, and ultimately mitigated microglial pyroptosis. Mechanistically, we found that MST1 knockdown modulated DPP8 protein expression, thereby regulating the NLRP1/Caspase-1/GSDMD-N signaling axis to inhibit microglial pyroptosis and attenuate neuroimmune inflammation. In summary, MST1 knockdown improved AD disease progression by preventing disruption to the immune-inflammatory homeostasis of microglia. Therefore, we propose targeting MST1 as a promising therapeutic strategy to halt neuroinflammation and progression in Alzheimer's disease.
    Keywords:  Alzheimer's disease; DPP8; MST1; Microglia; Neuroinflammation; Pyroptosis
    DOI:  https://doi.org/10.1186/s12974-026-03732-3
  23. Mol Neurobiol. 2026 Feb 12. 63(1): 435
    Microglia-Derived Extracellular Vesicles from Alzheimer's Disease Patients Carry miRNAs Driving a Neuroinflammatory Response.
    Skaiste Arbaciauskaite, Simona Silvestri, Pingyan Luo, Christina Krüger, Zoe Julia Mossmann, Susann Allelein, Alexander Scholz, Dennis Loeffler, Samuele Fiorenza, Anna Menale, Enza Torino, Dirk Kuhlmeier, Oliver Peters, Seija Lehnardt.
      Alzheimer's disease (AD) represents the most common cause of dementia and urgently requires sensitive biomarkers and effective therapies. Extracellular vesicles represent membranous nano-sized particles secreted from cells, which serve as intercellular messengers participating in central nervous system (CNS) homeostasis, but also are implicated in AD pathogenesis. In addition, EVs containing disease-specific signatures, such as microRNAs (miRNAs), are considered as potent tools for the diagnosis and treatment of AD and other brain disorders. In this study, we used TMEM119 antibody to immunocapture microglia-derived EVs from cerebrospinal fluid (CSF) of AD patients and control subjects. EVs harvested from these CSF samples contained distinct disease-specific miRNA profiles, as assessed by small RNA sequencing. Using a HEK TLR reporter cell system, we found that these miRNA are potent activators of human TLR8, an established RNA sensor. Out of the miRNAs present in AD-associated EVs, selected oligonucleotides were synthesized and loaded into BV2 microglia-derived EVs. Exposure of primary murine microglia to these miRNA-loaded EVs led to TNF release from these cells, thereby driving a neuroinflammatory response. Taken together, putatively microglia-derived EVs from the CSF of AD patients contain miRNAs, which are capable of activating hTLR8 and inducing an inflammatory response from microglia.
    Keywords:  Alzheimer’s disease; EV engineering; Extracellular vesicles; MicroRNA; Microglia; RNA delivery; Toll-like Receptors
    DOI:  https://doi.org/10.1007/s12035-026-05719-w
  24. Sci Adv. 2026 Feb 13. 12(7): eaeb0803
    Membrane-associated periodic skeleton regulates major forms of endocytosis in neurons through a signaling-driven positive feedback loop.
    Jinyu Fei, Yuanmin Zheng, Caden LaLonde, Yuan Tao, Ruobo Zhou.
      Endocytosis enables neurons to internalize molecules, maintaining homeostasis and responsiveness. The neuronal membrane-associated periodic skeleton (MPS), an actin spectrin-based cytoskeletal lattice, is known to restrict clathrin-mediated endocytosis (CME) in axons, but its broader role in other neuronal compartments and endocytic pathways remains unclear. Here, we show that all four major endocytic pathways-CME, caveolin-, flotillin-, and fast endophilin-mediated endocytosis-are spatially gated by the MPS and occur exclusively within MPS-free "clearing" zones throughout all neuronal compartments. Disrupting the MPS broadly enhances both basal and ligand-induced endocytosis. We also identify a previously unknown feedback loop in which ligand-triggered endocytosis activates extracellular signal-regulated kinase signaling, promoting protease-mediated spectrin cleavage and MPS disruption, which in turn facilitates further endocytosis. Furthermore, the MPS limits amyloid precursor protein endocytosis, thereby suppressing Aβ42 production and linking MPS integrity to neurodegeneration. Our findings establish the MPS as a dynamic, signal-responsive modulator coupling membrane trafficking with cortical cytoskeletal organization and neuronal health.
    DOI:  https://doi.org/10.1126/sciadv.aeb0803
  25. Mol Neurodegener Adv. 2026 ;2(1): 10
    Lysosomal protease-mediated APP degradation is pH-dependent, mutation-sensitive, and facilitates tau proteolysis.
    Caroline Ackley, Zoe Liau, Shruti Arya, Tara Antee, Emily Cheang, Giselle M Knudsen, Courtney Lane-Donovan, Paul J Sampognaro, Aimee W Kao.
       Background: The accumulation and aggregation of amyloid beta (A β )-a peptide fragment derived from the proteolytic processing of amyloid precursor protein (APP)-is a central pathological feature of Alzheimer's disease (AD) and a current target for disease-modifying therapies. Mutations in APP can also drive early-onset AD. While the roles of α -, β -, and γ -secretases and their respective cleavage sites in APP processing are well characterized, much less is understood about the routine degradation of APP within sub-cellular compartments like the lysosome.
    Methods: We applied Multiplexed Substrate Profiling by Mass Spectrometry (MSP-MS) to map cleavage sites within APP that may be targeted by lysosomal proteases, also known as cathepsins. We then employed cell-based and in vitro assays to examine the degradation of both wild-type and mutant APP by these enzymes.
    Results: Our findings confirm that APP is enriched in the endo-lysosomal compartment, where it is processed by many cathepsins. Our experiments reveal that cleavages at several mapped APP sites are sensitive to both changes in pH and the presence of pathogenic variants E693G and E693Q. Additionally, we discovered that the large soluble domain of APP (sAPP) enhances tau cleavage by a specific cathepsin, CTSG, in vitro.
    Conclusions: Collectively, these results underscore the importance of lysosomal processing of APP, identify a link between APP and tau, and suggest new avenues for exploring AD pathogenesis. They also highlight potential therapeutic targets related to the lysosomal function of APP and its impact on neurodegenerative diseases.
    Keywords:  Aβ ; APP; Alzheimer’s disease; Amyloid-beta; Amyloid-precursor protein; Autophagy; Cathepsin; Lysosome; Neurodegeneration; Protease; Tau
    DOI:  https://doi.org/10.1186/s44477-025-00017-6
  26. Science. 2026 Feb 12. 391(6786): eadr4661
    Myelin sheaths in the central nervous system can withstand damage and dynamically remodel.
    Donia Arafa, Julia van de Korput, Philipp N Braaker, Kieran P Higgins, Niels R C Meijns, Katy L H Marshall-Phelps, Julia Meng, Daniel Soong, Eleonora Scalia, Kyle Lathem, Marcus Keatinge, Claire Richmond, Anna Klingseisen, Marja Main, Sarah A Neely, David W Hampton, Greg J Duncan, Geert J Schenk, Marie Louise Groot, Siddharthan Chandran, Ben Emery, Antonio Luchicchi, Maarten H P Kole, Anna C Williams, David A Lyons.
      Myelin damage is a hallmark of several neurological disorders, but how it occurs remains to be fully understood. In this study, we found that early damage in zebrafish and rodent demyelination models is characterized by myelin swelling. We show, through live imaging, that myelin swelling does not always lead to myelin loss and that swellings can sometimes resolve, allowing sheaths to remodel. Increased neuronal activity during early demyelination exacerbates myelin damage, whereas reducing neuronal activity mitigates myelin swelling in both zebrafish and mice. In human multiple sclerosis tissue, myelin swelling is also dynamic and is prominent around active lesions. Our data indicate that myelin swelling is a conserved feature of demyelination and that damage to myelin sheaths can resolve, opening opportunities for targeting human disease.
    DOI:  https://doi.org/10.1126/science.adr4661
  27. bioRxiv. 2026 Feb 07. pii: 2026.02.04.703836. [Epub ahead of print]
    Th17 effector cytokines induce shared and distinct microglial and endothelial cell responses in post-streptococcal encephalitis.
    Charlotte R Wayne, Ugur Akcan, Travis E Faust, Violetta Duran-Laforet, Danny Jamoul, Luca Bremner, Nicole Ampatey, Busra Akcan, Sarah J Ho, Bogoljub Ciric, Shannon Delaney, Wendy S Vargas, Susan Swedo, Vilas Menon, Dorothy P Schafer, Tyler Cutforth, Dritan Agalliu.
      Group A Streptococcus (GAS) infections can lead to neuropsychiatric sequelae in children, yet the mechanisms driving post infectious brain pathology remain poorly defined. In a mouse disease model, Th17 lymphocytes induce microglial activation, blood brain barrier (BBB) dysfunction, and neural circuit impairment; however, the transcriptional programs underlying these effects, and the specific Th17 derived cytokines involved are unclear. Using mouse genetics, single cell RNA sequencing, and spatial transcriptomics, we show that GAS infections induce inflammatory gene programs in microglia and brain endothelial cells (BECs), accompanied by downregulation of BBB associated transcripts in BECs. Spatial transcriptomic analyses reveal that GAS-responsive microglia are enriched near infiltrating T cells. Several chemokines upregulated in microglia following GAS infection in mice are elevated in sera from affected patients. Conditional ablation of GMCSF in CD4 T cells partially attenuates microglial chemokine gene expression, but does not restore BBB integrity. Neutralization of IL17A partially rescues BBB transcriptional changes in BECs and reduces microglial chemokine expression; however, compensatory peripheral immune responses associated with persistent infection exacerbate BBB disruption. In contrast, microglia/macrophage-specific deletion of IL17 receptor A partially rescues BBB deficits following GAS infection. Together, these findings identify IL17A / IL17RA signaling in microglia as a critical driver of BBB dysfunction after GAS infections.
    DOI:  https://doi.org/10.64898/2026.02.04.703836
  28. J Exp Med. 2026 Apr 06. pii: e20252290. [Epub ahead of print]223(4):
    Liver-X-receptor agonism enhances T cell priming and activation to promote anti-tumor immunity.
    Benjamin N Ostendorf, Jonathan G Goldstein, Shuang Liu, Foster C Gonsalves, Jana Bilanovic, Mathias Yuan, Ji-Young Kim, Christopher Rouya, Masoud Tavazoie, Sohail F Tavazoie.
      Many cancer patients do not benefit from current immunotherapies. This lack of efficacy may be, in part, due to insufficient priming and activation of T cells. Here, we show that activation of liver-X-receptors (LXRs) promotes adaptive anti-tumor immunity by enhancing priming of T cells. Genetic LXR deletion in the host and depletion of dendritic and CD8+ T cells, but not of macrophages, abrogated anti-tumor effects of LXR-agonistic therapy. In cross-presentation assays, LXR agonism promoted T cell activation upon DC/T cell cross talk. Genetic deletion of LXRs in T cells, but not in dendritic cells, blunted this effect. Dissection of the temporal dynamics of LXR-enhanced T cell effector function showed that LXR agonism rendered T cells more receptive to adopting effector states upon stimulation. Consistently, LXR agonist therapy elicited T cell expansion in cancer patients enrolled in a phase I trial. Our findings establish LXR activation as an effective approach for enhancing T cell priming.
    DOI:  https://doi.org/10.1084/jem.20252290
  29. Cell Tissue Res. 2026 Feb 02. 403(2): 15
    Alterations in secondary lipids are associated with neuroinflammation in the brain of Neu1-deficient mice.
    Ebru Ada, Volkan Seyrantepe.
      Neu1 (lysosomal sialidase 1) is essential for removing sialic acid from oligosaccharides and glycoconjugates. Neu1 deficiency impairs lysosomal digestion, leading to sialidosis and sialoglycoprotein accumulation. It also increases lipids, including gangliosides GM3, GD3, GM4, and LM1, in the kidney, liver, and spleen. Neu1-/- mice display symptoms resembling Type II sialidosis, including enlarged spleen and liver, kidney issues, neurological problems, spinal defects, and oligosaccharide buildup. The study examined secondary lipid alterations and inflammation in the cortex and cerebellum of these mice. Lipidomic, molecular, and immunohistochemical analyses of tissues from 2 and 5 M Neu1-/- mice revealed reduced levels of lipids, including PC, PE, PS, and CL, along with increased pro-inflammatory cytokines and loss of oligodendrocytes and neurons. Signs of astrogliosis and microgliosis emerged in specific brain regions. These results indicate that reduced levels of glycerophospholipids could serve as an indicator of inflammation in sialidosis mice. Future research should investigate therapies targeting these lipid changes, as modulating glycerophospholipids might slow disease progression in sialidosis patients.
    Keywords:  Mouse model; Neu1 sialidase; Neuroinflammation; Secondary lipids
    DOI:  https://doi.org/10.1007/s00441-026-04045-w
  30. Brain Pathol. 2026 Feb 11. e70080
    A 6-year-old boy with left temporal lobe mass.
    Kaiyu Liu, Shilei Zhang, Mengqiu Cao, Renhua Huang, Jiong Hu, Hongda Shao, Yichao Jin, Bingqian Shen, Hongyu Zhou, Lihua Sun, Xiaohua Zhang.
      
    Keywords:  desmoplastic; ganglioglioma; infantile; meningioma
    DOI:  https://doi.org/10.1111/bpa.70080
  31. J Neuroinflammation. 2026 Feb 10.
    FKBP5 regulates interferon signaling leading to myeloid cell activation in multiple sclerosis.
    Cinthia Gonzalez Cruz, Jessica Gibson, Maggie Kita, Narendra V Sankpal, Ignazio S Piras, Claudia Cantoni.
      
    Keywords:  Experimental autoimmune encephalomyelitis; FKBP5; Interferon; Macrophage; Microglia; Multiple sclerosis
    DOI:  https://doi.org/10.1186/s12974-026-03703-8
  32. bioRxiv. 2026 Feb 02. pii: 2026.01.30.702946. [Epub ahead of print]
    Early microglial priming in Alzheimer's disease revealed by ME-seq.
    Bohan Zhu, Anurupa Ghosh, Zhe Wang, Zhicong Liao, Michael Appiah, Jiayi Li, Mimi Zhang, Federico Di Tullio, Agata Kurowski, John Fullard, Elvin Wagenblast, Martin J Walsh, Alison Goate, Panos Roussos, Ka Lung Cheung, Nan Yang, Sai Ma.
      Epigenetic modifications, particularly DNA methylation, change dynamically with aging and are implicated in Alzheimer's Disease (AD), yet how methylation interfaces with transcriptional and chromatin regulation at single-cell resolution remains poorly understood. Progress has been limited by a lack of scalable technologies capable of jointly profiling these regulatory layers. Here, we present ME-seq, a highly scalable technologies capable of simultaneously profiling DNA methylation, gene expression, and chromatin accessibility, while achieving a 100-fold reduction in cost. We generated over 400,000 single-nucleus trimodal profiles from the aging and AD mouse brain across ages, producing the first such atlas of neurodegeneration. We found AD progression triggers pronounced, disease-specific shifts in cellular composition, characterized by accelerated epigenetic aging and the expansion of disease-associated microglia (DAM). Integrative analyses, including aging clocks, revealed that DNA methylation acts as an early priming layer preceding transcriptional activation with IRF1 identified as a methylation-sensitive transcription factor serving as a gatekeeper for DAM activation. Our results establish ME-seq as a transformative tool for large-scale epigenomic dissection, revealing DNA methylation as a primary coordinator of cell-state transitions in the aging brain.
    Graphic abstract:
    DOI:  https://doi.org/10.64898/2026.01.30.702946
  33. Sci Adv. 2026 Feb 13. 12(7): eaea0449
    Munc13-1 couples DAG and Ca2+ signaling to dynamic vesicle priming, synaptic short-term plasticity, and posttetanic potentiation.
    Mrinalini Ranjan, Kun-Han Lin, Brian D Mueller, Sonja M Wojcik, Mareike Lohse, Thomas C Südhof, Erik M Jorgensen, Erwin Neher, Noa Lipstein, Nils Brose, Holger Taschenberger.
      Synaptic strength and plasticity are fine-tuned by neuromodulation and use-dependent second-messenger signaling. Presynaptic diacylglycerol (DAG), Ca2+, and Ca2+-calmodulin signaling converge on the essential synaptic vesicle (SV) priming protein Munc13-1 via its regulatory C1, C2B, and CaM-binding domains. Using brainstem-specific heterozygous mice expressing a DAG-binding-deficient Munc13-1 variant (Munc13-1H567K), we compared synaptic transmission in situ at glutamatergic calyx of Held synapses carrying either a single Munc13-1H567K or a single Munc13-1wt allele. Munc13-1H567K/- synapses show enhanced initial strength but impaired steady-state release and slower recovery from depression. These deficits result from an increased initial abundance of fully primed SVs and a loss of activity-dependent acceleration of SV priming. Posttetanic potentiation (PTP) is strongly reduced in Munc13-1H567K/- synapses and either increased or attenuated by C2B mutations that enhance or weaken Ca2+-phospholipid binding. Our data identify Munc13-1 as a target of presynaptic TrkB-phospholipase C-γ signaling and demonstrate that C1 and C2B domain-dependent regulation of Munc13-1 determines synaptic strength and shapes short-term plasticity and PTP.
    DOI:  https://doi.org/10.1126/sciadv.aea0449
  34. Mol Neurobiol. 2026 Feb 12. 63(1): 433
    A Protective Role of Hydrogen Sulfide Donor GYY4137 Through Activated Microglia-induced Anti-inflammatory Cytokines in the Spinal Cord of Diabetic Rats.
    Alyaa M A Mousa, Muneera AlDhaen, Bedoor Qabazard, Waleed M Renno, Mariam H M Yousif.
      The increasing significance of inflammation in the pathophysiology of diabetes and its complications, such as diabetic peripheral neuropathy, has generated significant interest in targeting inflammation for disease prevention and control. Hydrogen sulfide (H₂S) has emerged as a promising therapeutic candidate due to its regulatory role in neuroinflammation. The present study investigated the anti-inflammatory effects of prolonged treatment with H₂S donor GYY4137 on microglial and astrocyte activation, along with the subsequent release of anti-inflammatory cytokines, including interleukin (IL)-4, IL-10, IL-13, transforming growth factor-beta (TGF-β), and arginase-1, in the spinal cords of streptozotocin-induced diabetic male rats. We also examined the effect of GYY4137 on signal transducer and activator of transcription 3 (STAT3) and the expression of pro-inflammatory cytokine IL-12. STAT3 is crucial for cytokine release signaling and microglial polarization, while IL-12 is a key marker of inflammation severity in diabetes. GYY4137 treatment effectively suppressed microglial activation, STAT3 activation, and IL-12 expression, while significantly increasing the secretion of anti-inflammatory cytokines in diabetic rats during weeks 4, 8, and 10 post-treatments. Our previous work demonstrated that 4-week-GYY4137 treatment suppressed pro-inflammatory cytokines in diabetic rats. Here, we show that prolonged GYY4137 treatment facilitated microglial transition from a pro-inflammatory M1 phenotype to an anti-inflammatory M2 phenotype. The treatment also prevented the loss of astrocytes and neuronal cells in the spinal cord, indicating neuroprotective effects. In conclusion, our findings suggest that H₂S can shift microglial activity from neuroinflammation to neuroprotection, highlighting its potential as a possible candidate for novel therapeutic strategy for diabetes and its complications.
    Keywords:  Anti-inflammatory cytokines; Diabetic peripheral neuropathy; GYY4137; Hydrogen sulfide (H2S); Microglial polarization; Neuroinflammation
    DOI:  https://doi.org/10.1007/s12035-025-05643-5
  35. J Neuroimmunol. 2026 Feb 10. pii: S0165-5728(26)00037-8. [Epub ahead of print]414 578889
    Docosahexaenoic acid supplementation aggravates myasthenia gravis through immune dysregulation.
    Linqi Liu, Dan Lu, Wenjun Que, Rui Fan, Wei Zheng, Yaoqi Gan, Fei Xiao.
      Myasthenia gravis (MG) is an autoimmune disorder characterized by the disruption of immune cell homeostasis and inflammatory processes. However, the impact of metabolic abnormalities on immune regulation in MG has not been well defined. The objective of this study was to identify serum metabolites causally linked to MG and to explore their role in the onset and progression of the disease. This will provide a theoretical foundation for targeted clinical interventions and therapeutic strategies. To establish the causal relationship between serum metabolites and MG, we employed Mendelian randomization. Furthermore, we conducted dietary interventions with docosahexaenoic acid (DHA) to observe its effects on the disease progression and immune cell subpopulations in experimental autoimmune myasthenia gravis (EAMG) rats. We also performed metabolomic and transcriptomic analyses of regulatory T cells (Treg) during MG progression. Our findings suggest that dysregulated lipid metabolism, particularly elevated DHA levels, is a significant risk factor for MG, influencing various markers associated with Treg cells in both MG patients and in EAMG models. The addition of 1% DHA to the diet exacerbated the severity of EAMG, enhanced B cell immune responses, and promoted antibody production. However, it also led to an increase in the proportion of Treg cells. Further in vitro experiments confirmed that DHA accumulation in Treg cells enhances their proliferation but impairs their inhibitory function, partially through the PI3K-Akt signaling pathway. These results imply that modulating lipid metabolism, especially through the PI3K-Akt pathway in Treg cells, could be critical in controlling MG.
    Keywords:  Docosahexaenoic acid; Mendelian randomization; Myasthenia gravis; Regulatory T cell
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.578889
  36. Acta Neuropathol Commun. 2026 Feb 10.
    Alterations in cerebrospinal fluid levels of myelin- and oligodendrocyte-related proteins in sporadic Creutzfeldt-Jakob disease.
    Fabian Maass, Carolina Thomas, Lille Kurvits, Peter Hermann, Matthias Schmitz, Mathias Bähr, Christine Stadelmann, Sabrina Zechel, Sezgi Canaslan, Inga Zerr.
      
    Keywords:  Biomarker; CNPase; Cerebrospinal fluid; Creutzfeldt–Jakob disease; Myelin basic protein; NG2
    DOI:  https://doi.org/10.1186/s40478-026-02247-5
  37. Acta Neuropathol. 2026 Feb 10. 151(1): 14
    D178N prion protein mutation endows RML prions with new strain properties that do not mimic human genetic prion diseases.
    Antonio Masone, Anna Grasso, Liliana Comerio, Rosalia Bruno, Giada Lavigna, Ilaria Vanni, Claudia D'Agostino, Christina D Orrù, Byron Caughey, Hermann C Altmeppen, Joaquín Castilla, Giorgio Giaccone, Fabrizio Tagliavini, Michele A Di Bari, Romolo Nonno, Roberto Chiesa.
      Genetic prion diseases are caused by mutant prion protein (PrP) misfolding, eventually leading to the formation of PrPSc, the infectious prion isoform that propagates by inducing misfolding of native PrP. Different mutations are thought to generate distinct prion strains with unique self-replicating and neurotoxic properties, contributing to the phenotypic diversity of genetic prion diseases. We previously showed that transgenic mice expressing the mouse PrP homologs of the D178N-M129 and D178N-V129 mutations linked to fatal familial insomnia (FFI) and genetic Creutzfeldt-Jakob disease (CJD178) accumulate misfolded, mildly proteinase-K (PK)-resistant PrP in their brains. These mice develop spontaneous neurological illnesses resembling FFI and CJD178, but their diseases have not been found to be transmissible to various mouse lines. In this study, we further assessed their prion propagation potential by inoculating bank voles-shown here to be susceptible to human FFI and CJD178 prions-and by using RT-QuIC. Negative results from both approaches corroborate the idea that these mice do not generate infectious prions. However, when brain homogenates from Tg(FFI) and Tg(CJD) mice were subjected to protein misfolding cyclic amplification with RML PrPSc as a seed, they generated highly PK-resistant mutant prions (RMLFFI and RMLCJD) able to propagate in Tga20 mice overexpressing wild-type PrP. To determine whether these in vitro-converted prions modeled the human diseases better, we examined their transmissibility, biochemical traits, and neuropathological features. Despite successful serial propagation in Tga20 mice, RMLFFI and RMLCJD displayed long incubation times, poor transmissibility to C57BL/6 mice, identical PK-resistant PrP fragments, and distinctive neuropathological changes including large submeningeal and perivascular plaques enriched in endogenous proteolytically shed PrP lacking membrane anchorage. These findings indicate that, regardless of the M129V polymorphism, the D178N mutation imparts novel, stable strain properties to RML that do not recapitulate the features of FFI and CJD178. Our results offer new insights into how genetic PrP mutations influence prion strain characteristics and suggest that spontaneous and templated prionogenesis may follow distinct mechanistic pathways.
    DOI:  https://doi.org/10.1007/s00401-026-02976-w
  38. bioRxiv. 2026 Jan 28. pii: 2026.01.26.701799. [Epub ahead of print]
    Spatial transcriptomics reveals brain-wide circadian disruption in an Alzheimer's disease model.
    Alon Gelber, Haylie Romero, Dominic Burrows, Daniel S Whittaker, Daniel Carlin, Eran A Mukamel, Paula Desplats.
      Diurnal rhythms in brain transcription align neural, immune, and metabolic processes with the light-dark cycle and are profoundly disrupted in Alzheimer's disease (AD). However, the regional organization of diurnal transcription in the healthy and diseased brain remains poorly defined. Using large-scale spatial transcriptomics, we mapped 24-hour rhythmic transcription across cortical and subcortical regions of the mouse brain. We identified marked regional differences in rhythmicity, including distinct oscillatory signatures across cortical areas and along the rostro-caudal axis. In the APP23 mouse model of AD, pathology-vulnerable brain regions exhibited early, region-specific disruption of diurnal transcription prior to substantial amyloid plaque deposition. These findings reveal a spatially organized architecture of brain diurnal rhythms and identify early rhythmic dysregulation as a feature of Alzheimer's disease pathogenesis.
    DOI:  https://doi.org/10.64898/2026.01.26.701799
  39. Nat Commun. 2026 Feb 12. 17(1): 1493
    Tissue-resident macrophage survival depends on mitochondrial function regulated by SerpinB2 in chronic inflammation.
    Sathish Babu Vasamsetti, Samreen Sadaf, Mohammad A Uddin, Jixing Shen, Ebin Johny, Awishi Mondal, Jonathan Florentin, Liqun Lei, Aleef Mannan, Krithika Sudhakar Rao, John Sembrat, Mauricio Rojas, Ian Sipula, Jake Kastroll, Michael J Jurczak, Sruti Shiva, Robert M O'Doherty, Vijay Yechoor, Partha Dutta.
      How cellular metabolism facilitates tissue-resident macrophage maintenance remains elusive. Here we show that visceral adipose tissue (VAT)-resident macrophages, unlike monocyte-derived macrophages, are enriched with mitochondrial-specific antioxidant enzymes restraining inflammation and promoting VAT homeostasis and insulin sensitivity. Additionally, VAT resident macrophages express high levels of plasminogen activator inhibitor type 2, encoded by SerpinB2, which is involved in the blood coagulation cascade. SerpinB2 promotes adipose resident macrophage survival by regulating mitochondrial oxidative phosphorylation and preventing the release of pro-apoptotic cytochrome c from the mitochondria into the cytoplasm via antioxidant glutathione production. Chronic inflammation, such as obesity, diminishes SerpinB2 expression in VAT macrophages in patients and mice, leading to the decline of this macrophage subset. Mechanistically, interferon-γ elevation in diabetes induces Ikaros, a transcriptional suppressor, which binds to the SerpinB2 promoter and decreases SerpinB2 expression. Congruently, selective depletion of the IFN-γ receptor in myeloid cells or supplementation of macrophage-specific SerpinB2 deficient mice with N-acetylcysteine, a glutathione precursor, restores VAT resident macrophage survival, decreases adipocyte size, and improves glucose tolerance and insulin sensitivity. Our data thus reveal an unexpected function of SerpinB2 in the regulation of mitochondrial function and survival of tissue-resident macrophages.
    DOI:  https://doi.org/10.1038/s41467-026-69196-4
  40. J Neuroinflammation. 2026 Feb 12.
    APOE4-driven T cell dysregulation in Alzheimer's disease: single-cell genomics and Mendelian randomization reveal novel therapeutic targets.
    Dongming Zheng, Jian Gu, Jianfei Nao, Miao Sun, Xiaoyu Dong.
      
    Keywords:  APOE4; Alzheimer’s disease; Mendelian randomization; Neuroinflammation; Single-cell RNA sequencing; T cells; Therapeutic targets
    DOI:  https://doi.org/10.1186/s12974-026-03727-0
  41. Neuroscience. 2026 Feb 05. pii: S0306-4522(26)00085-0. [Epub ahead of print]
    Comparative analysis of key phagocytic genes in humans and mice using machine learning integrated with single-cell RNA sequencing.
    Li Chengcheng, Liu Hang.
      Microglial phagocytosis is essential for neurological recovery after intracerebral hemorrhage (ICH). Using single-cell RNA sequencing, we compared microglial responses in murine and human ICH and identified striking species-specific temporal patterns. Murine microglia exhibited a sustained enhancement of phagocytic activity, whereas human microglia showed only a transient increase followed by a decline and persistent inflammation. To identify genes associated with phagocytic differences, we evaluated five machine learning models and selected XGBoost as the best-performing model. This analysis identified Tlr2 in mice and CLEC7A in humans as genes associated with microglial phagocytic status. Inferred transcription factor activity analysis further revealed stronger phagocytosis- and inflammation-associated transcriptional activity in murine phagocytic microglial subclusters, whereas human microglia were predominantly characterized by inflammation-associated transcription factors. Consistent with these results, Tlr2 expression was markedly increased at day 14 in single-cell data, and immunostaining confirmed its colocalization with IBA1+ microglia and upregulation at days 3 and 7 after ICH. Together, our findings demonstrate that integrating single-cell RNA sequencing with machine learning facilitates the identification of phagocytosis-associated genes and reveals both conserved and divergent patterns of microglial phagocytosis, providing new insights into species-specific responses to ICH.
    Keywords:  Inflammation; Intracerebral hemorrhage; Machine Learning; Microglia; Phagocytosis
    DOI:  https://doi.org/10.1016/j.neuroscience.2026.02.002
  42. Neurosci Lett. 2026 Feb 11. pii: S0304-3940(26)00041-8. [Epub ahead of print] 138543
    Human microglia express anti-inflammatory ISG15 in response to Neisseria meningitidis.
    Andrew M Dunphy, Krishna Majithia, Quinton A Krueger, M Brittany Johnson, Ian Marriott.
      Glial cells respond to the presence of bacteria by producing inflammatory mediators but these responses can result in damage to the central nervous system (CNS). However, glia can also produce immunosuppressive mediators that can serve to mitigate such effects. Here, we demonstrate that human microglial cells and, to a lesser extent, primary human astrocytes, can express and secrete interferon stimulated gene 15 (ISG15) in response to a clinically relevant CNS pathogen, Neisseria meningitidis, and ligands for Toll-like receptor 4 (TLR4) that include lipopolysaccharide and lipooligosaccharide derived from N. meningitidis. Exogenous ISG15 failed to elicit human neutrophil-like cell migration and induce or augment their inflammatory responses. Similarly, recombinant ISG15 application did not elicit inflammatory cytokine or chemokine production by either human microglial cells or astrocytes, and did not augment their responses to TLR stimulation or N. meningitidis infection. Rather, ISG15 treatment limited N. meningitidis-induced NF-κB activation and associated inflammatory cytokine production by these cells, perhaps via a non-canonical TLR-mediated pathway. These observations may be indictive of a novel negative feedback loop whereby the recognition of bacterial motifs precipitates ISG15 expression by resident microglia that subsequently mitigates further neuroinflammatory responses.
    Keywords:  Anti-inflammatory; Astrocytes; Human; ISG15; Microglia; Neisseria meningitidis
    DOI:  https://doi.org/10.1016/j.neulet.2026.138543
  43. Nature. 2026 Feb 11.
    Sleep-dependent clearance of brain lipids by peripheral blood cells.
    Bumsik Cho, Diane E Youngstrom, Samantha Killiany, Camilo Guevara, Caitlin E Randolph, Connor H Beveridge, Pooja Saklani, Gaurav Chopra, Amita Sehgal.
      Sleep is viewed typically through a brain-centric lens, with little known about the role of the periphery1,2. Here we identify a sleep function for peripheral macrophage-like cells (haemocytes) in the Drosophila circulation, showing that haemocytes track to the brain during sleep and take up lipids accumulated in cortex glia due to wake-associated oxidative damage. Through a screen of phagocytic receptors expressed in haemocytes, we discovered that knockdown of eater-a member of the Nimrod receptor family-reduces sleep. Loss of eater also disrupts haemocyte localization to the brain and lipid uptake, which results in increased brain levels of acetyl-CoA and acetylated proteins, including mitochondrial proteins PGC1α and DRP1. Dysregulation of mitochondria, reflected in high oxidation and reduced NAD+, is accompanied by impaired memory and lifespan. Thus, peripheral blood cells, which we suggest are precursors of mammalian microglia, perform a daily function of sleep to maintain brain function and fitness.
    DOI:  https://doi.org/10.1038/s41586-025-10050-w
  44. Immunity. 2026 Feb 10. pii: S1074-7613(26)00042-7. [Epub ahead of print]59(2): 235-237
    Shedding light on interventions for brain aging.
    Juan Zhang, Qiang Liu.
      Immunotherapeutic approaches to brain aging remain largely preclinical and in early translational stages, and they have focused mostly on modulating innate immunity. In this issue of Immunity, Negredo et al. identify T cells bearing exhaustion-like signatures as a hallmark of brain aging and reveal the beneficial effects of an engineered IL-10 variant that functionally uncouples pro- and anti-inflammatory signaling in microglia.
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.021
  45. Nat Commun. 2026 Feb 13.
    A neuron type-specific microexon in Ank3/ankyrin-G modulates calcium activity and neuronal excitability.
    Shah Alam, Georgia Dermentzaki, David Cabrera-Garcia, Miao Li, Ruizhi Wang, Melissa Campbell, Ilaria Balbo, Brittany L Phillips, Min Li, Jessica Estrada, Marianna Zazhytska, Yow-Tyng Yeh, Lia Min, Elizabeth Rafikian, Elizabeth Valenzuela, Brian Joseph, Tulsi Patel, Dmytro Ustianenko, Helene Lovett, Huijuan Feng, Xiaojian Wang, Susan Brenner-Morton, Chyuan-Sheng Lin, Clarissa L Waites, Hynek Wichterle, Lizhen Chen, Mu Yang, Edmund Au, Marko Jovanovic, Stavros Lomvardas, Paul M Jenkins, Rui Yang, Sheng-Han Kuo, Yueqing Peng, Guang Yang, Neil L Harrison, Chaolin Zhang.
      Recent studies have revealed many alternative exons differentially spliced across diverse neuron types in the mammalian brain, but their links to neuronal physiology remain unclear. Here we characterize a deeply conserved microexon E35a in Ank3 encoding ankyrin-G (AnkG), a multifaceted adaptor protein best known as a master organizer of the axon initial segment (AIS) and as a leading genetic risk factor for bipolar disorder. E35a is predominantly skipped in cortical glutamatergic neurons but included in cortical GABAergic neurons and cerebellar neurons, which is dictated by multiple neuronal splicing factors. In E35a-deletion mice we generated, interneurons show increased excitability and somatic Ca2+ activity, without disruption in AIS. Biochemical analyses suggest that E35a inclusion facilitates AnkG interaction with a protein complex involving inositol trisphosphate receptors (InsP3Rs) important for intracellular Ca2+ signaling. Alternative splicing therefore allows AnkG to modulate neuron type-specific excitability in addition to its ubiquitous pan-neuronal role in organizing the AIS.
    DOI:  https://doi.org/10.1038/s41467-026-69486-x
  46. Immunity. 2026 Feb 10. pii: S1074-7613(26)00028-2. [Epub ahead of print]59(2): 229-231
    Microglia makeover: On-demand control panel revamp.
    Takahiro Masuda.
      Microglia display remarkable plasticity, with their cellular states evolving in response to developmental stage, regional context, and environmental or pathological stimuli. In this issue of Immunity, Hamagami et al. demonstrate that adaptive reconfiguration of regulatory networks, particularly the dynamics of enhancers, underlies these state transitions. Conserved enhancers link developmental and Alzheimer's-related microglial states, suggesting shared epigenetic frameworks that influence neurodegenerative susceptibility.
    DOI:  https://doi.org/10.1016/j.immuni.2026.01.007
  47. Mol Neurodegener Adv. 2026 ;2(1): 11
    Distinct CSF lipidomic profiles are associated with five proteomic subtypes in patients with Alzheimer's disease.
    Georgia Malliou, Lianne M Reus, Yolande A L Pijnenburg, Wiesje M van der Flier, Nienke M de Wit, Serhii Chornyi, Gijs Kooij, Helga E de Vries, Charlotte E Teunissen, P J Visser, Roel A Ophoff, Betty M Tijms.
       Background: Alzheimer's disease (AD) is molecularly heterogeneous. In our previous cerebrospinal fluid (CSF) proteomic study in AD, we identified and validated five distinct molecular subtypes characterized by neuronal hyperplasticity (subtype 1), innate immune activation (subtype 2), RNA dysregulation (subtype 3), choroid plexus dysfunction (subtype 4) and blood-brain barrier impairment (subtype 5). These subtypes also differed in the CSF levels of proteins involved in lipid metabolism, suggesting that lipid dysregulation in AD might be subtype specific.
    Methods: We performed untargeted lipidomics on CSF samples from 601 individuals in the Amsterdam Dementia Cohort who were previously included in our proteomic study (n = 416 AD, 185 controls). Using the CSH-QTOF platform for complex lipids, 3,532 lipids were detected in CSF, 270 of which could be mapped to 13 different lipid classes. Lipid levels were compared between each AD subtype and controls using linear regression models adjusted for age and sex (R v4.2.1). Lipids with significantly different levels (p < 0.05) were included for pathway enrichment analysis with MetaboAnalyst6.0.
    Results: We observed alterations in the levels of 1,893 lipids, with the majority associated with a single AD subtype. Subtype 3 (RNA dysregulation) exhibited the most pronounced alterations, with altered CSF levels of 669 lipids, including triglycerides and fatty acids, which were reduced compared to controls. Subtype 4 (choroid plexus dysfunction) and subtype 5 (blood-brain barrier dysfunction) both had alterations in the same set of 150 lipids, but with changes occurring in opposite directions (i.e., decreased in subtype 4, and increased in subtype 5). These lipids were associated with sphingolipid metabolism and lipid transport. Subtype 1 (neuronal hyperplasticity) and subtype 2 (innate immune activation) had less pronounced differences compared to the other subtypes. Subtype 1 had increased levels of several phospholipids, indicating neuronal membrane remodeling, and subtype 2 decreased arachidonic acid levels, a precursor of immunoregulatory oxylipins.
    Conclusion: Our findings reveal subtype-specific lipid metabolism alterations in AD. Currently, five lipid-targeting drugs are in phase 1 and 2 trials. Our results suggest that treatment efficacy may vary by subtype. Understanding these molecular differences can inform trial design and analysis, advancing the development of tailored therapies for AD.
    Supplementary Information: The online version contains supplementary material available at 10.1186/s44477-026-00018-z.
    Keywords:  Alzheimer’s disease; Heterogeneity; Lipid metabolism; Lipidomics; Molecular subtypes
    DOI:  https://doi.org/10.1186/s44477-026-00018-z
  48. bioRxiv. 2026 Feb 04. pii: 2026.02.02.703345. [Epub ahead of print]
    Mitochondrial double-stranded RNA accumulation in brain aging and Alzheimer's disease.
    Rachel L Doser, Thomas J LaRocca.
      Mitochondria and inflammation are tightly linked in aging and Alzheimer's disease (AD), and recent evidence implicates mitochondrial double-stranded RNA (mt-dsRNA) as a potential trigger of inflammation. We examined mt-dsRNA accumulation and dsRNA signaling in brain aging and AD using human brain tissue and complementary in vitro transcriptomic datasets, quantifying mitochondrial transcripts and dsRNA editing. We found that mt-dsRNA accumulated after midlife and coincided with reduced expression of mitochondrial RNA processing and translation machinery, along with increased expression of dsRNA antiviral signaling proteins, consistent with cytoplasmic mt-dsRNA-driven inflammation. In AD brains, mt-dsRNA accumulation was further increased and correlated with cognitive impairment, neuropathological severity, and AD risk genotypes. Genes associated with these measures reflected altered ubiquitin-dependent regulation of antiviral signaling, potentially indicating altered sensitivity to mt-dsRNA. Together, these findings highlight mitochondrial RNA homeostasis as an unrecognized contributor to age- and AD-related neurodegeneration by identifying mt-dsRNA as a potential driver of chronic inflammation.
    Abstract Figure:
    DOI:  https://doi.org/10.64898/2026.02.02.703345
  49. CNS Neurosci Ther. 2026 Feb;32(2): e70777
    TREM2 Facilitates Myelin Debris Clearance but Exacerbates Chronic Inflammation and Fibrosis After Spinal Cord Injury.
    Zhonghan Wu, Shuisheng Yu, Yixue Hu, Xuyang Hu, Linhan Yang, Yan Jiang, Mengdi Zhang, Yiyang Mu, Ziyu Li, Fei Yao, Dasheng Tian, Juehua Jing, Li Cheng.
       BACKGROUND: The accumulation of myelin debris after spinal cord injury (SCI) inhibits axon regeneration and remyelination. Triggering receptor expressed on myeloid cell 2 (TREM2) is crucial for cellular debris clearance and disease-associated microglia (DAM) activation. However, whether TREM2 mediates these processes after SCI remains unclear.
    METHODS: A mouse model of spinal cord crush injury was employed. Female TREM2-/- mice were used to delete TREM2, while COG1410 was administered to activate TREM2 in female wild-type mice. Tissue immunostaining and western blotting were performed to analyze TREM2 expression after SCI. Tissue immunostaining was conducted to evaluate the cellular origin of TREM2 and its impact on phagocytosis, foamy macrophage formation, DAM activation, axon regeneration, and neuronal survival. Basso Mouse Scale and footprint analysis were used to evaluate locomotor function recovery.
    RESULTS: TREM2 was primarily localized to Iba1+ macrophages/microglia around the lesion core, with its expression increasing during the subacute stage, peaking at 7 days post-injury. TREM2 deficiency impaired engulfment and degradation of myelin debris, increased foamy macrophage formation, and hindered DAM activation. In vivo rescue experiments further confirmed that TREM2 promotes DAM activation via the PI3K/AKT pathway. However, TREM2 exacerbated fibrosis, as indicated by increased extracellular matrix deposition, enhanced fibroblast accumulation, and widespread inflammation. COG1410-mediated long-term activation of TREM2 impaired long-term locomotor function recovery, inhibited axon regeneration, and reduced neuronal survival, whereas short-term activation improved early locomotor function without structural neuroprotection.
    CONCLUSIONS: Our study suggests that TREM2 promotes myelin debris clearance but exacerbates chronic inflammation and fibrosis after SCI. These findings underscore the promise of TREM2 as a target for developing effective treatment strategies for SCI.
    Keywords:  TREM2; disease‐associated microglia; foamy macrophage; myelin debris; spinal cord injury
    DOI:  https://doi.org/10.1002/cns.70777
  50. Nat Commun. 2026 Feb 12.
    A macrophage-induced subpopulation of mesenchymal cells expressing Fcer1g contributes to wound-induced fibrosis.
    Xinyi Ma, Ergang Wang, Vijitha Puviindran, Ziyuan Su, Xiaoxi Liu, Eijiro Shimada, Chengsong Yan, Yining Liu, Zhenyu Li, Puvi Nadesan, Koji Ishikawa, Makoto Nakagawa, Zeyu Huang, Xiao-Fan Wang, Benjamin Aaron Alman.
      Fibrosis commonly occurs during adult skin wound healing, characterized by excessive extracellular matrix (ECM), leading to scarring. Mesenchymal cells, the primary ECM-producing population, are heterogeneous with varying fibrotic propensity during healing. While pro-fibrotic embryonically derived mesenchymal lineages have been identified, adult mesenchymal cells responsible for fibrosis are not yet fully characterized. In adult mice with conditional macrophage depletion during the early phase of wound healing, wounds exhibit attenuated fibrosis and a reduction in mesenchymal cell numbers. Here we show that early phase macrophage induces a distinct PDGFRα⁺ mesenchymal population expressing Fcer1g. This cell population expands rapidly after injury, shows high proliferative activity, and is largely absent when macrophages are depleted. Targeted ablation of this cell population does not delay wound closure but results in diminished scarring. Human wound datasets identified a transcriptionally conserved FCER1G-expressing mesenchymal subset, suggesting that this pro-fibrotic mesenchymal state is preserved in human wound healing.
    DOI:  https://doi.org/10.1038/s41467-026-69449-2
  51. Proc Natl Acad Sci U S A. 2026 Feb 17. 123(7): e2520566123
    Natalizumab exacerbates astrocytopathy in NMOSD via blockade of endothelial VCAM1-astrocytic integrin α4 interaction.
    Tingting Cui, Qing Wen, Zixuan An, Jingqi Kang, Pei Li, Yuechen Zeng, Lan Lin, Rui Gao, Guo Cheng, Luhang Dai, Zhe Feng, Ye Gong, Xin Zhang, Ke Li, Xiaoli Ding, Xiaochang Xue, Luting Yang, Lei Zhang, Yaling Zhang, Yaping Yan.
      Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disorder of the central nervous system (CNS) that shares clinical features with multiple sclerosis (MS) but typically manifests with more severe symptoms. The presence of pathogenic IgG autoantibodies targeting aquaporin-4 (AQP4) channels on astrocytes serves as a highly specific biomarker that distinguishes NMOSD from MS. Unlike MS, NMOSD is characterized by profound astrocytic destruction and exhibits a distinct response to therapies. Notably, disease-modifying therapies (DMTs) effective in MS, including natalizumab, interferon-β, and fingolimod, not only fail to benefit NMOSD patients but may also exacerbate disease progression. The precise molecular mechanisms underlying this immunomodulator-induced exacerbation, however, remain not yet fully elucidated. Here, we demonstrate that natalizumab alleviated experimental autoimmune encephalomyelitis (EAE) while exacerbating the autoimmune astrocytopathy in an "EAE-NMOSD" mouse model, a phenomenon associated with a reduction in actively proliferating astrocytes. Through molecular and signaling pathway analyses, we identify that endothelial-derived vascular cell adhesion molecule 1 (VCAM1) activates astrocytes via integrin α4 signaling, thereby mitigating astrocytopathy in NMOSD-like mice. Furthermore, astrocyte-specific integrin α4 deficiency exacerbates astrocytopathy, and notably, natalizumab-induced disease exacerbation does not occur in integrin α4-conditional knockout (CKO) mice. Finally, pharmacological activation of astrocytes rescues natalizumab-induced damage and ameliorates demyelination in NMOSD-like mice. Collectively, our findings provide mechanistic gaps regarding the clinical phenomenon underlying natalizumab-induced NMOSD exacerbation and suggest astrocyte-targeted therapeutic strategies as a potential intervention for NMOSD.
    Keywords:  astrocytopathy; demyelination; integrin α4; natalizumab; neuromyelitis optica spectrum disorder (NMOSD)
    DOI:  https://doi.org/10.1073/pnas.2520566123
This page is being maintained by Thomas Krichel. It was last updated on 2026‒02‒24 at 1:36.