bims-micgli Biomed News
on Microglia
Issue of 2026–05–24
thirty-two papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.
  2. A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions.
  3. Genetic suppression of myeloid receptor Clec7a attenuates microglia neuroinflammation and promotes microglial phagocytosis to delay disease progression in ALS models.
  4. A GPCR atlas across human microglial states in Alzheimer's disease: Insights from snRNA-seq and hiPSC models.
  5. Microglial sTREM2 limits dyskinesia and acts on TrkB to support circuit plasticity.
  6. Enhanced engraftment of transplanted microglia through host microglia depletion in the embryonic brain.
  7. Identification of secondary microglial formation centers in the human fetal brain.
  8. High-dimensional Spatial Immune Profiling Highlights Microglia-Like Cells in Human Dorsal Root Ganglia.
  9. ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.
  10. Spatially Resolved Microglial State Transitions Govern Strain-Specific Zika Neuropathogenesis.
  11. Resilience to neuronal hyperactivity and restoration of the neuroimmune interactome and decision-making by blocking fibrin in a model of Alzheimer's disease.
  12. How does type 2 diabetes modify the risk of Alzheimer's disease?
  13. Microglial senescence and epigenetic reprogramming in alzheimer's disease: An immunometabolic perspective.
  14. Targeting MEF2A suppresses microglial hyperactivation and synaptic phagocytosis to attenuate epilepsy pathogenesis.
  15. CD11c+ CD8 T cells cause IFN-γ-dependent autoimmune neuroinflammation that is restrained by PD-1 signaling.
  16. TRIM21 facilitates inflammasome assembly and contributes to autoinflammatory disease.
  17. Targeting microglia: A new strategy for the treatment of Alzheimer's disease.
  18. Primary and immortalized microglia exhibit divergent responses to hemoglobin.
  19. Spatial proteomic analysis in human Alzheimer's disease brains enables identification of microenvironment-dependent microglial cell states.
  20. Stress impairs your brain's ability to link memories - dampening insight.
  21. Microglia maintain retinal redox homeostasis following ablation of rod photoreceptors in zebrafish.
  22. Parkinson's disease beyond the brain: erythrocyte α-synuclein transfer across the blood-brain barrier.
  23. Foamy microglia link oxylipins to disease progression in multiple sclerosis.
  24. Maraviroc Attenuates Neuronal Apoptosis by Inhibiting CCR5-Mediated Microglial Activation After Subarachnoid Hemorrhage.
  25. Single-cell atlas reveals the key role of pro-inflammatory IREB2⁺ microglia subsets in the microenvironment of Alzheimer's disease.
  26. Astrocyte glucocorticoid receptor signalling restricts neuronal plasticity.
  27. Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation.
  28. Before synapses are lost: Do endogenous retroviruses drive microglial overpruning in autism spectrum disorders?
  29. Treating the immune system to repair the brain.
  30. Highly focused human CD8+ T-cell response in the lower airways during acute influenza infection.
  31. Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
  32. Lipid metabolism and contact site homologs are present at the chloroplast envelope-thylakoid interface.
  1. Mol Neurodegener. 2026 May 22.
    Dual orexin receptor antagonism with lemborexant enhances microglial clearance of β-amyloid in mice.
    Ashish Sharma, Emiko Segawa, Xiaoying Chen, Sohui Park, Shoutang Wang, Riley E Irmen, Nicholas J Constantino, Chanung Wang, Michael F Kanan, Marco Colonna, Shannon L Macauley, Jocelyn Y Cheng, Ken Hatanaka, Margaret Moline, Erik S Musiek.
       BACKGROUND: Sleep disturbances elevate brain amyloid-beta (Aβ) levels and represent a modifiable risk factor for Alzheimer's disease (AD). The orexin/hypocretin system regulates sleep-wake behavior and has emerged as a therapeutic target in AD; however, the effects of FDA-approved dual orexin receptor antagonists (DORAs) on amyloid pathology remain unclear. We compared lemborexant, an FDA-approved DORA, to doxepin, an antihistaminergic sleep medication, on amyloid pathology and microglial responses in PSAPP mice.
    METHODS: PSAPP mice received lemborexant (10 or 30 mg/kg/day), doxepin (35 mg/kg/day), or vehicle for 6 weeks beginning prior to plaque onset or 4 weeks after established pathology. Sleep was assessed by piezoelectric monitoring and EEG/EMG polysomnography. Amyloid pathology and microglial responses were quantified by immunohistochemistry, confocal microscopy, and single-cell RNA sequencing. Microglial depletion was induced with the CSF1R inhibitor PLX3397.
    RESULTS: Lemborexant enhanced sleep quality with less active-phase sedation than doxepin. Both drugs reduced initial diffuse plaque deposition, but only lemborexant prevented fibrillar plaque accumulation in young mice and slowed plaque growth in older mice. Lemborexant increased peri-plaque microglial CD68 expression and enhanced Aβ phagocytosis in vivo. Single-cell transcriptomics revealed a shift toward activated, DAM-like microglial states with upregulation of phagocytic genes without broad inflammatory induction. Microglial depletion abolished lemborexant's anti-amyloid effects.
    CONCLUSIONS: Lemborexant mitigates amyloid pathology by augmenting microglial phagocytic function, positioning DORAs as promising therapeutics that couple sleep promotion with beneficial microglial modulation.
    Keywords:  Alzheimer’s disease; Amyloid plaques; Microglia; Orexin; Sleep
    DOI:  https://doi.org/10.1186/s13024-026-00948-y
  2. Nat Commun. 2026 05 18. pii: 3858. [Epub ahead of print]17(1):
    A comparative transcriptomic analysis of mouse demyelination models and multiple sclerosis lesions.
    Erin L Aboelnour, Veronica R Vanoverbeke, Elizabeth A Maupin, Madelyn M Hatfield, Katrina L Adams.
      Demyelinating diseases, including multiple sclerosis (MS), are characterized by loss of myelin and progressive neurodegeneration. It remains unclear if demyelination mouse models, such as cuprizone (CPZ) and lysophosphatidylcholine (LPC) elicit distinct responses or are comparable to human disease. Here, we integrate new and published single-cell transcriptomic datasets from CPZ- and LPC-induced demyelination and compare them with human MS data. We find that CPZ induces a distinct, stressed oligodendrocyte (OL) state, marked by Cdkn1a and Nupr1, that resembles phenotypes in MS lesions. The models converge on an immune responsive OL state expressing Socs3, B2m, and interferon-response genes during remyelination. Mouse microglia share a conserved activation program, although LPC drives a stronger, prolonged response. However, neither model captures the oligodendrocyte progenitor and microglial heterogeneity observed in MS. These results provide a cross-model, cross-species atlas of glial states and offer a framework to strategically leverage mouse models to study myelin injury and repair.
    DOI:  https://doi.org/10.1038/s41467-026-72383-y
  3. bioRxiv. 2026 May 07. pii: 2026.05.04.722437. [Epub ahead of print]
    Genetic suppression of myeloid receptor Clec7a attenuates microglia neuroinflammation and promotes microglial phagocytosis to delay disease progression in ALS models.
    Xuan Chen, Huilan Yan, Haichao Wei, Sanaz Sajadi, Jingwen Hu, Vinicius Vasconcellos, Ashley Kim, Tarun Shriram, Huizhong Tan, Kyoeun Keum, Jiaqian Wu, Martin Paukert, Yongjie Yang.
      Microglial activation has been closely associated with accelerated ALS disease progression. However, specific microglial pathways that regulate microglial activation and ALS disease progression remain limitedly understood. Here, we determined the role of Clec7a (or Dectin-1), a core signature gene of disease-associated microglia (DAM) in ALS, in regulating microglial activation and ALS disease progression. Our spinal cord scRNA-Seq results found that Clec7a deficiency specifically attenuated microglial neuroimmune gene expression in SOD1G93A mice and human ALS. In addition, in vivo two-photon imaging of human (h) TDP43 phagocytosis by microglia in the cortex showed that Clec7a deficiency promotes microglial phagocytosis of pathological hTDP43 by enhancing microglial process dynamics. Subsequent survival analysis further showed that selective deletion of Clec7a in microglia mitigates motor neuron degeneration and delays disease progression in SOD1G93A ALS mice. Together, our results establish that Clec7a is a key regulator in shaping disease microglial functions and promotes disease progression in ALS.
    DOI:  https://doi.org/10.64898/2026.05.04.722437
  4. Exp Neurol. 2026 May 21. pii: S0014-4886(26)00210-4. [Epub ahead of print] 115845
    A GPCR atlas across human microglial states in Alzheimer's disease: Insights from snRNA-seq and hiPSC models.
    Bing Zhang, Zhao Ran, Xiao-Yan Li, Zi-Han Wei, Dong-Mei Wang, Mei-Hong Lu.
      Microglia are the resident immune cells of the central nervous system, and their state heterogeneity is closely associated with the pathological progression of Alzheimer's disease (AD). Single-nucleus RNA sequencing (snRNA-seq) studies have identified multiple transcriptional states of microglia in human AD brain. However, the characteristics and potential functions of G protein-coupled receptors (GPCRs) across different states remain poorly systematized. This review systematically searched and reviewed snRNA-seq studies based on human brain tissue published between 2020 and 2025. By re-analyzing GPCR expression across these datasets, we focuses on characterizing the differential expression characteristics and potential functions of GPCRs in five key AD-related microglial states: disease-associated microglia, tau-associated microglia, inflammation-associated microglia, proliferation-associated microglia, and interferon-associated microglia. Furthermore, we cross-reference these findings with single-cell sequencing data from human induced pluripotent stem cell (hiPSC)-derived microglia to prioritize a conserved set of GPCRs of high interest. In summary, by integrating transcriptomic evidence from both post-mortem human brain and hiPSC models, this review not only refines the understanding of microglial heterogeneity in AD but also also provides a set of candidate GPCR targets for subsequent validation and drug discovery efforts against AD.
    Keywords:  Alzheimer's disease; GPCRs; Heterogeneity; Microglia states; snRNA-seq
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115845
  5. bioRxiv. 2026 May 07. pii: 2026.05.06.723382. [Epub ahead of print]
    Microglial sTREM2 limits dyskinesia and acts on TrkB to support circuit plasticity.
    Caitlin Castagnola, Roberta Marongiu, Yuansong Wan, Eileen Ruth S Torres, Li Fan, Minwoo Wendy Jang, Qiaoling Cui, Jihye Kim, Pearly Ye, Jingjie Zhu, Alisa Panichkina, Alexandra B Fall, Kendra Norman, Beichen Gao, Nessa Foxe, Man Ying Wong, Daphne Zhu, Maitreyee Bhagwat, Shiaoching Gong, Anna G Orr, Francis S Lee, D James Surmeier, Michael G Kaplitt, Li Gan.
      Microglia continuously survey the brain and shape neuronal activity, but their contribution to experience-dependent synaptic plasticity is unclear. Levodopa-induced dyskinesia (LID) is a disabling complication of late-stage Parkinson's disease (PD) that is linked to maladaptive striatal remodeling and is often assumed to reflect detrimental neuroinflammation. Here we identify a dyskinesia-associated microglial gene program in the striatum of PD patients and show that microglia instead act as a protective brake on LID. In a mouse model, microglial depletion exacerbated dyskinesia, whereas microglial repopulation mitigated it. Delivery of AAV expressing soluble TREM2 (sTREM2) similarly reduced LID without impairing the therapeutic benefit of levodopa. Single-nucleus transcriptomics revealed that microglial loss drives extensive remodeling of both direct and indirect spiny projection neurons (SPNs), while repopulation or sTREM2 reverses a large fraction of LID-associated transcriptional changes. Mechanistically, sTREM2 directly engages TrkB and potentiates BDNF-dependent TrkB-ERK signaling, consistent with positive allosteric modulation. Functionally, sTREM2 enhances BDNF-TrkB-dependent hippocampal synaptic plasticity and acutely rebalances striatal dendritic excitability in a compartment- and cell type-specific manner. These findings reveal an unexpected neuroimmune pathway in which microglia restrain maladaptive plasticity via sTREM2-TrkB signaling, with therapeutic implications.
    DOI:  https://doi.org/10.64898/2026.05.06.723382
  6. Neurosci Res. 2026 May 15. pii: S0168-0102(26)00058-1. [Epub ahead of print]228 105071
    Enhanced engraftment of transplanted microglia through host microglia depletion in the embryonic brain.
    Ayaka Osumi, Tsukasa Shimamura, Takaki Miyata, Yuki Hattori.
      Transplantation of microglia into the embryonic brain could provide a powerful approach to trace microglial fate and test their functional contribution during development. However, embryonic microglial transplantation remains technically challenging because only a limited number of donor cells can be obtained and transplantation efficiency is low. Here, we investigated whether transient depletion of endogenous microglia could improve the engraftment of transplanted microglia in the embryonic mouse brain. Pregnant mice were fed a diet containing a colony-stimulating factor 1 receptor inhibitor (PLX5622) in advance to reduce resident microglia in the embryos. CD11b-positive cells isolated from embryonic day (E) 12.5 CX3CR1-GFP donor brains were transplanted into the lateral ventricles of E12.5 embryos, and brains were analyzed at E14.5. In embryos fed a normal diet, most transplanted cells remained in the ventricular space, whereas PLX5622-treated embryos showed a marked increase in GFP-positive cells within the brain parenchyma, suggesting improved engraftment. Furthermore, early microglial depletion caused enlargement of cavities in the cortico-striato-amygdalar boundary (CSA), a developmental boundary region in the ganglionic eminence. Microglial transplantation significantly reduced the size of these cavities. These results suggest that transient depletion of host microglia enhances embryonic microglial transplantation and that transplanted microglia can partially restore structural abnormalities caused by microglial loss.
    Keywords:  Brain; Development; Embryo; Engraftment; Ganglionic eminence; Microglia; Pallium; Transplantation
    DOI:  https://doi.org/10.1016/j.neures.2026.105071
  7. J Exp Med. 2026 Jun 01. pii: e20251801. [Epub ahead of print]223(6):
    Identification of secondary microglial formation centers in the human fetal brain.
    Chenyun Song, Xinyu Chen, Rong Ji, Yang Liu, Yawen Han, Fangzhou Ye, Ling Zhang, Li Li, Lu Gao, Qizhi He, Lixiang Ma, Hexige Saiyin.
      Microglia migrate from the yolk sac and populate the developing brain. How microglia expand rapidly to meet the microglial demand in fast-expanding human fetal brains remains uncharted. Using thick sections in 5-22-gestational week (gw) brains and super-resolution scanning, we identified a large proliferative microglial aggregate (2.129 mm2) near the lateral ganglionic eminence (>12.5 gw), expanding in Down's syndrome (DS) (4.767 mm2) and Edwards syndrome (ES) (3.437 mm2) fetal brains. Ki67+ microglia within the aggregates accounted for 26.65% (DS: 38.9%; ES: 46.3%) compared with 6.32% (DS: 6.01%; ES: 5.2%) in scattered microglia. This aggregate region contained a distinct microglial population characterized by the absence of phagocytic structures and complex processes, high CSF-1R expression, abundant IL-34+ cells, and some SPP1+ bipolar microglia. We termed this structure the secondary microglial formation center (SMFC). Chimeric microglia-human cortical organoids recapitulated the SMFC in an IL-34- and CSF-1R-dependent manner, indicating that the human SMFC may compensate for the microglial shortage during the fastest expansion period.
    DOI:  https://doi.org/10.1084/jem.20251801
  8. Eur J Immunol. 2026 May;56(5): e70211
    High-dimensional Spatial Immune Profiling Highlights Microglia-Like Cells in Human Dorsal Root Ganglia.
    Marius Schwabenland, Busranur Oeztuerk, Thomas Blank, Juergen Beck, Bertram Bengsch, Marco Prinz.
      The human dorsal root ganglia (DRG) are increasingly recognized as immunologically active sites within the peripheral nervous system. While single-cell transcriptomics has recently identified myeloid populations with microglia-like profiles in DRG across species, an in-depth, spatially resolved protein-level characterization in human tissue is lacking. Here, we used highly multiplexed Imaging Mass Cytometry (IMC) to map and phenotype myeloid cells in human DRG at subcellular resolution. A 41-marker panel enabled in-depth profiling of immune and neural cell types in situ. We identified a subset of Iba1+ myeloid cells co-expressing canonical microglial markers such as P2RY12, TMEM119, and SLC2A5, located in close spatial proximity to neuronal somata. Unsupervised clustering (FlowSOM) of >6000 Iba1+ cells identified eight distinct clusters. Among them, distinct myeloid cell subsets exhibited a clear microglial-like signature and were localized near neurofilament+ neurons. In contrast, Iba1+ clusters expressing CD68, HLA-DR, and other activation markers were spatially segregated. These findings provide a spatially resolved, protein‑level atlas of Iba1+ myeloid subsets in human DRG and offer a resource for dissecting neuroimmune niches relevant to chronic pain and peripheral neuropathies.
    Keywords:  dorsal root ganglia; imaging mass cytometry; microglia, microglia‐like cells; myeloid cells; spatial immune profiling
    DOI:  https://doi.org/10.1002/eji.70211
  9. bioRxiv. 2026 May 07. pii: 2026.05.04.722733. [Epub ahead of print]
    ApoE Lipidation State Directs Immunometabolic Reprogramming of Human Microglia.
    Tsion G Shiferaw, Snigdha Sarkar, Katelyn M Baker, Rowan S Wooldridge, Hannah M Binfet, Victoria N Prozapas, Chinemerum P Ogbu, Athena A Schepmoes, Isaac K Attah, Christy S Niemeyer, Kayla G Sprenger, James E Hassell, Robert H Eckel, John T Melchior, Kimberley D Bruce.
       Introduction: ApoE4 is the strongest genetic risk factor for Alzheimer's disease (AD). Emerging evidence suggests that ApoE4 increases AD risk by disrupting microglial metabolism and function. However, whether ApoE lipidation state contributes to microglial dysfunction remains poorly understood.
    Methods: Human microglia were treated with lipid-free or lipid-bound ApoE3 or ApoE4. Label-free live-cell holotomography and global proteomics were used to assess isoform- and lipidation-specific effects on lipid droplet dynamics, mitochondrial morphology, and microglial phenotype.
    Results: ApoE4 treatment resulted in fewer but enlarged lipid droplets and increased mitochondrial fragmentation compared to ApoE3, effects that were enhanced by lipid-bound ApoE4. Proteomic analyses revealed a strong type I interferon response in cells exposed to lipid-free ApoE, which was exacerbated by lipid-free ApoE4.
    Discussion: These findings indicate that lipid-bound ApoE4 drives metabolic reprogramming, whereas lipid-free ApoE4 promotes inflammatory signaling, identifying ApoE lipidation as a critical modifier of ApoE4-associated AD risk.
    DOI:  https://doi.org/10.64898/2026.05.04.722733
  10. bioRxiv. 2026 May 05. pii: 2026.04.30.721456. [Epub ahead of print]
    Spatially Resolved Microglial State Transitions Govern Strain-Specific Zika Neuropathogenesis.
    Md Musaddaqul Hasib, Wen Meng, Gonzalo Mena, Hugh Halloway, Suzane Ramos da Silva, Gary Kohanbash, Yufei Huang, Shou-Jiang Gao.
      Neurotropic viruses disrupt brain homeostasis through complex interactions among infected cells, resident immune responses, and tissue architecture, yet how these processes unfold across space, time, and cell types, and how viral strain differences shape disease severity, remains poorly understood. Here, we integrate high-resolution spatial transcriptomics with infection-aware cell-type profiling to construct a spatiotemporal atlas of Zika virus (ZIKV) infection in the mouse brain. Comparing Asian and African ZIKV strains across early and late infection stages, we uncover structured, strain-dependent reorganization of immune and structural cell populations that defines discrete infection-associated tissue niches. Microglia undergo region-specific state transitions characterized by both cell-intrinsic antiviral programs and widespread bystander activation, producing tissue-wide immune amplification. In Asian strain infection, we identify disease-associated microglia (DAM) as critical mediators of infection containment: DAM accumulate in regions where viral burden stabilizes, are promoted by Apoe-Trem2 signaling from infected cells and are governed by transcription regulators that restrain inflammatory programs while preserving phagocytic and antiviral functions. In contrast, African strain infection is marked by impaired Apoe-Trem2 signaling, persistent inflammatory microglial activation, and failure of containment. Progressive infection leads to depletion of oligodendrocytes, astrocytes, and neurons, loss of local cellular diversity and disruption of tissue architecture concentrated in somatosensory and motor regions associated with myelination and synaptic programs. These architectural disruptions correlate with severe neurological phenotypes in African strain infection and are preceded by transcriptional dysregulation in infected glial cells, including sustained stress responses, inflammatory signaling, and suppression of myelination and homeostatic pathways. Together, our study establishes a spatially resolved framework linking viral strain-specific microglial states to tissue disorganization and neurological functional impairment, providing mechanistic insight into how neurotropic viruses reshape microenvironments to drive neurological disease.
    DOI:  https://doi.org/10.64898/2026.04.30.721456
  11. bioRxiv. 2026 May 06. pii: 2026.05.01.722077. [Epub ahead of print]
    Resilience to neuronal hyperactivity and restoration of the neuroimmune interactome and decision-making by blocking fibrin in a model of Alzheimer's disease.
    Zhaoqi Yan, Andrew S Mendiola, Kelli Lauderdale, Keun-Young Kim, Yu Yong, Kun Leng, Eric A Bushong, Renaud Schuck, Anke Meyer-Franke, Ayushi Agrawal, Michela Traglia, Natalie Gill, Reuben Thomas, Jonah N Keller, Nikolaos Karvelas, Miguel F Vasquez, Daniel C Ballard, Matthew Madany, Jeffrey Simms, Brandon Guo, Reshmi Tognatta, Maria Del Pilar S Alzamora, Rosa Meza-Acevedo, Belinda Cabriga, Kellie N Pierson, Lida Kourita, Kayoung Han, Jae K Ryu, Bruce L Miller, Fanny M Elahi, Mark H Ellisman, Jorge J Palop, Katerina Akassoglou.
      Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimer's disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand-receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimer's disease and related conditions.
    Highlights: Vascular-microglia axis drives neuronal hyperactivityFibrin inflammatory activity disrupts the microglia-neuron interactomeMicroglia activation by fibrin impairs decision-making in AD miceSynaptic dysfunction and immune biomarkers correlate with CSF fibrinogen in AD patients.
    DOI:  https://doi.org/10.64898/2026.05.01.722077
  12. Alzheimers Dement. 2026 05;22(5): e71471
    How does type 2 diabetes modify the risk of Alzheimer's disease?
    G T Sutherland, A Chen, H-T Nguyen-Hao, H Mundell, E Aladyeva, M J Hofer, O Harari, S M Twigg.
      Type 2 diabetes (T2D) and Alzheimer's disease (AD) are both increasing exponentially worldwide. T2D has also been identified as one of 14 modifiable risk factors for dementia, but the mechanism is unknown. T2D could promote dementia via vascular or AD neuropathological changes, and mechanistic hypotheses include central insulin resistance and T2D's peripheral inflammation promoting central inflammation. Here we examine these different hypotheses by reviewing the recent literature in combination with re-analysis of post mortem brain tissue molecular data. Collectively, recent studies and single-cell transcriptomic data suggest that peripheral lipid anomalies and inflammation seen in T2D act together to reduce brain-blood barrier integrity, facilitating aberrant immune signaling between the periphery and the brain. The subsequent promotion of AD-specific microglial subtypes is the most likely mechanism linking T2D and AD. These AD-specific microglial subtypes may be reduced by therapeutic targeting of triggering receptor expressed on myeloid cells 2-apolipoprotein E signaling pathway.
    Keywords:  Alzheimer's disease; Type 2 diabetes; glucose; lipids; microglia; transcriptomics
    DOI:  https://doi.org/10.1002/alz.71471
  13. Exp Gerontol. 2026 May 16. pii: S0531-5565(26)00156-7. [Epub ahead of print] 113177
    Microglial senescence and epigenetic reprogramming in alzheimer's disease: An immunometabolic perspective.
    Jinye Ma, Baiqi Yang, Xuefan Jiang, Luping Wang, Wei Wei, Yu Cao, Hao Li.
      Microglial senescence has emerged as a potentially important aging-related mechanism in Alzheimer's disease (AD), shaped in part by epigenetic reprogramming and closely coupled to immunometabolic dysfunction. While microglia initially mount adaptive responses to amyloid-beta (Aβ), tau, and tissue stress, persistent exposure to chronic neurodegenerative cues may drive subsets of microglia toward senescence-like states characterized by altered chromatin regulation, transcriptional remodeling, stable cell-cycle arrest, and a sustained senescence-associated secretory phenotype (SASP). These changes are accompanied by impaired phagocytosis, lysosomal and autophagic dysfunction, mitochondrial stress, and disrupted lipid handling, collectively weakening homeostatic surveillance and promoting a neurotoxic microenvironment. In turn, senescence-associated microglial dysfunction may contribute to amyloid and tau pathology, synaptic injury, neurovascular unit impairment, and chronic neuroinflammation across the AD continuum. In this review, we synthesize current evidence on the phenotypic and molecular features of senescent microglia, with particular emphasis on epigenetic and transcriptional reprogramming as an organizing framework linking aging, immune dysregulation, and metabolic vulnerability. We further discuss how senescent microglia relate to other disease-associated microglial states, and we highlight unresolved questions regarding causality, biomarker specificity, and the distinction between chronic activation and true senescence in human AD. Finally, we evaluate emerging therapeutic approaches-including senolytic strategies, microglial depletion-repopulation paradigms, and metabolic or epigenetic interventions-and discuss their opportunities, limitations, and translational challenges. Together, this perspective positions microglial senescence not as an isolated driver, but as a biologically relevant and potentially targetable component of the aging neuroimmune landscape in AD.
    Keywords:  Alzheimer's disease; Epigenetic reprogramming; Immunometabolism; Microglial senescence; Neuroinflammation; Senotherapeutics
    DOI:  https://doi.org/10.1016/j.exger.2026.113177
  14. Cell Death Dis. 2026 May 22.
    Targeting MEF2A suppresses microglial hyperactivation and synaptic phagocytosis to attenuate epilepsy pathogenesis.
    Jingheng Wu, Jiayuanyuan Fu, Shuai Wang, Yuzhang Wu, Xu Wang, Shangang Feng, Qi Shi, Yuhao Wang, Yetong Shi, Yehong Fang, Yu Lan, Qiaoli Wu, Chuan Du, Shaoya Yin, Lixia Xu, Hua Yan.
      Microglia's role in epilepsy through neuroimmune communication is poorly understood. Mechanisms by which neurons activate microglia and how microglia affect neuronal activity to drive seizure-related inflammation remain unclear. Here, we elucidated a crucial axis connecting pathological adenosine triphosphate (ATP) release induced by epileptiform neuronal activity to microglial MEF2A-dependent hyperactivation, which exacerbates epilepsy pathology. In epilepsy models, seizures cause excessive ATP release, activating microglial P2X7 receptors, causing CAMKII phosphorylation. This triggers HDAC5 translocation, freeing MEF2A for acetylation, and enhancing transcription. Acetylated MEF2A increases CD74 and NEK7 expressions, enhancing NLRP3 inflammasome activation and microglial hyperactivation, worsening neuronal hyperexcitability by increasing inhibitory synapses clearance. Targeting microglial MEF2A with parecoxib or AAV knockdown reduced seizure severity and cognitive deficits and maintained synaptic inhibition by reducing excessive microglial phagocytosis. This reveals an ATP-P2X7-Ca2⁺- MEF2A signaling axis connecting neuronal injury with pathogenic microglial activation, suggesting MEF2A as a therapeutic target for microglial-neuronal homeostasis restoration in epilepsy pathology.
    DOI:  https://doi.org/10.1038/s41419-026-08860-5
  15. JCI Insight. 2026 May 22. pii: e179789. [Epub ahead of print]11(10):
    CD11c+ CD8 T cells cause IFN-γ-dependent autoimmune neuroinflammation that is restrained by PD-1 signaling.
    Daniel Hwang, Gholamreza Azizi, Larissa Lumi Watanabe Ishikawa, Maryam Seyedsadr, Arin Cox, Soohwa Jang, Ezgi Kasimoglu, Abdolmohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric.
      In multiple sclerosis (MS) lesions, CD8 T cells outnumber CD4 T cells, suggesting that they contribute to MS pathology. However, little is known about the role of CD8 T cells in MS, partly due to the prevalent use of experimental autoimmune encephalomyelitis (EAE) models mediated by CD4 T cells, which have limited involvement of CD8 T cells. Importantly, MS and EAE differ in both their distribution of CNS lesions and neurologic deficits, indicating differences in CNS inflammation. MS lesions are more commonly found in the brain, whereas EAE lesions are more frequent in the spinal cord. Additionally, neurologic deficits in MS rarely parallel the ascending paralysis typical for CD4 T cell-mediated EAE (CD4-EAE). In contrast, CD8-EAE models suggest that CD8 T cells preferentially cause brain inflammation; however, little is known about how brain and spinal cord inflammation may differ, or how CD8 T cells contribute to these differences. We have established an adoptive CD8-EAE mouse model characterized by brain-centered inflammation, ataxia, and weight loss. CNS inflammation in the brain and spinal cord differed in immune cell numbers, cellular composition, and inflammatory signatures. CD8-EAE could be suppressed by blocking IFN-γ, and exacerbated by blocking PD-1, with concomitant changes in the numbers of CNS-infiltrating monocytes. Most CD8 T cells in the CNS were CD11c+, suggesting that they are the pathogenic subset. We describe a robust CD8-EAE model, identify differences between brain and spinal cord inflammation, and characterize mechanisms that control CD8 T cell-mediated neuroinflammation, thereby furthering understanding of EAE and MS.
    Keywords:  Autoimmunity; Mouse models; Multiple sclerosis; Neuroscience; T cells
    DOI:  https://doi.org/10.1172/jci.insight.179789
  16. Nat Commun. 2026 May 22.
    TRIM21 facilitates inflammasome assembly and contributes to autoinflammatory disease.
    Jessica Carriere, Chawon Yun, Sonal Khare, Sana Ismaeel, Elisabeth Jäger, Vinicius Dantas Martins, Kaiden A Sims, Lan H Chu, Huyen Nguyen, Lucia de Almeida, Janset Onyuru, Justin Ruiz, Hemisha Khatri, Savita Devi, Jae Jin Chae, Daniel L Kastner, Lori Broderick, Hal M Hoffman, Andrea Dorfleutner, Christian Stehlik.
      Inflammasomes are cytosolic multiprotein complexes facilitating the maturation and release of the inflammatory cytokines interleukin (IL)-1β and IL-18 and pyroptosis. ASC (apoptosis-associated-speck-like protein containing a CARD) is the central inflammasome adaptor. ASC polymerization is crucial for inflammasome assembly, and ASC particle release propagates inflammasome responses to bystander cells. However, control of inflammasome and ASC particle assembly to limit chronic inflammation and the emergence of autoinflammatory diseases is still incompletely understood. Here, we show that the E3 ubiquitin ligase TRIM (tripartite-motif-containing protein) 21, a common autoantigen in autoimmune diseases, is involved in inflammasome assembly. Specifically, TRIM21 binds to and ubiquitinates ASC to facilitate ASC/NLRP3 interactions, ASC polymerization and the release of ASC/TRIM21-containing particles during pyroptosis in human and mouse macrophages. Furthermore, we detect systemic ASC/TRIM21 particles and autoantibodies in human and mouse autoinflammatory disease. Thus, our findings highlight a previously unrecognized role of TRIM21 as an inflammasome component and driver of autoinflammation.
    DOI:  https://doi.org/10.1038/s41467-026-73350-3
  17. J Neuroimmunol. 2026 May 14. pii: S0165-5728(26)00114-1. [Epub ahead of print]418 578966
    Targeting microglia: A new strategy for the treatment of Alzheimer's disease.
    Manyv Zheng, Mingjuan Yang, Wenya Su, Luyao Tian, Wenyuan Gao.
      Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation, remains without curative therapies. Emerging evidence underscores microglia, the brain's resident immune cells, as pivotal players in AD pathogenesis, exerting dual roles in neuroprotection and neurotoxicity. This review synthesizes current knowledge on microglial dynamics, including their heterogeneous activation states (e.g., disease-associated microglia), metabolic reprogramming, aging-related dysfunction, and subset heterogeneity, which collectively influence Aβ clearance, tau propagation, and synaptic integrity. We highlight the interplay between microglial receptors-such as TREM2, APOE, and neurotransmitter receptors (e.g., cholinergic, glutamatergic, and cannabinoid receptors)-and AD pathology, emphasizing their roles in modulating neuroinflammation, phagocytosis, and neuronal excitotoxicity. Furthermore, we evaluate therapeutic strategies targeting microglia, including pharmacologic modulation of neuroinflammatory pathways, metabolic interventions, and cell transplantation, which aim to restore homeostatic microglial functions. Challenges in clinical translation, such as temporal specificity of interventions and microglial plasticity, are critically discussed. By integrating recent advances in single-cell genomics and neuroimmunology, this review provides a roadmap for developing microglia-centric therapies to disrupt the vicious cycle of neuroinflammation and neurodegeneration in AD, offering novel insights for future research and therapeutic innovation.
    Keywords:  Alzheimer's disease; Microglia; Neurotransmitter receptor; Targeted; Treatment
    DOI:  https://doi.org/10.1016/j.jneuroim.2026.578966
  18. Exp Neurol. 2026 May 15. pii: S0014-4886(26)00202-5. [Epub ahead of print] 115838
    Primary and immortalized microglia exhibit divergent responses to hemoglobin.
    Kiara P Umpornpun, Braden B Oldham, Hemendra J Vekaria, Miriam Zamorano, Matias Merchant, George Johnson, Gavin Y Wang, Ramin Eskandari, Brandon A Miller.
      Microglia are the resident innate immune cells of the central nervous system and play critical roles in normal development and pathology. In hemorrhagic stroke, including neonatal intraventricular hemorrhage (IVH), microglia are thought to orchestrate the brain's immune response to blood breakdown products such as hemoglobin (Hgb) (Erdei et al., 2020). To better understand the pathology of neuroinflammatory diseases such as IVH, in vitro models, using primary microglia and immortalized microglia such as BV-2 cells, are widely used. However, fundamental differences between these cell types remain poorly characterized. Here, we compare inflammatory, cytotoxic, and metabolic responses of primary rat microglia and BV-2 cells in response to Hgb that is released after IVH. Metabolic profiling demonstrated higher basal metabolic activity and non-mitochondrial respiration indicative of reactive oxygen species production in primary microglia, with adaptive metabolic switching in response to Hgb exposure. In contrast, BV-2 cells exhibited high energy demand and limited metabolic shifts in response to Hgb. Primary microglia exhibited robust tumor necrosis factor alpha (TNF-α) release at low Hgb concentrations, consistent with our prior studies. In contrast, BV-2 cells required higher Hgb concentrations to elicit measurable TNF-α release. Cytotoxicity assessments revealed elevated baseline lactate dehydrogenase (LDH) release in BV-2 cells, whereas higher doses of Hgb were needed to elevate LDH levels in primary microglia. Together, these findings demonstrate critical immunometabolic distinctions between primary and immortalized microglial cells and establish that BV-2 cells do not reliably recapitulate primary microglial responses to blood breakdown products. Researchers using in vitro microglial preparations to study brain hemorrhage must carefully consider these differences when designing experiments, as reliance on BV-2 cells alone risks misrepresenting the neuroinflammatory response to IVH.
    Keywords:  Brain injury; Hydrocephalus; Intraventricular hemorrhage; Microglia
    DOI:  https://doi.org/10.1016/j.expneurol.2026.115838
  19. Nat Neurosci. 2026 May 18.
    Spatial proteomic analysis in human Alzheimer's disease brains enables identification of microenvironment-dependent microglial cell states.
    Paula Sanchez-Molina, Dennis-Dominik Rosmus, Dillon Brownell, Mert Meral, Cavanagh Gohlich, Aditya Pratapa, Yaser Peymanfar, Alyssa Whitley, Yue Hou, Nadezhda Nikulina, Alina Bogachuk, Ellen Lara Bouchard, Aude Chiot, Heidrun Kuhrt, Peter Wieghofer, Randall Woltjer, Fabian Svara, Oliver Braubach, Bahareh Ajami.
      Disease-associated microglial states are thought to contribute to Alzheimer's disease (AD) progression, but characterizing them and their relationships to pathology remains challenging. Here we introduce CODEX-CNS-a multiplexed protein imaging technology with a custom data analysis pipeline for use in human brain samples. We profiled 704,706 cells in samples from the frontal cortex of 8 people with AD and 8 healthy controls and mapped features including blood-brain barrier, meningeal components and cell-cell interactions within the same tissue sections. Amongst the myeloid cell populations we identified, we found a border-associated macrophage-like microglial subset associated with aging. Further classifying myeloid cell subsets based on their spatial neighborhood, we identified a border-associated macrophage-like microglial subpopulation that was associated significantly with dense amyloid-β plaques, which we termed human plaque-associated microglia. This work offers insights into myeloid cell heterogeneity in AD and provides a new spatial approach to characterizing brain cells at the single-cell protein level.
    DOI:  https://doi.org/10.1038/s41593-026-02267-3
  20. Nature. 2026 May 22.
    Stress impairs your brain's ability to link memories - dampening insight.
    Simon Spichak.
      
    Keywords:  Brain; Human behaviour; Neuroscience
    DOI:  https://doi.org/10.1038/d41586-026-01644-z
  21. J Biol Chem. 2026 May 18. pii: S0021-9258(26)02041-7. [Epub ahead of print] 113169
    Microglia maintain retinal redox homeostasis following ablation of rod photoreceptors in zebrafish.
    Michael Morales, Diana M Mitchell.
      Microglia rapidly respond to injury, stress, and perturbations to neurons in the brain and retina and perform phagocytosis to clear dying cells and debris. Oxidative stress is a feature of neurodegeneration, and while glia are crucial for managing such stress, microglia may also be dysfunctional in diseased tissue. Here we examine the role of microglia in management of oxidative stress and restoring redox homeostasis following death of rod photoreceptors in the larval zebrafish retina. Using rho:nfsb-eGFP transgenic zebrafish and treatment with the pro-drug metronidazole (MTZ), we coupled the generation of reactive oxygen species (ROS) in dying rods to their ablation. Microglia efficiently engulfed and cleared the ROS-laden rods, effectively undertaking the oxidative load. Despite abundant ROS upon MTZ-mediated cell death, oxidative stress overall was minimal in retinal tissue when microglia were present, indicating that they rapidly and efficiently performed redox functions. In irf8-/- mutants, which are deficient in microglia, retinas with MTZ-induced rod ablation showed widespread ROS that localized, at least in part, to Müller glia. Microglia deficient retinas showed evidence of increased oxidative stress, and increased numbers of "off-target" inner retinal neurons that stained positive for the cell death marker TUNEL. Supplementation with the antioxidant Glutathione modestly reduced the number of off-target TUNEL+ cells detected in microglia-deficient retinas following rod ablation. We also found that microglia may be important for mitigating effects of MTZ alone in the absence of Nfsb enzyme. Our results suggest that microglial redox functions are important in maintaining and restoring homeostasis following acute retinal damage.
    Keywords:  Microglia; Müller glia; cell death; oxidative stress; photoreceptors; redox balance; retina
    DOI:  https://doi.org/10.1016/j.jbc.2026.113169
  22. Brain. 2026 May 19. pii: awag179. [Epub ahead of print]
    Parkinson's disease beyond the brain: erythrocyte α-synuclein transfer across the blood-brain barrier.
    Ying Yang, Qi Liu, Tao Zhou, Jun Chen, Wenjing Li, Wentao Chen, Shaopeng Zeng, Huan Liu, Pan Wang, Peizheng Yang, Bin Xu, Shiping Liu, Xiao Xiong, Bingbing Cheng, Jing Zhang.
      Parkinson's disease is characterized by the accumulation and propagation of α-synuclein pathology in the central nervous system, yet the contribution of peripheral α-synuclein sources remains unclear. Here, we identify erythrocytes as an important reservoir of α-synuclein and demonstrate that bone marrow-derived erythrocytic α-synuclein likely contributes to brain pathology and Parkinson's disease-related neurodegeneration. Using human tissues and mouse models, we show that erythrocytes harbour abundant α-synuclein species. Bone marrow transplantation revealed widespread distribution of bone marrow-derived α-synuclein in peripheral organs, with detectable but substantially lower levels in the brain. Within the central nervous system, bone marrow-derived α-synuclein preferentially accumulated in resident microglia, as confirmed by immunophenotyping and single-nucleus RNA sequencing, and was associated with microglial activation. Furthermore, erythrocyte-derived extracellular vesicles carrying α-synuclein can be readily taken up by microglia in vivo. Functionally, elevated levels of bone marrow-derived α-synuclein in the mouse brain resulted in dopaminergic dysfunction with a mild neurodegenerative phenotype under baseline conditions. Importantly, blood-brain barrier integrity critically regulated peripheral α-synuclein entry into the central nervous system. Disruption of the blood-brain barrier by endotoxin administration, mannitol treatment or focused ultrasound markedly increased the entry of peripheral α-synuclein into the brain, aggravating neurodegeneration and behavioural deficits. Collectively, these findings identify bone marrow-derived erythrocytic α-synuclein as a systemic contributor to the pathogenesis of Parkinson's disease and highlight blood-brain barrier integrity as a key permissive regulator of peripheral-to-central α-synuclein transmission.
    Keywords:  Parkinson’s disease; blood–brain barrier; bone marrow; red blood cells; synucleinopathies; α-synuclein
    DOI:  https://doi.org/10.1093/brain/awag179
  23. Nat Neurosci. 2026 May 21.
    Foamy microglia link oxylipins to disease progression in multiple sclerosis.
    Netherlands Brain Bank
      Multiple sclerosis (MS) is a chronic neuroinflammatory disease in which demyelinating white matter lesions accumulate and expand, driving irreversible disability. Here we identify a distinct population of foamy GPNMB+ microglia/macrophages associated with lesion expansion in secondary progressive MS. Using integrated lipidomic, transcriptomic, proteomic, chemical proteomic and histological analyses of human postmortem MS lesions, we show that lesions containing foamy microglia/macrophages exhibit disrupted lipid metabolism, lysosomal stress and markers associated with heightened phagocytosis and antigen presentation without classical pro-inflammatory signatures. These lesions are enriched for oxylipins, bismonoacylglycerolphosphates and cholesterol esters, and are associated with increased B cell infiltration and IgG1. Monoacylglycerol lipase (MAGL), a lipid-metabolizing enzyme enriched in lesions with foamy microglia/macrophages, emerged as a potential therapeutic target. Inhibition of MAGL promoted lesion recovery and reduced microgliosis in a mouse model of demyelination. Finally, oxylipins in cerebrospinal fluid correlate with the proportion of foamy lesions, suggesting potential biomarkers for progression. Our findings implicate disturbed lipid metabolism in chronic MS pathology and suggest that foamy microglia/macrophages are an interesting cell type to target for progressive disease.
    DOI:  https://doi.org/10.1038/s41593-026-02302-3
  24. Neurochem Res. 2026 May 20. pii: 161. [Epub ahead of print]51(3):
    Maraviroc Attenuates Neuronal Apoptosis by Inhibiting CCR5-Mediated Microglial Activation After Subarachnoid Hemorrhage.
    Jiasen Ye, Hangyang Li, Zhenghong Peng, Zuoyue Duan, Qiang Chen, Yong Jiang, Tianqi Tu, Jianhua Peng.
      Subarachnoid hemorrhage (SAH) triggers robust neuroinflammatory responses that contribute to secondary brain injury, with microglia acting as central mediators; however, the upstream regulators governing microglial activation remain incompletely understood. To address this, we investigated the role of C-C chemokine receptor 5 (CCR5) using a murine endovascular perforation SAH model. Expression profiling revealed that CCR5 is rapidly upregulated after SAH, with prominent expression in microglia in the cortex and perilesional region. We then evaluated the therapeutic efficacy of pharmacological inhibition using the intranasal CCR5 antagonist maraviroc (MVC). MVC treatment successfully shifted microglia toward an anti-inflammatory phenotype and reduced pro-inflammatory cytokines. This inflammatory modulation attenuated brain edema, suppressed neuronal apoptosis, and significantly improved both early and long-term neurological outcomes. Furthermore, in vitro experiments confirmed that MVC reverses oxyhemoglobin-induced pro-inflammatory microglial polarization, indirectly protecting neurons from microglia-dependent injury. Collectively, these findings identify CCR5 as an important regulator of microglia-associated neuroinflammation after SAH and suggest that MVC exerts neuroprotection, at least in part, through modulation of the CCR5-related inflammatory microenvironment.
    Keywords:  CCR5; Maraviroc; Microglia; Neuroinflammation; Subarachnoid hemorrhage
    DOI:  https://doi.org/10.1007/s11064-026-04779-7
  25. Clin Exp Med. 2026 May 20.
    Single-cell atlas reveals the key role of pro-inflammatory IREB2⁺ microglia subsets in the microenvironment of Alzheimer's disease.
    Wenzheng Rong, Jing Xu, Bo Li, Yapeng Li, Yuming Xu.
      Chronic neuroinflammation driven by activated microglia is a critical hallmark of Alzheimer's disease (AD) progression. Metabolic dysregulation, particularly iron metabolism, has been implicated in neurodegeneration, yet the role of iron-responsive element-binding protein 2 (IREB2) in AD-associated neuroinflammation remains poorly understood. We performed integrative analysis of single-cell RNA sequencing (scRNA-seq) data from AD brain tissues, using non-negative matrix factorization (NMF) and intercellular communication algorithms to map cellular landscapes. We identified microglial subpopulations and their inflammatory signaling. To experimentally validate the functional role of IREB2 in inflammatory responses, we conducted siRNA-mediated knockdown in the human neuroblastoma cell line SH-SY5Y, which serves as a neuronal model for assessing IREB2's effect on cytokine expression. Single-cell analysis revealed a distinct microglial subpopulation (IREB2⁺ MC C1) that is significantly expanded in AD. This subpopulation exhibits a hyper-inflammatory state, with enrichment of Toll-like receptor and IL-17 signaling pathways, and functions as a primary source of outgoing inflammatory signals (CCL3, CCL4). Furthermore, IREB2 knockdown in SH-SY5Y cells significantly suppressed the expression of key pro-inflammatory cytokines (IL6, IL-1β, and TNF-α), confirming that IREB2 positively regulates inflammation in neurons as well. IREB2 drives both microglial activation and neuronal inflammatory responses in AD, potentially via the NF-κB pathway. The IREB2⁺ microglial subpopulation represents a specific pathogenic entity that orchestrates the inflammatory microenvironment. Targeting IREB2 may therefore offer a dual-pronged therapeutic strategy to mitigate neuroinflammation and slow AD progression.
    Keywords:  Alzheimer’s disease; IL-6; IREB2; Neuro-inflammation; TNF-a
    DOI:  https://doi.org/10.1007/s10238-026-02188-2
  26. Nature. 2026 May 20.
    Astrocyte glucocorticoid receptor signalling restricts neuronal plasticity.
    Bruno Gegenhuber, Takuma Sonoda, Lisa Traunmüller, Christopher P Davis, Shon A Koren, Eric C Griffith, Chinfei Chen, Michael E Greenberg.
      Sensory experience refines neural circuits during critical periods of postnatal development1-3. Although neuronal activity is known to orchestrate the circuit wiring that underlies this process4,5, the environmental cues that restrain developmental plasticity as animals mature are less clear. Here we examine the experience-dependent maturation of the mouse primary visual cortex across postnatal development using paired single-cell transcriptomic and chromatin accessibility sequencing. In addition to identifying the activity-dependent gene programs that emerge within each cortical cell type, we find that light exposure drives astrocyte maturation through cell-type-specific recruitment of the glucocorticoid receptor (encoded by Nr3c1) to chromatin. Astrocyte glucocorticoid receptor signalling activates an extensive gene regulatory program that is partially conserved in human brain development and promotes maturation processes that may regulate critical period closure. Collectively, these findings reveal that astrocyte glucocorticoid receptor signalling restricts neuronal plasticity. Glucocorticoid regulation of astrocyte maturation may also contribute to the effects of early-life stress across the brain, and the disruption of this process may increase susceptibility to neuropsychiatric disease.
    DOI:  https://doi.org/10.1038/s41586-026-10512-9
  27. Nat Immunol. 2026 May 18.
    Monocyte infiltration induces CNS arginine catabolism to fuel neuroinflammation.
    Martina Kerndl, Laszlo Musiejovsky, Andrea Komljenovic, Hon Shing Lam, Andrea Vogel, Tobias Bausbacher, Christian J Riedl, Roko Sango, Lenka Matejovicova, Anja Dobrijevic, Laura Oberbichler, Melanie Hofmann, Markus Kieler, Lucia Quemada Garrido, Lara Veronika Perko Budja, Julia Stefanie Brunner, James Lucas Cairns, Paul Cheng, Kerstin Kitt, Christine Isaguirre, Thomas Köcher, Kristaps Klavins, Thomas Rattei, Simon Hametner, Stephan Blüml, Carsten Hopf, Ryan D Sheldon, Omar Sharif, Gernot Schabbauer.
      Inflammatory responses are associated with recruitment of monocyte-derived cells (Mdcs) into tissues. Although tissue-specific Mdc reprogramming is well established, how Mdc infiltration alters tissue metabolism remains unclear. Here, using a mouse neuroinflammation model coupled with genetic fate mapping, metabolomics and metabolite imaging, we identify that central nervous system (CNS) Mdc infiltration is associated with substantial metabolic changes and assign disease-linked metabolites therein. In particular, we found that increased arginine catabolism driven by lesion-associated arginase 1 (Arg1)-expressing Mdcs promoted oxidative damage, lipid accumulation and Mdc dysfunction. Genetic ARG1 deficiency within Mdcs during neuroinflammation increased extracellular arginine and was associated with rewiring of the CNS metabolic landscape, including attenuated disease-linked metabolites. This was accompanied by enhanced Mdc-driven anti-inflammation, regulatory T cell expansion and improved disease outcome. Opposing effects were observed following dietary arginine deficiency. Together, our work highlights key roles for Mdcs in CNS metabolism and reveals the pleiotropic beneficial effects of arginine in neuroinflammation.
    DOI:  https://doi.org/10.1038/s41590-026-02516-4
  28. Neuron. 2026 May 20. pii: S0896-6273(26)00284-9. [Epub ahead of print]114(10): 1699-1701
    Before synapses are lost: Do endogenous retroviruses drive microglial overpruning in autism spectrum disorders?
    Jiangshan Zhan, Hyun Kyoung Lee.
      Endogenous retroviruses (ERVs) are epigenetically silenced genomic elements whose reactivation can influence host gene regulation. In this issue of Neuron, Chen et al. identify ERV-derived RNA-DNA hybrids that activate neuronal C4b, driving microglial synaptic overpruning and autism-like behaviors.
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.015
  29. Sci Transl Med. 2026 May 20. 18(850): eaeb1677
    Treating the immune system to repair the brain.
    Michal Schwartz, Tommaso Croese.
      Non-neuronal brain cells and systemic immunity play a central role in Alzheimer's disease (AD) and other brain disorders. The immune system, initially protective, becomes dysfunctional as the disease progresses. Here, we discuss next-generation therapeutic approaches aimed at treating the immune system rather than the brain to combat AD and other neurodegenerative diseases.
    DOI:  https://doi.org/10.1126/scitranslmed.aeb1677
  30. J Immunol. 2026 May 14. pii: vkag068. [Epub ahead of print]215(5):
    Highly focused human CD8+ T-cell response in the lower airways during acute influenza infection.
    Adam Saidu, Jeremy Chase Crawford, Sarah Walden, Jia-Hua Qu, Heather M Machkovech, Fangjie Han, Resha Sisti, E Kaitlynn Allen, Daniel Reynolds, Nicholas Borcherding, Jackson S Turner, Thomas C Friedrich, Derek E Byers, Ali H Ellebedy, Paul G Thomas, Philip A Mudd.
      Lung tissue-resident CD8+ T cells facilitate viral clearance and protective immunity to influenza viruses in animal models. Their role during acute human infection is not clear. Here we use bronchoalveolar lavage samples collected from human subjects naturally infected with influenza B virus to show that influenza-specific CD8+ T cells are expanded in the lower airways during acute infection and target only a few epitopes from phylogenetically conserved internal influenza virus proteins. The lower airway influenza-specific CD8+ T-cell immunodominance hierarchy is different from the hierarchy observed in matched blood samples. Transcriptional and protein-level analyses using HLA class I tetramers reveal a tissue-resident profile and less expression of cytotoxic effector molecules in lower airway influenza-specific CD8+ T cells. Collectively, our data show that high-frequency influenza-specific CD8+ T cells with a tissue-resident phenotype are found in the lower airways during viral clearance. These cells recognize a handful of conserved viral epitopes and exhibit a functional phenotype different from cells found in blood. These cells may play a role in controlling human influenza infection.
    Keywords:  T cells; T-cell receptors; human; lung; viral infections
    DOI:  https://doi.org/10.1093/jimmun/vkag068
  31. Sci Immunol. 2026 May 29. 11(119): eaef0098
    Mitochondrial complex I activity promotes antigen cross-presentation in dendritic cells.
    Sofía C Khouili, Elena Priego, Ignacio Heras-Murillo, Gillian Dunphy, Annalaura Mastrangelo, Sarai Martínez-Cano, Vanessa Nuñez, Manuel Rodrigo-Tapias, Adrián Belinchón-García, Johan Garaude, Salvador Iborra, Navdeep S Chandel, Patricia González-Rodríguez, Michel Enamorado, David Sancho.
      Mitochondrial metabolism modulates immune cell signaling, yet how individual electron transport chain complexes fine-tune dendritic cell (DC) function remains unclear. Here, we identify mitochondrial complex I (CI) as a critical metabolic checkpoint controlling antigen cross-presentation by DCs in mice. Deficiency of the CI subunit NDUFS4 in DCs led to the formation of a nonfunctional CI subcomplex, resulting in mildly impaired mitochondrial respiration without triggering a compensatory glycolytic shift. NDUFS4 deficiency limited endosomal escape of internalized antigens, thereby impairing antigen cross-presentation while largely preserving direct presentation. CI dysfunction lowered the NAD+/NADH ratio, concomitant with decreased ATP levels, and diminished neutral lipid storage and lipid peroxidation. Restoration of the NAD+/NADH ratio rescued cross-presentation in NDUFS4-deficient DCs. NDUFS2-deficient DCs showed similar defects in cross-presentation, which were also rescued by rebalancing the NAD+/NADH ratio. Together, these findings reveal a link between mitochondrial CI integrity, NAD+-driven redox metabolism, and antigen cross-presentation.
    DOI:  https://doi.org/10.1126/sciimmunol.aef0098
  32. Nat Commun. 2026 May 19.
    Lipid metabolism and contact site homologs are present at the chloroplast envelope-thylakoid interface.
    Evan W LaBrant, Cailin N Smith, Alondra D Torres-Gerena, Joslin Ishimwe, Fan Huang, Allan Tullis, Lauren Litterer, Bhoomi F Modi, Michael J Naldrett, Bara Altartouri, Rebecca L Roston.
      Biogenesis and maintenance of the photosynthetic thylakoid membrane requires transport of lipids from their site of synthesis in the chloroplast envelopes to their destination in the thylakoid. While vesicle trafficking is likely involved, we hypothesized a complementary mechanism involving direct membrane interactions. Using domain homology and proteomic profiling of chloroplast membrane fractions, we identified candidate lipid transport proteins present in a distinct, intermediate-density membrane population. This fraction contained an overrepresentation of lipid metabolic enzymes and proteins homologous to known membrane organization factors. Several candidates, including TVP38 FAMILY PROTEIN (TVPFP), PLASMA MEMBRANE FUSION PROTEIN (PMFP), and LETM1-LIKE, localized to discrete subdomains within chloroplasts. Loss-of-function tvpfp or pmfp mutants exhibited altered chloroplast ultrastructure, including changes in thylakoid-envelope proximity, supporting their roles in maintaining membrane architecture. These findings, which identify a chloroplast membrane subdomain enriched in proteins with specialized functions, offer a foundation for elucidating the molecular architecture of these regions.
    DOI:  https://doi.org/10.1038/s41467-026-73514-1
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