bims-micgli Biomed News
on Microglia
Issue of 2026–03–01
forty-two papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Single-Cell Nanodroplet Processing Proteomics Pipeline for Analysis of Human-Derived Microglia.
  2. Mutant ATXN1 impacts human and mouse microglia and contributes to cognitive, mood, and motor deficits in SCA1 mice.
  3. A ligand-mimetic anti-TREM2 agonist antibody elevates soluble TREM2 and ameliorates pathology in mouse models of Alzheimer's disease and multiple sclerosis.
  4. The Arp2/3 complex controls the development of homeostatic microglia.
  5. Tau, amyloid-β and α-synuclein co-pathologies synergistically enhance neuroinflammation and hippocampal neuron loss.
  6. Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
  7. ApoE-Dependent Lipid Handling by Median Eminence Microglia Preserves Myelin Integrity and Metabolic Function.
  8. Immunity in Alzheimer's disease: From mechanisms to therapies.
  9. Microglia modulate information processing in the mouse barrel cortex.
  10. Disruption of CSF-1 receptor-mediated metal ion homeostasis in the murine brain promotes neurodegenerative disease.
  11. Reprogramming brain-resident macrophages: from disease drivers to therapeutic allies in neurological disorders.
  12. Microglia-T cell interactions drive α-synuclein pathology in a Parkinson's disease mouse model.
  13. TRPV4 Deficiency Shifts Mitochondrial Dynamics Toward a Fragmented Morphology in Primary Microglia.
  14. Acetate enhances long-term memory in female mice by sex-, context-, and brain region-specific epigenetic and transcriptional remodeling.
  15. Isogenic cortical organoids enable precision targeting of APP variant-specific pathways in Alzheimer's disease.
  16. Neuronal Activity Promotes Node-Like Cluster Assembly Prior to Myelination and Remyelination in the Central Nervous System.
  17. Microbiome depletion rejuvenates the aging brain.
  18. Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures.
  19. Identification of distinct and shared biomarker panels in different manifestations of cerebral small-vessel disease through proteomic profiling.
  20. Ubiquitin ligase Nedd4 regulates the abundance and toxicity of mutant huntingtin.
  21. Digital medicine for infectious diseases.
  22. CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.
  23. Microglia heterogeneity and therapeutic strategies in Parkinson's disease.
  24. CASPR2 Autoimmune Antibodies Induce Neuronal Hyperactivity in Human Brain Organoids.
  25. Microglial serine racemase knockout alleviates Alzheimer-like neuropathology and behavioral deficit via lactylation-mediated anti-inflammation.
  26. High-fat diet and a high amyloid load interact to induce PKC-α dependent synaptic insulin resistance.
  27. Reciprocal regulation of fibroblast-macrophage equilibrium governs skin integrity.
  28. The protein carriers of hundreds of lipids have been identified.
  29. Activated Microglia-Derived Extracellular Vesicles Elicit a Pro-Inflammatory Astrocytic Response via Cargo-Dependent Mechanisms.
  30. The Arp2/3 complex is required for in situ haptotactic response of microglia to iC3b.
  31. HAPI Cells are SIM-A9-related Mouse Microglial Cells Useful for In Vitro Modeling of Microglial Immunometabolism.
  32. Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model.
  33. Parkinson's disease affects network of brain regions that controls whole-body action.
  34. Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
  35. Microglial Senescence in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives.
  36. mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
  37. β-Asarone Mediates the Alleviation of Neuroinflammation in Alzheimer's Disease Via Modulation of the TREM2/PI3K/AKT Signaling Pathway.
  38. Microglial Autofluorescence in the Brain and Retina is Dynamically Modulated by Systemic Inflammation.
  39. Neuroimmune Interactions in Neurodegeneration: The Role of Microglia in Alzheimer's and Parkinson's Disease Pathogenesis.
  40. Magnetic resonance microscopy maps widespread effects of Alzheimer's disease on brain structures and behavior in mice.
  41. More than microglial depletion: PLX5622 activates the hepatic constitutive androstane receptor to alter anesthesia and addiction.
  42. CNS-targeted NLRP3 Inhibition by NT-0527 confers therapeutic advantage in a CAPS mouse model.
  1. Proteomics. 2026 Feb 25. e70112
    Single-Cell Nanodroplet Processing Proteomics Pipeline for Analysis of Human-Derived Microglia.
    Ashley N Ives, James M Fulcher, Alex R Bautista, Reta Birhanu Kitata, Sarah M Williams, David A Bennett, Philip L De Jager, Vladislav A Petyuk.
      Single-cell omics tools provide unique insights into heterogeneous cell populations and their responses to stimuli. For example, single-cell RNA sequencing has identified several transcriptionally distinct populations of microglia, which are resident immune cells of the central nervous system (CNS) that are responsive to CNS injury, infection, and neurodegeneration. To date, single-cell studies of microglia have focused on RNA-sequencing or cytometry by time of flight (CyTOF), which provide indirect readouts of protein abundance or quantification of a limited number of targets. Herein, we present a workflow based on FACS-assisted isolation, cryopreservation, and nanodroplet-based processing for single-cell mass spectrometry proteomics analysis of the postmortem human brain cortex-derived microglia. From a single microglial cell, 1039 proteins could be identified on average. As a proof-of-principle, we applied single-cell proteomics for exploring the heterogeneity of brain microglia at the cellular level. This pilot proteomics data partially recapitulates the prior microglia subtypes. Specifically, we determined that mitochondrial proteins, in particular members of NADH dehydrogenase (Complex I), cytochrome b-c1 (Complex III), cytochrome c oxidase (Complex IV), F1-ATPase (Complex V), and Na+/K+-ATPase complex, drive variation across microglia. This pipeline offers the potential for identifying functionally and analytically relevant protein targets for microglia in Alzheimer's disease and other neurological disorders. SIGNIFICANCE OF THE STUDY: Microglia are a key brain cell type that may contribute to pathogenesis in neurodegenerative disease. Transcriptomic profiling of microglia from the central nervous system of humans and animal models has identified several subtypes of microglia, and complementary proteomic profiling of microglia is likely to provide functionally and therapeutically relevant targets. Single-cell proteomics studies of human-derived microglia are lacking. This work describes a label-free, single-cell proteomics approach for microglia isolated by fluorescence-activated cell sorting from a human donor that yields comparable numbers of identifications in comparison to prior single-cell RNA sequencing studies of microglia. This approach holds promise for enabling large-scale proteomics-based subtyping of microglia and studying their roles in neurodegenerative diseases.
    Keywords:  label‐free quantification; microglia; single‐cell proteomics
    DOI:  https://doi.org/10.1002/pmic.70112
  2. bioRxiv. 2026 Feb 17. pii: 2026.02.10.705104. [Epub ahead of print]
    Mutant ATXN1 impacts human and mouse microglia and contributes to cognitive, mood, and motor deficits in SCA1 mice.
    Adem Selimovic, Gourango Talukdar, Gavin Fuchs, Vamika Sharma, Khadija N Abbas, Sriyan C Reddy, Eshaan Parnerkar, Ian M Brooks, Ying Zhang, Michael Koob, Yasushi Nakagawa, Harry Orr, Marija Cvetanovic.
      Microglia, resident immune cells of the brain, are important players in neurodegeneration. While microglial activation is a hallmark of many neurodegenerative diseases, the specific role of microglia intrinsic factors in microglial activation and disease pathogenesis remains unknown. Spinocerebellar ataxia type-1 (SCA1) is an inherited autosomal dominant neurodegenerative disease characterized by severe neuronal loss and early microglial activation in the cerebellum. SCA1 is caused by CAG repeat expansion in the ubiquitously expressed ATAXIN1 (ATXN1) gene. Using human microglia differentiated from SCA1 patient derived iPSCs, we found that mutant ATXN1 is sufficient to alter morphology, gene and protein expression in human microglia in a cell-autonomous manner. Moreover, compared to controls, human SCA1 microglia exhibited increased phagocytosis and pro-inflammatory cytokine production, indicating an immune priming. To determine the extent to which mutant ATXN1 in microglia contributes to SCA1 pathogenesis and behavioral symptoms, we removed mutant ATXN1 from microglia and macrophages in a novel conditional SCA1 mouse model, f-ATXN1146Q/2Q mice. Microglial mutant ATXN1 reduction led to a marked correction in microglia phenotype, in particular in the transcriptomic signature of interferon type 1 mediated immune response, reduced microglial density and resulted in smaller microglia with reduced branching in the cerebellum. Pathology of Purkinje neurons and cerebellar astrogliosis were also ameliorated. Utilizing a battery of behavioral tests, we found that microglia and macrophage mutant ATXN1 reduction ameliorated cognitive, mood, and motor deficits in SCA1 mice. Together, these results indicate that mutant ATXN1 directly impacts microglial phenotype in SCA1, contributing to SCA1 pathology and behavioral deficits.
    DOI:  https://doi.org/10.64898/2026.02.10.705104
  3. J Neuroinflammation. 2026 Feb 23.
    A ligand-mimetic anti-TREM2 agonist antibody elevates soluble TREM2 and ameliorates pathology in mouse models of Alzheimer's disease and multiple sclerosis.
    Buxin Chen, Hsueh-Chung Lu, Lei Huang, Jean Wang, Matthew Bujold, Lingyun Tang, Xin Du, Yubin Wang.
       BACKGROUND: Triggering receptor expressed on myeloid cell-2 (TREM2) signaling promotes disease-associated microglia (DAM) and phagocytosis in neurodegenerative diseases. Traditional anti-TREM2 agonist antibodies block receptor shedding, lowering soluble TREM2 (sTREM2) and leading to mixed outcomes. We developed 03O05, a ligand-mimetic anti-TREM2 agonist antibody that activates TREM2 while preserving physiological shedding.
    METHODS: Binding epitope and cross-reactivity were defined by Bio-Layer Interferometry (BLI) and epitope mapping/mutagenesis. Functional activity was assessed using nuclear factor of activated T cells luciferase reporter (NFAT-luciferase), in vivo DAP12 phosphorylation, and microglial phagocytosis. In vivo effects on sTREM2 levels were evaluated in wild-type (WT), human TREM2 knock-in, and 5xFAD mice by ELISA. Amyloid-beta (Aβ) plaque clearance, microglial state and neuronal health were evaluated in 5xFAD model. Remyelination and microglial status were assessed in the cuprizone model.
    RESULTS: Anti-TREM2 antibody 03O05 binds a conformational epitope (M41-W44, L89) within the immunoglobulin-like domain, distal from the cleavage site, activates TREM2 signaling in vitro and in vivo, and enhances phagocytosis. A single dose treatment of 03O05 increased sTREM2 in serum and brain of WT and human TREM2 knock-in mice. In 5xFAD mice, chronic 03O05 treatment elevated serum and brain sTREM2, promoted clearance of filamentous Aβ plaques, reduced microgliosis while enhancing microglial phagocytosis, and ameliorated neuronal dystrophy. In the cuprizone model, 03O05 enhanced microglial phagocytosis and promoted remyelination by reducing degraded myelin basic protein (MBP) during recovery.
    CONCLUSIONS: Unlike stalk-binding anti-TREM2 agonist antibodies, 03O05 preserves ectodomain shedding, leading to transient receptor activation and increased sTREM2 levels. This approach promotes a neuroprotective microglial phenotype without inducing neuroinflammation, reduces amyloid pathology and neuronal dystrophy, as well as supports remyelination in multiple sclerosis (MS). These findings suggest the therapeutic potential of shedding-permissive TREM2 agonism in neurodegenerative disease.
    Keywords:  Alzheimer’s disease; DAP-12; Microglia; Multiple sclerosis; Phagocytosis; Soluble TREM2; TREM2
    DOI:  https://doi.org/10.1186/s12974-026-03733-2
  4. EMBO Rep. 2026 Feb 27.
    The Arp2/3 complex controls the development of homeostatic microglia.
    Shima Safaiyan, Maximilian Frosch, Tom Bickel, Gianni Monaco, Roie Dvir, Christian Madry, Lance Fredrick Pahutan Bosch, Katrin Kierdorf, Metello Innocenti, Josef Priller, Marco Prinz, Tim Lämmermann.
      Microglial dynamics and homeostasis are crucial for maintaining central nervous system (CNS) function. To fulfill their homeostatic functions, microglia develop into ramified cells with highly dynamic cell protrusions. However, the detailed mechanisms underlying this developmental transition are largely unknown. Here, we investigate the role of the Actin-related protein 2/3 (Arp2/3) complex, a critical actin nucleator that controls the formation of actin branches, for the biology of tissue-resident microglia. By conditionally targeting Arpc4 in mice, we show that Arp2/3 depletion in tissue-resident microglia causes phenotypes beyond previously reported functions in other immune cell types. Our results identify an important role of Arp2/3 for controlling the developmental transition of microglia into cells with ramified morphology, homeostatic gene profile, and surveillance function in the CNS. Together, our results link actin remodeling to microglial maturation and activation, highlighting the Arp2/3 complex as a critical factor for maintaining the plasticity and preventing pathological activation of endogenous microglia.
    Keywords:  Actin; Arp2/3 Complex; Microglia; Myelin Degeneration; TGFβ Signaling
    DOI:  https://doi.org/10.1038/s44319-026-00721-8
  5. Neurobiol Dis. 2026 Feb 24. pii: S0969-9961(26)00067-7. [Epub ahead of print] 107323
    Tau, amyloid-β and α-synuclein co-pathologies synergistically enhance neuroinflammation and hippocampal neuron loss.
    Jhodi M Webster, Ya-Ting Yang, Aidan T Miller, Asta Zane, Kasandra Scholz, William J Stone, Nikhita Mudium, Nicole J Corbin-Stein, Woong-Jai Won, Anna C Stoll, Kelsey M Greathouse, Noelle H Cooper, Lillian F Long, Phaedra N Manuel, Jeremy H Herskowitz, Talene A Yacoubian, Daniel J Tyrrell, Ivette M Sandoval, Fredric P Manfredsson, Jeffrey H Kordower, Ashley S Harms.
      Alzheimer's (AD) and Parkinson's disease (PD) pathology often co-occur. Amyloid-β and phosphorylated tau are found in 30-50% of idiopathic PD cases, while α-synuclein inclusions are present in over 50% of AD cases. These co-pathologies are linked to increased mortality and earlier onset of cognitive decline. Immune activation is a hallmark of these neurodegenerative diseases, but current model systems primarily examine each pathology in isolation. As such, how these co-pathologies drive inflammation and neuronal loss remains poorly understood. To address this gap, we developed a mouse model combining tau, amyloid-β, and α-synuclein as co-pathologies. We found that co-pathologies synergistically trigger a distinct and amplified neuroimmune response, marked by robust expansion of CD4+ and CD8+ tissue-resident memory T cells and CD68+ microglia, a population of activated, phagocytosing microglia, compared to single pathologies. These changes were abundant in the hippocampus and cortex, regions that showed elevated protein pathology load at 3- and 6-months post-induction and enhanced neuronal loss at 6-months post induction. Our findings demonstrate that co-pathologies promote accumulation of proteinopathy and synergistically enhance immune activation in the hippocampus and cortex and hippocampal neuronal loss. With this model as a novel tool to assess mixed-pathology mechanisms, our results support the need for combinatorial therapeutic strategies, that target both co-pathologies and inflammation, and identifies neuroinflammation as a prominent feature associated with co-pathology enhanced neurodegeneration.
    Keywords:  Amyloid beta; Co-pathologies; Microglia; Neuroinflammation; T cells; Tau; Α-Synuclein
    DOI:  https://doi.org/10.1016/j.nbd.2026.107323
  6. bioRxiv. 2026 Feb 20. pii: 2026.02.19.706884. [Epub ahead of print]
    Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
    Yongqing Liu, Minghua Fan, Yingzhi Ye, Henry Yi Cheng, Shuying Sun, Zhaozhu Qiu.
      Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of Cmpk2 , a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cGAS-STING and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease amyloid-β burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a promising therapeutic target for AD.
    DOI:  https://doi.org/10.64898/2026.02.19.706884
  7. bioRxiv. 2026 Feb 19. pii: 2026.02.18.706643. [Epub ahead of print]
    ApoE-Dependent Lipid Handling by Median Eminence Microglia Preserves Myelin Integrity and Metabolic Function.
    E R McGrath, A Folick, L J Morrissette, S M Brown Mayfield, V Pham, S N Pillutla, M K Choi, R T Cheang, W R Bolus, A Schwendeman, V Ntranos, S K Koliwad, M Valdearcos.
      Microglia regulate hypothalamic control of systemic metabolism, but the mechanisms underlying their contribution remain unclear. Here, we identify a distinct apolipoprotein E ( ApoE )⁺ microglial population enriched in the median eminence (ME), a brain region involved in sensing peripheral cues and metabolic regulation. These microglia engage multiple functional programs related to lipid handling, interferon signaling, and stress responses that are differentially regulated within the ME. Consumption of a Western diet (WD) increased interferon signaling and lipid accumulation in ME microglia. Expression of the human APOE4 isoform in mice exacerbated microglial lipid dysregulation, interferon signaling, and impaired ME myelin organization. Deleting APOE in microglia attenuated their ability to couple lipid accumulation to interferon signaling, identifying microglial APOE as a cell-intrinsic determinant of interferon responses. Finally, selective activation of liver X receptor signaling using synthetic HDL nanoparticles restored microglial lipid homeostasis, improved hypothalamic leptin responsiveness, and limited weight gain in WD-fed mice. Together, these findings define an Apoe -dependent regulatory program in ME microglia that is therapeutically targetable and clarify how nutritional stress disrupts hypothalamic control of metabolic homeostasis.
    DOI:  https://doi.org/10.64898/2026.02.18.706643
  8. Immunity. 2026 Feb 26. pii: S1074-7613(26)00074-9. [Epub ahead of print]
    Immunity in Alzheimer's disease: From mechanisms to therapies.
    Xiaoying Chen, David M Holtzman, Marco Colonna.
      Alzheimer's disease (AD) is a progressive neurodegenerative disorder that leads to cognitive decline, dementia, and ultimately death. Recent anatomical and functional discoveries of neuroimmune interactions during the development and progression of AD are beginning to shed light on disease mechanisms and potential precision immunotherapies. Here, we review the current understanding of the contribution of innate and adaptive immunity to AD pathogenesis and progression. We discuss how microglia and T cells shape stage-specific immune responses in AD, how genetic risk converges on microglial activation and antigen presentation pathways, and the protective and pathogenic roles of microglia and T cells during distinct stages of AD progression. In the context of this deeper understanding of immune cells in AD, we discuss emerging therapeutic approaches in the clinic and argue for the importance of interventions that precisely modulate neuroimmune dynamics at different stages of AD.
    Keywords:  Alzheimer’s disease; T cell; human; microglia; mouse; neuroimmunology; tau; β-amyloid
    DOI:  https://doi.org/10.1016/j.immuni.2026.02.004
  9. J Neurosci. 2026 Feb 24. pii: e0941252026. [Epub ahead of print]
    Microglia modulate information processing in the mouse barrel cortex.
    Bálint Király, Eszter Császár, Diána Balázsfi, Claire-Hélène de Badts, Katalin Sviatkó, Balázs Pósfai, Andor Domonkos, Balázs Hangya, Ádám Dénes.
      Microglia, the main immune cells of the central nervous system, are crucial for maintaining brain homeostasis by modulating immune processes and neurovascular function. However, the mechanisms by which microglia regulate neuronal networks and local microcircuits remain incompletely understood. Here, we identify microglia as important modulators of neuronal network activity at the single-cell level and brain-wide functional connectivity in male mice. We show that in the absence of microglia or microglial P2Y12 receptor (P2Y12R), the baseline firing rate of putative interneurons was increased, while whisker-stimulation-induced sensory responses remained unchanged in microglia-depleted and P2Y12R KO animals. Increase in cortical delta oscillations in both models and increased single neuron phase coupling to delta-band rhythms in microglia-depleted mice revealed cortical hypersynchrony. Microglia depletion led to a significant reduction in connectivity between the contralateral barrel cortex and the anatomically connected ventral posteromedial nucleus of the thalamus (VPMb) during somatosensory stimulation, while resting-state functional connectivity remained unchanged. Similarly, genetic blockade of P2Y12R resulted in diminished functional connectivity within this thalamocortical network. Our findings suggest that cortical interneuron hyperexcitability due to dysfunction of microglia could be a key cause for local hypersynchrony relevant to sensory processing.Significance statement Microglia have been shown to modulate neuronal activity, but the underlying mechanisms are insufficiently defined. In particular, it is not well understood how microglia could shape excitatory / inhibitory balance in the cerebral cortex and whether such modulatory processes could alter sensory processing. Here, we studied single cell-level effects in the barrel cortex by using two established models of microglia dysfunction. We show that the absence of microglia or the purinergic microglial receptor, P2Y12R, have both large-scale effects on thalamocortical networks and cortical slow oscillations, while specifically shape the firing rate of interneurons in cortical microcircuits. Such neuroglial interactions could have broad impact on sensory processing in health and under different disease states.
    DOI:  https://doi.org/10.1523/JNEUROSCI.0941-25.2026
  10. J Clin Invest. 2026 Feb 26. pii: e200121. [Epub ahead of print]
    Disruption of CSF-1 receptor-mediated metal ion homeostasis in the murine brain promotes neurodegenerative disease.
    Violeta Chitu, Julia Alvarenga, Wenna Chen, David Reynolds, Yang Liu, Daqian Sun, Anders Sandell, Virginjia Danylaite Karrenbauer, Per Uvdal, Iran An da Silva, Christophe Sandt, Oxana Klementieva, Ulf Johansson, Kavitha Subramanian Vignesh, Zbigniew K Wszolek, Dennis W Dickson, Jennifer Aguilan, Simone Sidoli, Deyou Zheng, E Richard Stanley.
      Dominant-inactivating mutations in the colony stimulating factor-1 receptor (CSF1R) cause CSF-1R related leukoencephalopathy (CRL), an adult-onset neurodegenerative disease that is modeled in the Csf1r+/- mouse. CRL is caused by microglial dysfunction. However, the primary microglial deficit, is unknown. To address this question, we employed single-nucleus RNA sequencing of brains from young Csf1r+/- mice without pathological or behavioral alterations. Reduction of CSF-1R signaling caused metal ion accumulation in brain macrophages, with concomitant activation of cell death and stress response pathways in oligodendrocytes and neuronal subpopulations. Reduction of metallothionein 1 (Mt1) and 3 (Mt3) gene expression was a common feature in glial and neuronal cells of Csf1r+/- mice. Overexpression of Mt1 restored metal ion homeostasis, normalized ROS production in microglia, and prevented the development of behavioral deficits, while Mt3 deletion had disease-enhancing effects. These findings demonstrate CSF-1R regulation of metal ion homeostasis via metallothioneins in the brain.
    Keywords:  Cell biology; Demyelinating disorders; Neuroscience
    DOI:  https://doi.org/10.1172/JCI200121
  11. Front Cell Neurosci. 2026 ;20 1726194
    Reprogramming brain-resident macrophages: from disease drivers to therapeutic allies in neurological disorders.
    Peng Zhao, Su-Yi Li, Qun Liu, Xiao-Chun Peng, Lian Liu, Fu-Yuan Yang, Chao Wang, Feng Qian, Feng-Ru Tang.
      Brain-resident macrophages (BRMs), including microglia and border-associated macrophages (BAMs), are the core immune sentinels of the central nervous system (CNS). They originate from early embryonic yolk sac and fetal liver progenitors and maintain their population throughout life via self-renewal. During neurodevelopment, microglia maintain neural network homeostasis by phagocytosing apoptotic neural precursors and pruning synaptic connections. In adulthood, they rapidly respond to infection, injury, or protein aggregation, which can both promote repair and exacerbate neurotoxicity. BAMs, located in the meninges, perivascular spaces, and choroid plexus, play a key role in boundary homeostasis and peripheral immune signal surveillance. Recent studies reveal that BRMs exhibit dual roles in Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), multiple sclerosis (MS), as well as ischemic stroke, traumatic brain injury, and radiation-induced brain injury: they can protect neurons by clearing pathological proteins or cellular debris, but persistent inflammatory responses may drive neurodegeneration. In AD, microglia clear Aβ plaques via triggering receptor expressed on myeloid cells 2 (TREM2) and ADGRG1 signaling, while BAMs regulate synaptic damage and cerebrovascular function through CD36-ROS and SPP1 pathways. In PD and HD, BRMs contribute to α-synuclein- and mutant huntingtin-related inflammatory responses. In MS, BRMs modulate the pro-/anti-inflammatory balance through antigen presentation and cytokine signaling. Based on these mechanisms, therapeutic strategies targeting BRM functions are emerging, including NLRP3 inflammasome inhibitors, TREM2 agonists, and interventions promoting microglial neuroprotective phenotypes. Future approaches aiming to precisely modulate BRM plasticity and their interactions with the peripheral immune system may transform these immune sentinels from "disease drivers" to "therapeutic allies," offering novel strategies for treating neurodegenerative diseases and brain injuries.
    Keywords:  border-associated macrophage; brain injury; brain-resident macrophage; microglia; neurodegenerative disease
    DOI:  https://doi.org/10.3389/fncel.2026.1726194
  12. J Neuroinflammation. 2026 Feb 27.
    Microglia-T cell interactions drive α-synuclein pathology in a Parkinson's disease mouse model.
    Yosuke Ohtake, Nana Norikami, Bin Hong, Kyoka Manabe, Takahide Itokazu, Toshihide Yamashita.
      
    Keywords:  AAV; Alpha-synuclein; Microglia; Neurodegeneration; Parkinson’s disease; Pre-formed fibril; T cell
    DOI:  https://doi.org/10.1186/s12974-026-03734-1
  13. Cells. 2026 Feb 13. pii: 341. [Epub ahead of print]15(4):
    TRPV4 Deficiency Shifts Mitochondrial Dynamics Toward a Fragmented Morphology in Primary Microglia.
    Elena-Andreea Burlacu, Robin Schellingen, Amanda Moya-Gómez, Sanne G S Verberk, Nathan Stas, Sofie Kessels, Yeranddy A Alpizar, Jean-Michel Rigo, Annelies Bronckaers, Jerome J A Hendriks, Christel Faes, Bert Brône.
      Microglia perform surveillance and phagocytosis to maintain the homeostasis of the central nervous system (CNS). These processes are energetically demanding, and given the critical roles of mitochondria in providing ATP, the characteristics of the mitochondrial network can modulate microglial behavior. Although the Ca2+-permeable Transient Receptor Potential Vanilloid 4 (TRPV4) is known for regulating microglial morphology and migration, and it is implicated in mitochondrial calcium uptake, it is unknown whether TRPV4 affects the mitochondrial network in microglia. Our study provides evidence that TRPV4 plays a role in the integrity and complexity of the mitochondrial network in microglia. Quantification of the Mitochondrial Fragmentation and Complexity Index (MFCI) and increased pDrp1 (Ser616) showed a shift towards mitochondrial network fragmentation, and lowered complexity in Trpv4 knockout versus wild-type primary murine microglia in vitro. The distribution of mitochondria within microglia showed significant differences in density at 10-32 µm away from the nucleus. Furthermore, acute pharmacological TRPV4 inhibition with GSK2193874 did not induce significant mitochondria network fragmentation. Our findings establish TRPV4 as a regulator of mitochondrial dynamics and adaptive responses, highlighting its importance for maintaining homeostasis in microglia and the entire CNS.
    Keywords:  TRPV4; microglia; mitochondria
    DOI:  https://doi.org/10.3390/cells15040341
  14. Sci Signal. 2026 Feb 24. 19(926): eaec0496
    Acetate enhances long-term memory in female mice by sex-, context-, and brain region-specific epigenetic and transcriptional remodeling.
    Erica M Periandri, Kala M Dodson, Francisca N de Luna Vitorino, Benjamin A Garcia, Karl M Glastad, Gabor Egervari.
      Metabolic control of chromatin and gene expression is emerging as a key mechanism influencing critical neuronal functions. Here, we found that the intermediary metabolite acetate enhanced long-term memory in female mice, which was associated with epigenetic and transcriptional remodeling in the dorsal hippocampus. Acetate-enhanced memory was driven by increased acetylation of the histone variant H2A.Z and increased expression of genes implicated in learning in the female dorsal hippocampus. The effect of acetate on dorsal hippocampal histone modifications and gene expression differed markedly between the sexes during critical windows of memory consolidation and recall, and home cage exposure to acetate without the learning and recall tasks did not recapitulate these effects. These findings elucidate the ways in which acetate exposure enhances memory.
    DOI:  https://doi.org/10.1126/scisignal.aec0496
  15. bioRxiv. 2026 Feb 19. pii: 2026.02.19.706886. [Epub ahead of print]
    Isogenic cortical organoids enable precision targeting of APP variant-specific pathways in Alzheimer's disease.
    T Grass, I M Cosacak, A Ordureau, F D Price, S Kavali, A Caldarelli, M N Qiao, B Vardarajan, Joao A Paulo, Michele Marass, L L Rubin, C Kizil, N Rodriguez-Muela.
      Alzheimer's disease (AD) lacks disease-modifying therapies, in part due to the limitations of existing disease models, which have struggled to capture the early pathogenic events leading to neuronal degeneration. Unfortunately, recent therapies targeting hallmarks of AD have proven inefficient in humans, and it is thus necessary to identify alternative targets. Here, by generating an isogenic panel of hiPSC-derived cortical organoids carrying familial AD-associated APP variants or the protective A673T variant, we identified distinct, actionable pathogenic pathways specific to each variant. Proteomic analyses revealed variant-specific molecular disruptions: A673V organoids show impairments in proteostasis and cholesterol metabolism, whereas KM670/671NL organoids exhibit mitochondrial bioenergetic defects. These signatures overlapped with dysregulated proteins in post-mortem AD brains, demonstrating the reliability of our in vitro model. Importantly, targeted interventions restored neuronal survival in a variant-specific manner: overexpression of the master regulator of lysosomal biogenesis, TFEB, rescued A673V neurons, while ferroptosis inhibition selectively protected KM670/671NL neurons. Overall, our results indicate that differential treatments can be tailored based on distinct genetic backgrounds, supporting the development of precision medicine approaches in AD.
    DOI:  https://doi.org/10.64898/2026.02.19.706886
  16. Glia. 2026 Apr;74(4): e70138
    Neuronal Activity Promotes Node-Like Cluster Assembly Prior to Myelination and Remyelination in the Central Nervous System.
    Rémi Ronzano, Clément Perrot, Elisa Mazuir, Melina Thetiot, Marie-Stéphane Aigrot, Paul Stheneur, François-Xavier Lejeune, Bruno Stankoff, Catherine Lubetzki, Nathalie Sol-Foulon, Anne Desmazières.
      In recent years, myelination has been recognized as a key process in neural plasticity and network refinement, in addition to its role in axonal conduction and neuronal metabolic support. The fast saltatory conduction along myelinated fibers relies on the nodes of Ranvier. Node-like clusters can form prior to myelin deposition in development and repair and can regulate axonal conduction, myelin deposition initiation, as well as contribute to the formation of mature nodes of Ranvier. In this study, we show that node-like cluster assembly is modulated by neuronal activity and could thus be an intermediate step in activity-induced (re)myelination. We further identify the regulation of Nav1.1 expression, which we show to be required for node-like cluster formation, as part of the molecular mechanism implicated in the activity-dependent regulation of node-like cluster assembly. This process may serve in shaping neuronal networks and myelin patterns during development, plasticity and repair.
    DOI:  https://doi.org/10.1002/glia.70138
  17. bioRxiv. 2026 Feb 15. pii: 2026.02.13.705770. [Epub ahead of print]
    Microbiome depletion rejuvenates the aging brain.
    C Gasperini, K M Holton, F Limone, M Juttu, C C DeMeo, K Kekrtova, S Patankar, K M Wells, R M Giadone, L Ben Driss, G Wei, A Kiem, Q Xu, R T Lee, M Friedlander, D T Scadden, L L Rubin.
      Aging is associated with cognitive decline and increased vulnerability to neurodegeneration driven by an array of molecular and cellular changes like impaired vascular integrity, demyelination, reduced neurogenesis, and chronic inflammation. Recent studies implicate the gut microbiome as a modulator of brain aging, but the underlying mechanisms remain elusive. Here, we show that depleting the gut microbiome by administering antibiotics to aged mice induces widespread molecular and structural rejuvenation in the brain. Our transcriptomic analyses by single-nucleus RNA sequencing revealed pronounced transcriptional shifts across multiple brain cell types. We confirmed that antibiotic treatment improves vascular density, promotes myelination, enhances neurogenesis, and reduces microglial reactivity. Functionally, microbiome-depleted mice showed improved hippocampal memory performance. Analyses of brain and plasma cytokine levels showed a decrease in several pro-inflammatory factors post-treatment and identified candidate factors, including the chemokine eotaxin-1. Inhibiting eotaxin-1 alone can reverse several aspects of brain aging. Our findings demonstrate that age-associated microbial inflammation contributes to brain aging and that its attenuation can restore youthful features at the molecular, cellular, and functional levels. Targeting the gut microbiome or its circulating mediators may therefore represent a non-invasive approach to promote brain health and cognitive resilience in aging.
    DOI:  https://doi.org/10.64898/2026.02.13.705770
  18. Acta Neuropathol. 2026 Feb 24. pii: 20. [Epub ahead of print]151(1):
    Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures.
    Valentin T Laroche, Rachel Cavill, Morteza Kouhsar, Joshua Müller, Rick A Reijnders, Joshua Harvey, Adam R Smith, Jennifer Imm, Jarno Koetsier, Luke Weymouth, Lachlan MacBean, Giulia Pegoraro, Lars Eijssen, Byron Creese, Gunter Kenis, Betty M Tijms, Daniel van den Hove, Katie Lunnon, Ehsan Pishva.
      Growing evidence suggests that clinical, pathological, and genetic heterogeneity in late-onset Alzheimer's disease (LOAD) contributes to variable therapeutic outcomes, potentially explaining many trial failures. Advances in molecular subtyping through proteomic and transcriptomic profiling reveal distinct patient subgroups, highlighting disease complexity beyond amyloid-beta plaques and tau tangles. This underscores the need to expand subtyping across new molecular layers, to identify novel drug targets for different patient subgroups. In this study, we analyzed genome-wide DNA methylation (DNAm) data from three independent postmortem brain cohorts (N = 826) to identify epigenetic subtypes of LOAD. We used unsupervised clustering to define subtype-specific DNAm patterns and validated them across cohorts. We then mapped subtype signatures to brain cell types using purified-cell DNAm profiles and integrated bulk and single-nucleus RNA-seq to assess each subtype's impact on gene expression. Finally, we examined clinical and neuropathological correlates to evaluate biological and clinical significance. We identified two distinct epigenomic subtypes of LOAD, consistently observed across three cohorts. Both subtypes exhibit significant yet distinct microglial methylation enrichment. Bulk transcriptomic analyses highlighted distinct biological mechanisms underlying these subtypes: subtype 1 was enriched for immune-related processes, while subtype 2 was characterized by neuronal and synaptic pathways. Single-nucleus transcriptional profiling of microglia indicated that both subtypes share AD-associated innate-immune remodeling, with subtype differences emerging primarily as state-dependent transcriptional shifts rather than large changes in state abundance. Overall, subtype 1 showed a relative weighting toward more inflammatory microglial programs, whereas subtype 2 showed stronger transcriptional remodeling in specific microglial states alongside relatively greater engagement of regulatory and clearance-associated features. These findings reveal distinct epigenetic and functional microglial states underlying LOAD subtypes, advancing our understanding of disease heterogeneity. This work lays the groundwork for targeted therapeutic strategies tailored to specific molecular and cellular disease profiles.
    Keywords:  Alzheimer’s disease; DNA methylation; Epigenetics; Microglia; Subtyping
    DOI:  https://doi.org/10.1007/s00401-026-02990-y
  19. Nat Aging. 2026 Feb 24.
    Identification of distinct and shared biomarker panels in different manifestations of cerebral small-vessel disease through proteomic profiling.
    Ines Hristovska, Alexa Pichet Binette, Atul Kumar, Malin Wennström, Chris Gaiteri, Linda Karlsson, Olof Strandberg, Shorena Janelidze, Danielle van Westen, Erik Stomrud, Sebastian Palmqvist, Rik Ossenkoppele, Niklas Mattsson-Carlgren, Jacob W Vogel, Oskar Hansson.
      The pathophysiology underlying various manifestations of cerebral small-vessel disease (cSVD) remains poorly understood. Using high-throughput proteomics, we identified common and distinct proteomic signatures of white matter lesions (WMLs), microbleeds, infarcts and their subtypes, measured in 1,670 living patients. Across all cSVD manifestations, markers of extracellular matrix dysregulation and vascular remodeling were increased, including ELN, POSTN, CCN2 and especially MMP12, implicating endothelial and smooth muscle cells of the brain. These proteins were validated in cerebrospinal fluid from two additional datasets, and a subset detected in plasma predicted future cerebrovascular events in the UK Biobank better than risk scores currently used in clinical practice. Analysis focusing on WMLs found microglial-associated proteins associated with faster WML progression, whereas specific neuron-derived proteins mediated the link between WMLs and longitudinal cognitive decline. These data provide a comprehensive atlas of cSVD biomarkers, and our findings provide a promising roadmap for future diagnostics and therapeutics.
    DOI:  https://doi.org/10.1038/s43587-026-01081-7
  20. JCI Insight. 2026 Feb 23. pii: e181013. [Epub ahead of print]11(4):
    Ubiquitin ligase Nedd4 regulates the abundance and toxicity of mutant huntingtin.
    Hyunkyung Jeong, Yiyang Qin, Fangke Xu, Katarina Trajkovic, Myung Jong Kim, Nicolas Marotta, Kana Hamada, Ravi Allada, Su Yang, Dimitri Krainc.
      Huntington's disease (HD) is a neurodegenerative disorder caused by the expansion of CAG repeats in the gene encoding huntingtin. Since accumulation of mutant huntingtin (mHtt) leads to dysfunction of numerous cellular pathways and toxicity, reducing levels of the mutant protein represents a key therapeutic objective in HD. We found that ubiquitination of mHtt by E3 ubiquitin ligase Nedd4 promotes clearance of the mutant protein. Knockdown of Nedd4 increased toxicity of mHtt in mouse primary neurons and in a fly model of HD, suggesting the protective role of Nedd4. Importantly, levels of Nedd4 were decreased in mHtt-expressing neurons through impaired mTORC1 activity, suggesting a feedback loop of mHtt accumulation and Nedd4 reduction that leads to accumulation and, ultimately, toxicity of mHtt. These findings suggest that restoring Nedd4 activity may offer a novel therapeutic opportunity for HD.
    Keywords:  Cell biology; Neurodegeneration; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.181013
  21. Nat Commun. 2026 Feb 23. pii: 1943. [Epub ahead of print]17(1):
    Digital medicine for infectious diseases.
      
    DOI:  https://doi.org/10.1038/s41467-026-69871-6
  22. Mol Brain. 2026 Feb 25.
    CD4+T cell metabolic reprogramming as therapeutic targets in neurodegenerative diseases.
    Prince Amoah Barnie, Karen Pomeyie, Benjamin Amoani, Foster Kyei, Abdala Ussif Mumuni, Justice Afrifa, Samuel Essien-Baidoo, Daniel Boison.
      Neurodegenerative diseases are a group of disorders characterized by the progressive loss of structure and function of neurons in the brain and/or peripheral nervous system. The main pathological feature of neurodegenerative disease in the central nervous system (CNS) is the selective neuronal loss in the brain and spinal cord, leading to cognitive and/or motor dysfunction. The immune system plays a variety of roles in the pathophysiology of neurodegenerative diseases. CD4+T cells are being recognized as important immunometabolic modulators in the pathophysiology of neurodegenerative disorders (ND), including multiple sclerosis (MS), Parkinson's disease (PD), and Alzheimer's disease (AD). Their varied metabolic patterns provide a special therapeutic window for regulating neuroinflammation, spanning from lipid-dependent regulatory T cells (Tregs) to glycolysis-driven pro-inflammatory subsets (Th1, Th17). Abnormal immune metabolism raises the risk of oxidative stress, mitochondrial malfunction, and neuronal death in neurodegenerative environments. According to recent research, altering CD4 T cell metabolism to favour oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) may help Treg function return and inhibit harmful effector responses. Current research on CD4 T cell immunometabolic pathways, their interactions with CNS-resident cells, and the developing possibility of metabolic intervention to slow neurodegeneration is explained in this review. By examining important signaling pathways including AMPK, mTORC1, and ROS dynamics, we demonstrate how CD4+T cell metabolism may reshape ND treatment approaches.
    Keywords:  Autoimmunity; CD4+T cells; Metabolic reprogramming; Neurodegenerative diseases; Treg
    DOI:  https://doi.org/10.1186/s13041-026-01282-6
  23. Front Immunol. 2026 ;17 1739341
    Microglia heterogeneity and therapeutic strategies in Parkinson's disease.
    Jing Tian, Xuehui Liu, Zhuoqun Wang, Xue Shi, Chunlei Dai, Li Yang.
      Parkinson's disease (PD) is the second most common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and the abnormal aggregation of α-synuclein (α-syn). PD exhibits features of a chronic inflammatory disease, significantly affecting peripheral organs and the central nervous system (CNS). Clinical signs include motor symptoms such as rigidity, bradykinesia, and tremor, as well as non-motor symptoms such as psychological and cognitive issues. Microglia are resident immune cells of the CNS, exhibiting high heterogeneity and playing a crucial role in the neuronal degeneration and inflammation associated with PD. In PD, microglia play dual roles: maintaining PD homeostasis by phagocytosing and clearing α-syn aggregates while simultaneously becoming dysfunctional due to aggregate overload. This dysfunction drives their transition to a pro-inflammatory phenotype, exacerbating neurotoxicity. Recently, technological advances like single-cell transcriptomics have revealed the diverse functions and changing phenotypic lineages of microglia in PD, providing new insights into their mechanisms. This review systematically describes the biological traits of microglia and their functional, spatial, genetic, and gender-related differences in PD neurodegeneration. It summarizes new intervention and treatment strategies targeting microglia, highlights recent progress and challenges in preclinical research and clinical trials, and offers guidance for developing precision therapies for PD focused on modulating microglial function.
    Keywords:  PD; heterogeneity; immunotherapy; microglia; neuroinflammation
    DOI:  https://doi.org/10.3389/fimmu.2026.1739341
  24. J Neurochem. 2026 Feb;170(2): e70388
    CASPR2 Autoimmune Antibodies Induce Neuronal Hyperactivity in Human Brain Organoids.
    Ana Rafaela Oliveira, Giuseppe Cammarata, Catarina Seabra, Ana Maria Cardoso, Henrique J Santos, Joana Guedes, Diana Sequeira, João Miguel Marques Santos, Guiomar Oliveira, Ana Luísa Cardoso, Dominique Fernandes, Maria Isabel Leite, Ester Coutinho, Ana Luísa Carvalho, Lino Ferreira, João Peça.
      Gestational transfer of brain-reactive antibodies is a risk factor for neurodevelopmental disorders. Contactin-associated protein-like 2 (CASPR2) is a known target for pathogenic maternal autoantibodies which have been proposed to interfere with fetal neurodevelopment. However, the impact of CASPR2 antibodies on human brain development remains largely unknown. Here, to better understand the neurophysiological changes that occur in the presence of these pathogenic autoantibodies, we cultured unguided human neural organoids for a period of 6-months in media containing anti-CASPR2 antibodies. We then performed neurophysiological characterization via whole-cell patch-clamp and calcium imaging in acute organoid slices. Our results reveal that CASPR2 antibody exposure increased spontaneous synaptic activity, enhanced the maximal frequency of action potential firing and of spontaneous network activity. These findings are consistent with a state of neuronal hyperexcitability, a phenotype which is observed in several models of neurodevelopmental disorders. Mechanistically, the alterations observed in action potential waveform are in accordance with a role for CASPR2 in the regulation of voltage-gated potassium channels and a pathological role for CASPR2 autoantibodies in driving neuronal hyperexcitability.
    Keywords:  CASPR2; autism; brain organoids; electrophysiology; hyperexcitability; maternal autoantibodies; neurodevelopment
    DOI:  https://doi.org/10.1111/jnc.70388
  25. Commun Biol. 2026 Feb 25.
    Microglial serine racemase knockout alleviates Alzheimer-like neuropathology and behavioral deficit via lactylation-mediated anti-inflammation.
    Jing Zhou, Yuanhong Yang, Shuyi Liu, Juan Chen, Hongji Liao, Wenjing Liang, Zhiwen Zhang, Yan Wang, Yimei Liu, He Zhang, Haiyan Jiang, Wenchu Lin, Jia Qu, Steven W Barger, Shengzhou Wu.
      Serine racemase (SR) dysregulation associates with brain aging and Alzheimer's disease (AD), as both a deficiency and an excess of D-serine can impact synaptic neurotransmission and the integrity of synapses. Neuronal SR decreases with aging, while glial SR is upregulated in AD. However, the role of SR in microglia involved in AD remains elusive. Here, Srr knockdown/knockout in microglia enhanced whereas overexpression of SR inhibited phagocytosis. Lipopolysaccharide-treated Srr-/- microglia upregulated anti-inflammatory factors-an effect blocked by histone lactylation inhibition. Conditional microglial Srr knockout (5×FAD;Lyz2cre;Srrfl/fl) improved spatial memory and reduced amyloid plaques (male-specific) in 5×FAD mice, with elevated lactylation of histone H3 lysine 18 (H3K18la), pyruvate kinase M2, and arginase1 in plaque-associated microglia. Cerebral D-amino acid oxidase and microglial SR and H3K18la were more prominent in males. Collectively, microglia-specific Srr deletion reprograms microglia toward an anti-inflammatory phenotype and enhanced phagocytic capacity partialy mediated by histone lactylation, thereby mitigating AD neuropathology and improving cognitive function-where sex-specific modulation of D-serine contributes to these beneficial effects. Overall, this study delineates the functional roles of microglial SR in phagocytosis, inflammatory responses, and learning-memory behaviors in AD-related models, thereby implicating microglial SR as a potential therapeutic target for AD.
    DOI:  https://doi.org/10.1038/s42003-026-09772-y
  26. Mol Cell Proteomics. 2026 Feb 23. pii: S1535-9476(26)00033-2. [Epub ahead of print] 101537
    High-fat diet and a high amyloid load interact to induce PKC-α dependent synaptic insulin resistance.
    Alexander Wenger, Tingting Li, Chi Nguyen, Ali Celik, Eleonora Cuboni, Alexander Dityatev, Anna Karpova, Michael R Kreutz, Robert Ahrends.
      A plethora of studies suggest that a high-fat diet in combination with a high amyloid load causes synaptic insulin resistance and is a risk factor for Alzheimer's disease. Our understanding of the underlying mechanisms is still fragmented. To gain new insights, we conducted integrated proteomic and phosphoproteomic profiling of hippocampal synaptosomes from wild-type and a transgenic mouse line with a high amyloid load (heterozygous TBA2.1 mice) that show no overt signs of neurodegeneration and dementia. Mice were fed with a regular or high-fat diet. Data-independent acquisition quantified over 5,400 proteins, revealing a stable synaptic proteome across conditions. However, the combination of high amyloid load and high-fat diet triggered coordinated remodeling of lipid metabolism pathways, particularly mitochondrial and peroxisomal fatty acid catabolism. Phosphoproteomic analysis showed pronounced activation of lipid- and stress-responsive kinases, including PKC-α, along with increased inhibitory phosphorylation of insulin receptor substrates (IRS1/2). In vitro experiments indicate that blocking PKC-α indeed prevents synaptic insulin resistance in primary neurons. The findings suggest that this proteomic workflow, combined with kinase pathway analysis, can reveal nodal points for interventions in a complex disease state with a trajectory to Alzheimer's disease.
    Keywords:  Alzheimer’s disease; TMT; enrichment analysis; high-fat diet; network analysis; phosphoproteomics; synaptic insulin resistance; synaptosomes
    DOI:  https://doi.org/10.1016/j.mcpro.2026.101537
  27. Nat Immunol. 2026 Feb 27.
    Reciprocal regulation of fibroblast-macrophage equilibrium governs skin integrity.
    Apple Cortez Vollmers, Sunny Z Wu, Anthony Altieri, Erika E McCartney, Hannah Bender, Christopher D Davidson, Wyne P Lee, Juan Zhang, Crystal Hu, Surinder Jeet, Ben Hall, Ricardo A Irizarry-Caro, Alberto Guarnieri, Endi K Santosa, Jessica Preston, Salil Uttarwar, Jason A Vander Heiden, Yein Chung, Willie Ortiz, Michael Long, Raymond Asuncion, Yeqing Angela Yang, Jean X Jiang, Zora Modrusan, Subba Chintalacharuvu, Christine Moussion, Akshay T Krishnamurty, Wenxian Fu, Sören Müller, Matthew B Buechler, Shannon J Turley.
      Fibroblast-macrophage crosstalk is well-established in vitro, and fibroblast-derived colony-stimulating factor 1 (CSF1) supports macrophages in select tissues. However, whether macrophages regulate fibroblasts in vivo remains unknown. Leveraging genetic mouse models, single-cell multi-omics, flow cytometry and imaging, we show that fibroblast depletion or loss of fibroblast-derived growth factors impacts skin macrophage populations in the dermis and hypodermis. Conditional deletion of Csf1 in Dpt+ fibroblasts progressively decreases CD64+ and CD11c+ macrophages, impairing skin wound healing. Reduced macrophage abundance disrupts fibroblast cell cycle regulation, metabolism and immune signaling, and increases fibroblast abundance, affirming a reciprocal relationship. In human systemic sclerosis (scleroderma), elevated fibroblast-derived CSF1 and increased macrophage abundance correlate with disease severity, implicating the CSF1-CSF1R axis in pathology. These findings provide in vivo evidence of macrophage regulation of fibroblasts, revealing a bidirectional interplay that advances understanding of tissue homeostasis and immune regulation in skin.
    DOI:  https://doi.org/10.1038/s41590-026-02434-5
  28. Nature. 2026 Feb 25.
    The protein carriers of hundreds of lipids have been identified.
      
    Keywords:  Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-026-00570-4
  29. Biomolecules. 2026 Feb 02. pii: 224. [Epub ahead of print]16(2):
    Activated Microglia-Derived Extracellular Vesicles Elicit a Pro-Inflammatory Astrocytic Response via Cargo-Dependent Mechanisms.
    Miriam Scheld, Nadine Jülich, Katharina Vöhringer, Adib Zendedel, Cordian Beyer, Sebastian Kant, Natalie Tillmann, Nima Sanadgol.
      Neuroinflammation plays a dual role in brain health supporting defense and repair, but causes neurotoxicity when persistent. Microglia and astrocytes coordinate these responses through cytokine signaling and extracellular vesicles (EVs), though their vesicle-mediated communication remains unclear. This study investigated whether EVs from activated microglia (ABEVs) influence astrocyte polarization and inflammatory signaling. BV-2 microglial cells were activated with lipopolysaccharide (LPS), and microvesicle (ABMVs) and exosome (ABEXs) EVs were isolated via sequential ultracentrifugation. Primary mouse astrocytes were treated with LPS, ABMVs, or ABEXs, and expression of reactive astrocyte markers (C3, Serpina3n, S100a10, Sphk1) and inflammatory mediators (Lcn2, Il-1β, Ccl2, Ccl5, Cxcl10) was quantified, and EV protein cargo was analyzed by mass spectrometry and proteomics. LPS-treated astrocytes exhibited increased C3 and Serpina3n and decreased S100a10, consistent with reactive polarization. ABEXs mimicked this effect, significantly inducing C3, Serpina3n, and Sphk1, whereas ABMVs had a weaker influence. ABEXs also upregulated Lcn2 and Il-1β, partially reproducing microglial inflammatory effects. Proteomic profiling revealed marked cargo differences: ABEXs exhibited 16 upregulated proteins linked to NOD-like receptor signaling compared to non-activated BEXs, and 165 proteins associated with ribosome biogenesis and spliceosome pathways compared to ABMVs, indicating subtype-specific signaling potential. Collectively, our findings demonstrate that microglia-derived EVs modulate astrocytic polarization and cytokine profiles in a cargo-dependent manner, emphasizing their importance in interglial communication and revealing novel targets for neuroinflammatory modulation.
    Keywords:  astrocyte polarization; extracellular vesicles; microglia–astrocyte communication; neuroinflammation
    DOI:  https://doi.org/10.3390/biom16020224
  30. EMBO Rep. 2026 Feb 27.
    The Arp2/3 complex is required for in situ haptotactic response of microglia to iC3b.
    Summer G Paulson, Isabella Swafford, Fritz W Lischka, Jeremy D Rotty.
      Microglia maintain brain homeostasis via iC3b-mediated synaptic pruning. The Arp2/3 complex has been implicated in iC3b-mediated macrophage phagocytosis, but it is unclear whether it is similarly required in microglia in the CNS. We examined the question of CR3-dependent clearance of iC3b in microglia using a combination of in vitro and in situ physical confinement studies. Arp2/3 inhibition decreased iC3b phagocytosis and cell motility in vitro. Furthermore, microglia-like cells remove immobilized iC3b from the substrate in an Arp2/3-dependent fashion, in a process reminiscent of trogocytic synaptic pruning. We also used a novel approach to immobilize an iC3b gradient onto a substrate and demonstrate Arp2/3-dependent haptotactic migration toward increasing iC3b concentrations. While Arp2/3-deficient microglia robustly respond to ATP via chemotaxis within mouse hippocampal slices, they demonstrate a persistent inability to stably interact with iC3b-coated beads. The present study establishes new approaches to systematically interrogate molecular pathways relevant to synaptic pruning, advances the understanding of iC3b phagocytosis as a haptotactic response, and confirms that the Arp2/3-dependent haptotactic response is important for microglia function in the CNS microenvironment.
    Keywords:  Arp2/3 Complex; Haptotaxis; Microglia; Synaptic Pruning; iC3b Phagocytosis
    DOI:  https://doi.org/10.1038/s44319-026-00720-9
  31. bioRxiv. 2026 Feb 13. pii: 2026.02.11.705385. [Epub ahead of print]
    HAPI Cells are SIM-A9-related Mouse Microglial Cells Useful for In Vitro Modeling of Microglial Immunometabolism.
    Ryan P Mayers, Sausan M Jaber, Nicolas Verhoeven, Ayodele Jaiyesimi, Brian M Polster.
      Highly aggressively proliferating immortalized (HAPI) cells were initially described as a spontaneously immortalized rat cell line isolated from a mixed neonatal rat glial population. It was demonstrated that HAPI cells are phagocytic, stain for macrophage-/microglia-specific markers like CD11b and GLUT5, and exhibit lipopolysaccharide (LPS)-induced nitric oxide (NO) and tumor necrosis factor-alpha (TNF-α) release. These characteristics led to their widespread use as a rat microglial cell line. Here, we report that HAPI cells are mouse cells, not rat cells, but further establish that they have a microglia-like identity and properties useful for in vitro modeling. Cell line authentication by short tandem repeat (STR) profiling, a method that detects identifying DNA signatures, indicates that HAPI cells are a 100% match for SIM-A9 cells, a mouse microglial cell line reported to be spontaneously immortalized from primary cell culture. We find that both HAPI cells and SIM-A9 cells express the microglia-selective gene Tmem119 , as well as the microglia-/macrophage-selective marker Cx3cr1 , supporting a microglial origin. Like primary rodent microglia or macrophages, HAPI cells respond to combined stimulation with LPS and the Type II interferon, interferon-gamma (IFN-γ), with a pro-inflammatory morphology, NO production, NO-dependent suppression of mitochondrial oxygen consumption, and increased extracellular acidification (an indicator of glycolysis). The Type I interferon, interferon-alpha (IFN-α), also reduces mitochondrial oxygen consumption when administered alone or in combination with LPS. Overall, results indicate that HAPI cells are SIM-A9-related mouse cells of microglial origin and support their continued use to study microglial behavior in vitro , including immunometabolism.
    DOI:  https://doi.org/10.64898/2026.02.11.705385
  32. J Clin Invest. 2026 Feb 24. pii: e199818. [Epub ahead of print]
    Inflammasome adaptor ASC promotes sustained neuroinflammation and mild cognitive impairment in a closed-head injury model.
    Tao Li, Sergio Castro-Gomez, Pablo Botella Lucena, Ana Vieira-Saecker, Stephanie Schwartz, Yingying Ding, Yushuang Deng, Maling Guo, Valentin Stein, Douglas T Golenbock, Eicke Latz, Michael T Heneka.
      Mild traumatic brain injury (mTBI) from closed-head injuries (CHI) can lead to prevalent neuropsychiatric disorders, including mood disorders and an increased risk for neurodegenerative diseases and dementia. Inflammasomes are molecular complexes crucial for neuroinflammation and secondary damage after trauma, however their role in mild CHI is poorly understood. In this study, we investigate the cellular expression of inflammasome-related genes and their functional significance in CHI models. Single-cell RNA sequencing analysis of cortical tissue after trauma revealed selective expression of Asc (also known as Pycard), which encodes the inflammasome adaptor Apoptosis-associated Speck-like protein containing a Caspase recruitment domain (ASC), predominantly in microglial clusters. Sustained upregulation of inflammasome-related proteins, microglia activation and astrocyte reactivity persisted up to 21 days in a model for mTBI, with this pattern significantly reduced in Asc-/- mice. Importantly, mild cognitive impairment induced after mild CHI was largely abrogated in Asc-/- mice. These findings suggest that ASC, as the primary inflammasome adaptor, plays a critical role in sustaining neuroinflammation and contributes to cognitive deficits after mild CHI. This study provides insights into the molecular neuroinflammatory mechanisms underlying CHI, potentially informing future therapeutic strategies.
    Keywords:  Dementia; Inflammation; Innate immunity; Neuroscience; Transcriptomics
    DOI:  https://doi.org/10.1172/JCI199818
  33. Nature. 2026 Feb 25.
    Parkinson's disease affects network of brain regions that controls whole-body action.
      
    Keywords:  Brain; Neuroscience; Parkinson's disease
    DOI:  https://doi.org/10.1038/d41586-026-00573-1
  34. Nat Cell Biol. 2026 Feb 26.
    Mitochondria contact lipid droplets through the mitochondrial import complex binding to lipid metabolism enzyme Ayr1.
    Sandra Heinen, Vitasta Tiku, Alexander Grevel, Marie Hugenroth, Lars Ellenrieder, Isabelle Steymans, Mariya Licheva, Sara Bonini, Silke Oeljeklaus, Nicole Okon, Jessica Lambertz, Sylvia Poppe, Jiyao Song, Lars Fester, Chris Meisinger, Bettina Warscheid, Matthias Eckhardt, Nils Wiedemann, Dominic Winter, Claudine Kraft, Fabian den Brave, Maria Bohnert, Nikolaus Pfanner, Thomas Becker.
      Mitochondria play central roles in the energetics and metabolism of eukaryotic cells. Their outer membrane is essential for protein transport, membrane dynamics, signalling and metabolic exchange with other cellular compartments. The mitochondrial import (MIM) complex functions as main translocase for importing the precursors of more than 90% of integral outer-membrane proteins. Here we report that the MIM complex performs a second major function in lipid-droplet homeostasis. Lipid droplets are crucial in cellular lipid metabolism and as storage organelles for neutral lipids. The lipid metabolism enzyme Ayr1 captures the MIM complex, promoting the formation of mitochondria-lipid droplet contact sites. MIM and Ayr1 enhance the lipid droplet number in cells. Ayr1 binds to MIM via its single hydrophobic segment in a substrate-mimicry mechanism but remains bound and is not released into the outer membrane. The functional diversity is mediated by different MIM complexes: MIM-Ayr1 for recruiting lipid droplets and MIM-preprotein for protein insertion into the outer membrane. Our work uncovers translocase capture as a mechanism for functional conversion of a membrane protein complex from protein insertion to lipid metabolism.
    DOI:  https://doi.org/10.1038/s41556-026-01890-3
  35. ACS Chem Neurosci. 2026 Feb 24.
    Microglial Senescence in Neurodegenerative Diseases: Mechanisms and Therapeutic Perspectives.
    Yixiao Liu, Zexuan Hu, Yitong Xiao, Xinyuan Han, Xiaorui Cheng, Tianyuan Ye.
      The global aging population has led to a rising incidence of neurodegenerative diseases, casting a significant shadow on global health due to their complex and multifactorial nature. In addition to genetic predispositions, cellular senescence, particularly in microglia, the innate immune cells of the central nervous system, has become a significant contributor to neurodegeneration. In this review, we examine the mechanism of microglial senescence in neurodegenerative disease. We emphasize the need for continuous exploration of microglial senescence mechanisms and provide a future perspective for developing preventive drugs, encouraging researchers to develop new therapies for patients with neurodegenerative diseases.
    Keywords:  cellular senescence; microglia; neurodegenerative diseases; therapeutics
    DOI:  https://doi.org/10.1021/acschemneuro.6c00016
  36. Proc Natl Acad Sci U S A. 2026 Mar 03. 123(9): e2522313123
    mtDNA leakage promotes neuron-glia crosstalk to induce epilepsy by cGAS-STING-driven neuroinflammation and serine metabolic reprogramming.
    Jie Jiang, Meiling Zuo, Kehan Zhao, Zhihao Ling, Zhida Wu, Dongfang Xue, Shouyong Mo, Yuanhui Liu, Yongjun Chen, Jie Wang, Bin Lu, Chuanzhou Li, Yaqi Duan, He He, Zhiyin Song.
      Epilepsy is increasingly recognized as a disorder involving metabolic dysregulation beyond neural hyperexcitability, yet the underlying metabolic mechanisms remain poorly defined. Here, we identify a mitochondrion-immunity-metabolism axis that drives spontaneous chronic epilepsy. Brain-specific deletion of Mic19 impairs mitochondrial cristae structure and mitochondrial integrity in neurons, leading to activation of the Z-mitochondrial DNA (mtDNA)-ZBP1-RIPK3-mixed lineage kinase domain-like protein (MLKL) axis and p-MLKL-mediated pore formation on the mitochondrial membrane. This process results in cytosolic and extracellular leakage of mtDNA, which is subsequently taken up by microglia and triggers cyclic GMP-AMP synthase (cGAS)-STING-dependent inflammatory signaling. The resulting neuroinflammation promotes sustained activation of astrocytes. Critically, reactive astrocytes undergo profound metabolic reprogramming, marked by upregulated glycolysis and enhanced L-serine biosynthesis. Astrocyte-derived L-serine is subsequently transferred to neurons and converted into D-serine, a key NMDA receptor coagonist that enhances neuronal excitability. This metabolic shift in astrocytes exacerbates excitotoxicity and sustains epileptic activity. Importantly, pharmacologic inhibition of STING with H-151 treatment markedly suppresses seizures, reinforcing the therapeutic potential of targeting immunometabolic crosstalk in epilepsy. Our findings reveal that mtDNA-mediated cGAS-STING activation and D-serine act as important drivers of epilepsy initiation, offering mechanistic insights into neuron-microglia-astrocyte crosstalk and highlighting immunometabolic modulation as a promising therapeutic strategy for epilepsy.
    Keywords:  cGAS–STING; epilepsy; mitochondrial DNA; neuroinflammation; serine
    DOI:  https://doi.org/10.1073/pnas.2522313123
  37. Inflammation. 2026 Feb 24.
    β-Asarone Mediates the Alleviation of Neuroinflammation in Alzheimer's Disease Via Modulation of the TREM2/PI3K/AKT Signaling Pathway.
    Na Yang, Jiajun Jiang, Jianhong Shi, Xuan Liu, Chenshi Yu, Shunyuan Guo, Chengliang Zhang, Feng Gao, Zijian Yang, Huina Feng, Qiuyan Weng, Tao Qiu, Changyu Li, Liting Ji.
      Neuroinflammation, driven by dysregulated microglial polarization, is a hallmark of Alzheimer's disease (AD). Recently, the triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of microglial function, has emerged as a promising therapeutic target for AD. This study aimed to investigate the therapeutic potential and mechanism of action of the natural compound β-asarone in AD models. Our results demonstrate that β-asarone significantly improved cognitive function, reduced hippocampal neuronal damage, and decreased both Aβ deposition and Tau hyperphosphorylation in 3×Tg-AD mice. Mechanistically, β-asarone upregulated TREM2 expression, activated the PI3K/AKT pathway, and inhibited GSK3β activity, thereby promoting the polarization of microglia from the pro-inflammatory M1 phenotype toward the anti-inflammatory M2 phenotype and alleviating neuroinflammation. This study is the first to elucidate that β-asarone ameliorates AD pathology by modulating microglial polarization via the TREM2/PI3K/AKT/GSK3β signaling axis, providing experimental evidence supporting its potential as an immunomodulatory therapeutic agent for AD.
    Keywords:  Alzheimer's disease; Microglia; Neuroinflammation; TREM2; β-asarone
    DOI:  https://doi.org/10.1007/s10753-025-02435-w
  38. Cell Mol Neurobiol. 2026 Feb 22.
    Microglial Autofluorescence in the Brain and Retina is Dynamically Modulated by Systemic Inflammation.
    Mary Slayo, Hasan Ul Banna, Ying Zhi Cheong, Soniya Xavier, Kylie M Quinn, Luba Sominsky, Loretta Vocale, Philipp Reineck, Brant C Gibson, Blanca Del Rosal, Sarah J Spencer.
      The retina-an extension of the central nervous system-contains microglia that survey and respond to injury or pathogens. In response to their environmental milieu, these cells accumulate autofluorescent material likely reflective of cellular debris. Measuring these autofluorescence changes may be a useful tool for early diagnosis of brain-related inflammatory conditions or diseases by imaging the eye. To assess this, we gave Wistar rats a systemic immune challenge with lipopolysaccharide (LPS; 250 µg/kg, intraperitoneally) and examined autofluorescence characteristics of the microglia in brain and eye using confocal microscopy. Initial flow cytometry experiments verified that isolated microglia are highly autofluorescent compared to cells in immune-related organs such as spleen. In immunolabelled brain sections (arcuate, hippocampus, retrosplenial cortex), astrocytes, neurons, and microglia all displayed significant autofluorescence, with microglia displaying greatest levels. LPS led to predicted changes in microglial morphology in the brain and this was accompanied by an increase in the number of individual autofluorescent aggregates but a reduction in the total volume, indicative of changes in the dynamics of the material. While there were similarities in the microglial response to LPS in the retina, and the total volume of autofluorescence aggregates was also reduced, retinal autofluorescence changes did not simply predict those seen in brain. These findings suggest that the relationship between immune challenge states and autofluorescence accumulation is dynamic and complex. Understanding the role of microglia in accumulating and metabolising this autofluorescent material may assist our understanding of disease states and how they influence retina and brain.
    Keywords:  Autofluorescence; Brain; Inflammation; Microglia; Rat; Retina
    DOI:  https://doi.org/10.1007/s10571-026-01704-y
  39. Brain Sci. 2026 Jan 29. pii: 154. [Epub ahead of print]16(2):
    Neuroimmune Interactions in Neurodegeneration: The Role of Microglia in Alzheimer's and Parkinson's Disease Pathogenesis.
    Pradeep Goyal, Lalji Baldaniya, Lalit Kumar Tyagi, Kamal Kant Joshi, Suhas Ballal, A Sabarivani, Subhashree Ray, Deepak Nathiya, Ashish Singh Chauhan, Monica Gulati, Tapan Behl, Ansab Akhtar.
      Neuroimmune interactions play a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD), with microglia acting as key mediators of neuroinflammation. Microglia exhibit dual roles, contributing to both neuroprotection and neurotoxicity depending on their activation state. In AD, amyloid-beta (Aβ) aggregation leads to chronic microglial activation, resulting in excessive pro-inflammatory cytokine release (e.g., TNF-α, IL-1β, IL-6), oxidative stress, and synaptic dysfunction. In PD, α-synuclein aggregation triggers a similar neuroinflammatory cascade, exacerbating dopaminergic neuronal loss in the substantia nigra. Beyond inflammatory responses, microglia regulate synaptic plasticity, phagocytose pathological proteins, and interact with peripheral immune cells, influencing disease progression. Emerging evidence suggests that genetic variants in genes such as TREM2, CD33, and HLA modulate microglial function, thereby altering susceptibility to neurodegeneration. Dysregulated microglial responses, characterized by impaired clearance of protein aggregates and prolonged neuroinflammation, further amplify neuronal damage. Therapeutic strategies targeting microglial activation are under investigation, aiming to balance neuroinflammatory responses and enhance clearance mechanisms. Small-molecule inhibitors, monoclonal antibodies, and modulators of innate immune pathways are being explored to mitigate microglia-driven pathology. Understanding the complex interplay between microglia and neurodegeneration could pave the way for precision medicine approaches, optimizing treatments based on individual immune profiles. Further research is essential to delineate microglial heterogeneity across disease stages and uncover novel targets for therapeutic intervention.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; immune response; microglia; neuroimmune
    DOI:  https://doi.org/10.3390/brainsci16020154
  40. Nat Neurosci. 2026 Feb 26.
    Magnetic resonance microscopy maps widespread effects of Alzheimer's disease on brain structures and behavior in mice.
    Yuqi Tian, Kathryn Hornburg, Wyatt Austin, James J Cook, Yi Qi, Leonard E White, John T Killmar, Catherine C Kaczorowski, David G Ashbrook, G Allan Johnson, Robert W Williams.
      Alzheimer's disease has widespread effects on brain structure, function and behavior, but we lack a systematic dissection of its impact across hundreds of forebrain and brainstem regions. Here, using diffusion tensor MRI at 25 µm, we mapped the global consequences of mutations in APP and PSEN1 across 231 regions of interest (ROIs) in male and female 5×FAD BXD hybrid mice at 14 months. Over half of the ROIs change in volume along rostrocaudal and mediolateral axes of the CNS, with unexpected swelling in the neocortex, hippocampus and amygdala of up to 10%, counterbalanced by shrinkage in the thalamus, brainstem and most white matter tracts. Yet, total brain volume is unaltered. Variation in individual ROI volumes is highest in females. Differences in fear acquisition and contextual memory performance covary with volumes of several regions and can have opposite polarities between cases and controls. These structural benchmarks establish a foundation for testing therapeutic interventions in preclinical trials.
    DOI:  https://doi.org/10.1038/s41593-025-02199-4
  41. Neuron. 2026 Feb 23. pii: S0896-6273(25)01001-3. [Epub ahead of print]
    More than microglial depletion: PLX5622 activates the hepatic constitutive androstane receptor to alter anesthesia and addiction.
    Kelei Cao, Wang Cheng, Liyao Qiu, Zexi Wang, Yuqing Zhao, Ying Yuan, Weiying Wu, Jingyuan Xue, Linghui Zeng, Zhi-Ying Wu, Huan Ma, Tingjun Hou, David A Hume, Cunqi Ye, Shumin Duan, Zhihua Gao.
      The colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 has been widely used to deplete microglia for functional characterization and therapeutic support. Although diverse outcomes have been described after PLX5622 treatment, whether these phenotypes solely reflect microglial functions remains to be determined. Here, we show that transgenic microglial depletion did not mimic the accelerated anesthetic arousal or the alleviated nicotine addiction withdrawal symptoms observed after PLX5622 treatment in mice. We further identify that PLX5622 potently activates the mouse constitutive androstane receptor (CAR), leading to prominent induction of hepatic enzymes. The induced enzymatic activity enhances the metabolism and clearance of anesthetics and nicotine, thereby contributing to anesthetic insensitivity and addiction relief. Inactivation of CAR abolished these effects of PLX5622, indicating that the impact of PLX5622 treatment cannot be attributed exclusively to microglial depletion. Our findings raise awareness in evaluating consequences of PLX5622 treatment and provide insights into the design of specific CSF1R inhibitors.
    Keywords:  PLX5622; anesthesia; colony-stimulating factor 1 receptor; constitutive androstane receptor; metabolism; microglia
    DOI:  https://doi.org/10.1016/j.neuron.2025.12.044
  42. J Neuroinflammation. 2026 Feb 21.
    CNS-targeted NLRP3 Inhibition by NT-0527 confers therapeutic advantage in a CAPS mouse model.
    Beverly H Koller, MyTrang Nguyen, John R Doedens, David Harrison, Nicholas Clarke, Alan P Watt, Christopher A Gabel.
      
    Keywords:  Blood-brain barrier; CAPS; IL-1β; Inflammation; Meningitis; NLRP3 inflammasome; Neurodegeneration
    DOI:  https://doi.org/10.1186/s12974-026-03731-4
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