bims-microg Biomed News
on Microglia in health and disease
Issue of 2026–03–01
sixteen papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Neuron-Derived Sema3B Facilitates Microglial Hematoma Clearance After Intracerebral Hemorrhage.
  2. TRPV4 Deficiency Shifts Mitochondrial Dynamics Toward a Fragmented Morphology in Primary Microglia.
  3. Microglia modulate information processing in the mouse barrel cortex.
  4. Down-regulation of lipocalin-2 alleviates depressive-like behaviors in mice through modulation of microglial activation.
  5. Microglia-Neuron Crosstalk: An Intimate Molecular Conversation in Neurodegeneration.
  6. Microglial serine racemase knockout alleviates Alzheimer-like neuropathology and behavioral deficit via lactylation-mediated anti-inflammation.
  7. Danggui-Shaoyao San Promotes Microglia-Mediated Oligodendrocyte Maturation and White Matter Repair After Stroke.
  8. Microglia heterogeneity and therapeutic strategies in Parkinson's disease.
  9. The Arp2/3 complex controls the development of homeostatic microglia.
  10. The Arp2/3 complex is required for in situ haptotactic response of microglia to iC3b.
  11. Microglia-T cell interactions drive α-synuclein pathology in a Parkinson's disease mouse model.
  12. A ligand-mimetic anti-TREM2 agonist antibody elevates soluble TREM2 and ameliorates pathology in mouse models of Alzheimer's disease and multiple sclerosis.
  13. A new mechanism for ubiquitination in polystyrene nanoplastic-induced spatial cognitive dysfunction through microglial activation-induced apoptosis of neurons.
  14. Epigenomic subtypes of late-onset Alzheimer's disease reveal distinct microglial signatures.
  15. More than microglial depletion: PLX5622 activates the hepatic constitutive androstane receptor to alter anesthesia and addiction.
  16. Endogenous retrovirus-derived RNA-DNA hybrids induce microglial synaptic pruning in autism models.
  1. Antioxidants (Basel). 2026 Feb 08. pii: 220. [Epub ahead of print]15(2):
    Neuron-Derived Sema3B Facilitates Microglial Hematoma Clearance After Intracerebral Hemorrhage.
    Baisong Huang, Anqi Chen, Tong Zhou, Ying Xu, Yuanyuan Sun, Quanwei He.
      Intracerebral hemorrhage (ICH) is the deadliest subtype of stroke, and its primary harm to the human body arises from the formation of brain hematomas. Promoting microglial-mediated endogenous hematoma clearance has become a key focus in current ICH treatment strategies. Semaphorin 3s (Sema3s) are molecular signals involved in the regulation of the central nervous system, angiogenesis, and microenvironment homeostasis, and they are closely associated with various central nervous system diseases. Hematoma clearance and inflammation regulation are crucial to the role of microglia, yet the mechanisms by which Sema3s regulate microglia after ICH remain unclear. Here, using high-throughput RNA sequencing of a mouse ICH model, we identified that neuron-derived Sema3B is downregulated after ICH. Further mechanistic studies revealed that Sema3B can bind to PlexinA1 on microglia, activating NRF2 to promote the expression of the phagocytic receptor TREM2 and the key hematoma clearance molecule HO-1. Furthermore, Sema3B enhances the interaction between PlexinA1 and TREM2, cooperatively boosting microglial phagocytosis of the hematoma after ICH. Furthermore, Sema3B regulates the M2 polarization of microglia, exerting an anti-inflammatory effect. Our findings suggest that manipulating microglial phagocytosis of hematoma and inflammation suppression via regulation of Sema3B may be a potential strategy for treating patients with ICH.
    Keywords:  HO-1; Nrf2; Trem2; hematoma clearance; microglia; semaphorin class 3B
    DOI:  https://doi.org/10.3390/antiox15020220
  2. 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
  3. 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
  4. Neurotherapeutics. 2026 Feb 24. pii: S1878-7479(26)00032-2. [Epub ahead of print] e00862
    Down-regulation of lipocalin-2 alleviates depressive-like behaviors in mice through modulation of microglial activation.
    Xiaoyu Yu, Shulei Gao, Yunguang Chen, Long Ye, Bin Wang, Lvyang Xu, Ao Sun, Chenrui Liang, Sihan Lu, Xiaolu Li, Zhenyu Fan, Yu Wang.
      Although the pathophysiological underpinnings of major depressive disorder (MDD) are increasingly recognized to involve microglia-mediated neuroinflammation, the underlying molecular processes are still not fully understood. To identify key molecular regulators associated with neuroinflammatory processes, we conducted transcriptomic analysis on hippocampus tissue from chronic unpredictable stress (CUS) mouse models, as well as in vitro microglial inflammation models. Here, we identified lipocalin-2 (LCN2) as a crucial mediator of these neuroinflammatory processes. The expression of LCN2 was significantly upregulated in both MDD patients and CUS mice, and its expression level was positively correlated with the severity of depressive symptoms. In vitro experiments demonstrated that LCN2 knockdown effectively suppresses pro-inflammatory activation of primary microglia. Furthermore, in vivo studies revealed that inhibition of LCN2 expression via gene silencing or neutralizing antibodies markedly alleviates depressive-like behaviors in CUS mice. Mechanistic investigations indicated that knockdown of LCN2 inhibits mitochondrial dynamics imbalance of microglia and then inhibits its proinflammatory activation, thereby reducing neuroinflammation. This study not only identifies a promising therapeutic target for anti-neuroinflammatory interventions in depression but also provides systematic evidence that LCN2-induced mitochondrial dysfunction plays a pivotal role in the pathogenesis and progression of MDD.
    Keywords:  Depression; Inflammation; LCN2; Microglia; Mitochondrial dynamics
    DOI:  https://doi.org/10.1016/j.neurot.2026.e00862
  5. Int J Mol Sci. 2026 Feb 20. pii: 2011. [Epub ahead of print]27(4):
    Microglia-Neuron Crosstalk: An Intimate Molecular Conversation in Neurodegeneration.
    Shiqi Wang, Sichen Wang, Hongzhuan Chen, Jianrong Xu.
      Microglia are a unique cell population in the central nervous system (CNS) and serve as its resident immune cells. They have long been recognized for their critical contributions to CNS development and the maintenance of neuronal network health, particularly in the context of neuroprotection against neurodegenerative diseases. However, the mechanisms by which microglia interact with and influence neurons have remained largely unclear. Recent advances in genetics, pharmacology, and imaging technologies have begun to unveil the mechanisms underlying microglia-neuron communication. Here, from the perspective of microglia, we review the diverse direct and indirect pathways and key molecules through which microglia interact with neurons under both physiological and pathological conditions. This rapidly expanding knowledge is reshaping our understanding of neuron-glia physiology and pathology in neurodegenerative diseases.
    Keywords:  bioenergetics; crosstalk; inflammation; microglia; neurodegenerative disease; neuron
    DOI:  https://doi.org/10.3390/ijms27042011
  6. 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
  7. Aging Dis. 2026 Feb 20.
    Danggui-Shaoyao San Promotes Microglia-Mediated Oligodendrocyte Maturation and White Matter Repair After Stroke.
    Fang Tong, Yihan Liu, Nan Deng, Yong Yang, Sijie Li, Ziping Han, Jingfei Shi, Xunming Ji, Changhong Ren.
      Ischemic stroke is a leading cause of long-term disability, yet effective therapies that promote white matter repair and remyelination during the recovery phase remain limited. Danggui-Shaoyao-San (DSS) has demonstrated neuroprotective effects, but its mechanisms during the recovery phase are unclear. Here, we tested whether delayed DSS treatment improves long-term outcomes after transient focal ischemia by reprogramming microglia to support oligodendroglial differentiation and remyelination. In a mouse model of transient middle cerebral artery occlusion, DSS starting 30 min after reperfusion and continued throughout the recovery period produced sustained improvements in neurological function. These benefits were accompanied by preserved myelin-axon coupling, improved myelin ultrastructure in peri-infarct white matter, and enhanced progression of oligodendrocyte lineage cells toward a mature myelin-forming state. DSS reduced pro-inflammatory microglial activation while increasing repair associated microglial markers across the subacute period. Mechanistically, DSS enhanced microglial estrogen receptor ERα and ERβ signaling, increased expression of the ER associated corepressor CtBP, and suppressed NF-κB activation. In BV2 microglia, DSS containing serum dampened LPS-induced inflammatory gene expression programs and promoted repair associated markers, and pharmacological ER blockade reversed DSS-driven microglial polarization. Importantly, conditioned medium from DSS-treated microglia rather than direct exposure to DSS promoted oligodendroglial differentiation and induced pro-regenerative gene expression in oligodendrocyte lineage cells, supporting a paracrine signaling mechanism from microglia to oligodendroglia. Together, our findings identify DSS as a delayed recovery phase intervention that improves long term outcomes after ischemic stroke and suggest that ER dependent microglial reprogramming is a tractable upstream target for promoting remyelination and white matter repair.
    DOI:  https://doi.org/10.14336/AD.2026.10202
  8. 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
  9. 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
  10. 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
  11. 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
  12. 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
  13. J Hazard Mater. 2026 Feb 19. pii: S0304-3894(26)00530-3. [Epub ahead of print]505 141552
    A new mechanism for ubiquitination in polystyrene nanoplastic-induced spatial cognitive dysfunction through microglial activation-induced apoptosis of neurons.
    Qing Du, Ning Bu, Xuan Zhou, Hailan Wang, Zhenhao Jiang, Haibo Xia, Cheng Cheng, Jing Sun, Qizhan Liu.
      Growing evidence indicates that nanoplastics (NPs), particularly polystyrene nanoparticles (PS-NPs), cross the blood-brain barrier and reach the hippocampus, where they induce neurotoxicity through oxidative stress, neuroinflammation, and synaptic damage. In the present study, we demonstrate that PS-NPs downregulate RNF139 in microglia, impairing the degradation of SCAP. Elevated SCAP levels trigger SREBP activation, disordered lipid metabolism, and enhanced lipid synthesis. Subsequently, mitochondrial dynamics are dysregulated, characterized by elevated mitochondrial reactive oxygen species, a drop in membrane potential, and diminished ATP synthesis. Under these pathological conditions, microglia become abnormally activated and secrete inflammatory factors such as TNF-α, IL-1β, and IL-6. This neuroinflammatory cascade induces neuronal damage and apoptosis, resulting in spatial cognitive impairment. Thus, our findings reveal a link between PS-NPs exposure, changes in microglial lipid metabolism, and nerve damage. They also identify targets for treating NP-induced neurological disorders.
    Keywords:  Lipid metabolism; Mitochondrial dynamics; Polystyrene nanoplastics; Spatial cognitive dysfunction
    DOI:  https://doi.org/10.1016/j.jhazmat.2026.141552
  14. 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
  15. 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
  16. Neuron. 2026 Feb 24. pii: S0896-6273(26)00012-7. [Epub ahead of print]
    Endogenous retrovirus-derived RNA-DNA hybrids induce microglial synaptic pruning in autism models.
    Shaoxuan Chen, Boxin Zhang, Tianyu Qin, Mengyue Zhu, Qiang Chen, Lu Xia, Huifang Pan, Qihua Yang, Shuanghui Guo, Rui Gong, Qiwu Jiang, Hongda Li, Xueqin Zhang, Pu Cheng, Xuchen Qi, Wei Chen, Wei Mo.
      Microglia-mediated neuroinflammation is increasingly recognized as a key pathological component in autism spectrum disorders (ASDs), though the mechanisms driving microglial activation remain largely elusive. Our study reveals that deficiency in the high-risk ASD gene SETDB1, as well as maternal immune activation (MIA), elevates complement protein C4b expression specifically in prefrontal cortex (PFC) neurons. This upregulation triggers excessive microglial synaptic pruning, leading to autistic-like behaviors. Furthermore, we found that microglia elimination improved synaptic density, while complete C4b knockout rescued all observed autistic-like phenotypes in mice. C4b expression is driven by RNA-DNA hybrids formed through the reactivation of endogenous retroviruses (ERVs). Notably, we identify that existing FDA-approved HIV medications, which inhibit retrotranscriptional activity, substantially reduce C4b levels and alleviate ASD symptoms. These findings underscore the crucial role of C4b in microglia-mediated synaptic pruning in ASD and highlight the therapeutic potential of targeting ERV reactivation with existing HIV medications.
    Keywords:  ASD; C4b; ERV; MIA; RNA-DNA hybrids; RTIs; SETDB1; maternal immune activation; microglial; reverse transcriptase inhibitors; synaptic pruning
    DOI:  https://doi.org/10.1016/j.neuron.2026.01.011
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