bims-microg Biomed News
on Microglia in health and disease
Issue of 2026–11–08
eight papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Tau monomers and fibrils escape microglial clearance via distinct cellular mechanisms.
  2. APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer's disease.
  3. P2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy.
  4. Common transcriptional changes in the brain during hibernation and Alzheimer's disease.
  5. Histone H3K18 lactylation drives microglial ferroptosis and exacerbates neuroinflammation in sepsis-associated encephalopathy.
  6. Regulatory role of TIPE2 by inhibiting microglial pyroptosis and glycolysis in the treatment of sepsis-associated encephalopathy.
  7. ApoE-dependent lipid handling by median eminence microglia supports myelin remodeling and metabolic function.
  8. PAR4 exacerbates intracerebral hemorrhage by driving m6A-dependent microglial AIM2 release and neuronal PANoptosis.
  1. Nat Cell Biol. 2026 Nov 05.
    Tau monomers and fibrils escape microglial clearance via distinct cellular mechanisms.
    Vineet Vinay Kulkarni, Craig Fredrickson, Max Adrian, Jason Town, Hoangdung Ho, Przemysław Dutka, Julia Shangguan, Daniel Reid, Margaret Hayne, Marc Kschonsak, Ada Ndoja, Claire G Jeong, Casper C Hoogenraad.
      Tauopathies, such as Alzheimer's disease, are neurodegenerative disorders characterized by the accumulation and propagation of toxic extracellular forms of the microtubule-associated protein tau across brain regions. Microglia, the resident macrophages of the brain, are known for clearing and degrading toxic proteins. However, emerging evidence suggests that microglia also enhance tau spreading. To dissect the molecular mechanisms underlying microglial responses to extracellular tau, we use high-resolution imaging and biochemical approaches to assess the trafficking dynamics of different extracellular tau species in human induced pluripotent stem cell-derived microglia. Here we find that tau monomers are internalized by microglia via cell-surface LRP1 receptors but fail to reach terminally degradative lysosomes; instead, they are persistently recycled back to the extracellular space. In contrast, tau fibrils are not internalized and primarily adhere to the cell surface through an HSPG-dependent mechanism, triggering TLR4-mediated microglial activation and the release of pro-inflammatory cytokines. Heparin or anti-tau treatments dampen tau fibril-mediated microglial activation. In addition, disease-associated variants of the Alzheimer's disease-related protein APOE reduce microglia-tau interactions, further reducing tau uptake. Together, these findings demonstrate that microglia fail to efficiently clear extracellular tau monomers and fibrils through mechanistically distinct cellular processes, emphasizing the need for tailored therapeutic strategies to enhance extracellular tau clearance in neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41556-026-02118-0
  2. Nat Commun. 2026 Oct 08. pii: 11438. [Epub ahead of print]17(1):
    APOE2 attenuates APOE4-associated amyloid pathology and related toxicity in a mouse model of Alzheimer's disease.
    Kai Chen, Yixing Chen, Yingxue Ren, Zhen Wang, Ya Huang, Meixia Pan, Zonghua Li, Monica Castanedes Casey, Wenhui Qiao, Ji Shi, Dehui Kong, Gisela Xhafkollari, Hannah Santhakumar, Allison M Wetmore, E Aubrey Thompson, Xusheng Wang, Dennis W Dickson, David M Holtzman, Guojun Bu, Xianlin Han, Junmin Peng, Na Zhao.
      The apolipoprotein E (APOE) gene is the strongest genetic risk factor for Alzheimer's disease (AD), influencing amyloid-β (Aβ) aggregation, clearance, and glial function. While APOE4 promotes Aβ pathology and APOE2 is protective, how these opposing alleles interact in the heterozygous APOE2/4 state remains unknown. Here, using littermate-controlled heterozygous APOE mice (APOE2/3, APOE3/4, and APOE2/4) alongside APOE3/3 controls crossed with 5xFAD mice, we show that APOE3/4 mice exhibit increased Aβ deposition, maladaptive microglial activation, and reduced microglial interactions with plaques. These changes were attenuated in APOE2/4 mice, accompanied by a brain proteomic profile more similar to those of APOE3/3 and APOE2/3 mice. Increased myelin basic protein (MBP) abundance was observed in APOE2/3 but not APOE2/4 mice. Plasma lipidomics revealed shared alterations in APOE3/4 and APOE2/4 mice, with distinct signatures in APOE2/3 mice. These findings define allele interaction-dependent effects of APOE on brain and systemic phenotypes and provide a framework for understanding the biological consequences of the APOE2/4 genotype.
    DOI:  https://doi.org/10.1038/s41467-026-78407-x
  3. Neuron. 2026 Nov 04. pii: S0896-6273(26)00777-4. [Epub ahead of print]
    P2RX7 drives inflammatory microglia and pathogenic extracellular vesicle secretion in tauopathy.
    Victor Bodart-Santos, Arun Reddy Ravula, Yang You, Mohammad Abdullah, Zhi Ruan, Justice G Ellison, Stephanie Radhakishun, Nibedita Basu Ray, Bridgette C Melvin, Aishe Kurti, Zhewei Liang, Yuta Sakai, Daniel R O'Brien, Son N Nguyen, Scott A Shaffer, Lindsey Fiddes, Oleg Butovsky, Wolfdieter Springer, Seiko Ikezu, Tsuneya Ikezu.
      P2X purinoreceptor 7 (P2RX7), an ATP-gated ion channel, contributes to Alzheimer's disease (AD) progression, but its molecular mechanisms remain unclear. Here, we show that genetic disruption of P2rx7 mitigates brain atrophy, tau accumulation, and cognitive impairment in PS19 mice. Microglia-specific, but not astrocyte-specific, deletion of P2rx7 suppresses tau propagation. Single-cell RNA sequencing identifies a previously unrecognized first-responding microglial state (FRM) with prominent P2rx7 expression. P2RX7 promotes the transition from FRM to an inflammatory microglial state enriched in extracellular vesicle (EV) biogenesis. P2RX7 increases EV loading of tau and of mitochondrial proteins and DNA, which activate cytosolic DNA sensing and interferon signaling in recipient microglia. Tau-containing microglial EVs disrupt neuronal endolysosomal integrity and facilitate endosomal tau escape and phosphorylation. Thus, P2RX7 regulates the FRM branch point, driving inflammatory microglial transition and EV-mediated spread of tau and toxic mitochondrial molecules and highlighting the P2RX7-EV axis as a therapeutic target in AD.
    Keywords:  Alzheimer’s disease; P2X7 purinergic receptor; extracellular vesicles; gene targeting; microglia; mitochondria; proteomics; tau; tauopathy; transcriptomics
    DOI:  https://doi.org/10.1016/j.neuron.2026.10.007
  4. Sci Adv. 2026 Nov 06. 12(45): eaeg3486
    Common transcriptional changes in the brain during hibernation and Alzheimer's disease.
    Pablo Largo-Barrientos, Roman Praschberger, Gonzalo León-Espinosa, Pieter-Jan Bultynck, Anastasia Mallopoulou, João F Machado, Suresh Poovathingal, Kristofer Davie, Patrik Verstreken.
      Hibernation demands rapid brain adaptations, involving cycles of reduced metabolic rate during torpor, followed by brief periods of arousal. Previous studies show hibernation induces a drastic increase in Tau hyperphosphorylation, but a mechanistic connection to disease remains unclear. Using single-nucleus RNA sequencing on hippocampi of golden hamsters, we unveil large transcriptional shifts across the hibernation cycle in all cell types, especially glia. Common transcriptional changes in mitochondrial and ribosomal genes are observed in all different cell types. In addition, hibernation triggers an inflammatory-like response in microglia that in part resembles cell states observed in Alzheimer's disease, but here in the absence of Aβ-accumulation and neurodegeneration. These findings reveal brain transformations that might help preserve vital functions under extreme conditions and they suggest that early cellular changes in AD may be a natural adaptive process.
    DOI:  https://doi.org/10.1126/sciadv.aeg3486
  5. Free Radic Biol Med. 2026 Nov 05. pii: S0891-5849(26)01232-3. [Epub ahead of print]
    Histone H3K18 lactylation drives microglial ferroptosis and exacerbates neuroinflammation in sepsis-associated encephalopathy.
    Lijun Meng, Deshan Yao, Sichuan Wang, Xingxing Yang, Kun Chen, Xingyi Wang, Fan Liu, Yucheng Li, Zhen Liu, Wenjie Yuan, Weili Liu, Kaizheng Gong.
      Elevated lactate levels are a significant biomarker of sepsis and are positively associated with sepsis-related mortality. Sepsis-associated encephalopathy (SAE) is independently associated with increased mortality in clinical sepsis patients. However, the underlying mechanisms of lactate's involvement in SAE remain unclear. In this study, we demonstrate that H3K18 lactylation (H3K18la) levels are upregulated in LPS-stimulated BV2 microglial cells and the hippocampus of LPS-injected mice. Pharmacological inhibition of H3K18la by sodium oxamate (OXA) or 2-deoxy-D-glucose (2-DG) effectively attenuates neuroinflammation and reduces neuronal death. Furthermore, CUT& Tag and RNA-seq results revealed that SLC7A11 as a direct downstream target of H3K18la, thereby promoting microglia ferroptosis and amplifying neuroinflammation. Overexpressing SLC7A11 in BV2 cells or microglia-specific overexpression of SLC7A11 in Cx3cr1Cremice can effectively suppress neuroinflammation, attenuate neuronal damage and alleviate cognitive impairments in SAE. Taken together, our findings elucidate the role of histone lactylation in SAE, and provide novel insights into potential therapeutic strategies for SAE.
    Keywords:  H3K18la; Histone lactylation; SLC7A11; Sepsis-associated encephalopathy; ferroptosis
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.10.041
  6. Clin Transl Med. 2026 Nov;pii: e70881. [Epub ahead of print]16(11):
    Regulatory role of TIPE2 by inhibiting microglial pyroptosis and glycolysis in the treatment of sepsis-associated encephalopathy.
    Min Yuan, Yunzhao Yang, Huifan Liu, Qian Kong, Guoqing Jing, Hailong Gong, Yuxuan Wang, Zhengyu Zhang, Wanhong Liu, Xuemin Song, Zhongyuan Xia, Xiaojing Wu.
       BACKGROUND: Sepsis_associated encephalopathy (SAE) denotes acute cerebral dysfunction triggered by sepsis and is accompanied by high mortality. Our previous study showed that TIPE2 significantly ameliorated cognitive impairment in SAE mice by inhibiting neuroinflammation, but the specific mechanism was unknown.
    METHODS: TIPE2 expression and cell specificity were analysed by scRNA‑seq and immunofluorescence. To establish SAE, cecal ligation and puncture (CLP) was carried out in TIPE2 knockout (KO) and WT mice. Neuronal/synaptic damage was assessed by TUNEL and TEM; cognitive function by behavioural tests and EEG. Hippocampal scRNA‑seq compared WT and TIPE2 KO mice. In vitro, primary microglia and BV2 cells were stimulated with LPS/nigericin. Protein expression (Western blot/IF), RhoA activation (GST‑pulldown), glucose/lactate levels, ROS production, and TIPE2‑RhoA interaction (Co‑IP/confocal) were examined.
    RESULTS: scRNA‑seq confirmed that TIPE2 is predominantly expressed in microglia and downregulated in SAE; its deficiency promotes pro‑inflammatory microglia associated with pyroptosis and glycolysis. TIPE2 KO significantly aggravated cognitive impairment, promoted M1 polarisation, enhanced pyroptosis (GSDMD cleavage, caspase‑1 activation), and increased ROS production. Mechanistically, TIPE2 directly bound to RhoA and inhibited its activation, thereby suppressing NLRP3‑mediated pyroptosis and glycolysis in microglia. Treatment with the RhoA‑specific inhibitor Rhosin reversed TIPE2 deficiency‑induced microglial polarisation, pyroptosis, ROS production, and glycolytic reprogramming, and also ameliorated cognitive dysfunction in TIPE2 KO mice.
    CONCLUSIONS: TIPE2 protects against SAE by directly interacting with RhoA, inhibiting its activation, and subsequently suppressing NLRP3‑mediated microglial pyroptosis and glycolysis.
    Keywords:  TIPE2; glycolysis; microglia; pyroptosis; sepsis‑associated encephalopathy
    DOI:  https://doi.org/10.1002/ctm2.70881
  7. Cell Rep. 2026 Nov 05. pii: S2211-1247(26)01334-3. [Epub ahead of print]45(11): 118255
    ApoE-dependent lipid handling by median eminence microglia supports myelin remodeling and metabolic function.
    Emily R McGrath, Andrew Folick, Luke J Morrissette, Stephen M Brown Mayfield, Hyehyun Kim, Li-Fang Weng, Vivian Pham, Sriya N Pillutla, Moon Kyung Choi, Connor Tomaka, Annika N Mechelke, Rachel T Cheang, William R Bolus, Anna Schwendeman, Vasilis Ntranos, Suneil K Koliwad, Martin Valdearcos.
      Microglia regulate hypothalamic control of systemic metabolism, but the mechanisms underlying their contribution remain unclear. Here, we identify apolipoprotein E (ApoE)-associated microglial transcriptional states enriched in the median eminence (ME), a brain region involved in sensing peripheral cues and metabolic regulation. These transcriptional states are characterized by programs related to lipid handling, interferon-associated responses, and cellular stress. Consumption of a Western diet (WD) increased microglial lipid accumulation and altered myelin remodeling within the ME, while expression of the human APOE4 isoform exacerbated these changes. Deletion of Apoe altered microglial responses to nutritional stress, supporting a role for ApoE in microglial lipid handling. Finally, activation of liver X receptor using synthetic high-density lipoprotein (sHDL) nanoparticles enhanced microglial lipid-handling programs, improved hypothalamic leptin responsiveness, reduced food intake, and limited weight gain in WD-fed mice. Together, these findings identify ApoE-dependent lipid handling as a key component of adaptive microglial responses to metabolic stress.
    Keywords:  CP: metabolism; CP: neuroscience; apolipoprotein E; hypothalamus; interferon signaling; lipid metabolism; liver X receptor; median eminence; microglia; myelin remodeling; neurovascular interface; nutritional stress
    DOI:  https://doi.org/10.1016/j.celrep.2026.118255
  8. Cell Biol Toxicol. 2026 Aug 05. pii: 130. [Epub ahead of print]42(1):
    PAR4 exacerbates intracerebral hemorrhage by driving m6A-dependent microglial AIM2 release and neuronal PANoptosis.
    Zhengyu Li, Bing Bao, Xinyu Yang, Jun Min, Zhiping Wu, Weiping Chen, Min Yin.
       BACKGROUND: Intracerebral hemorrhage (ICH) is a neurological disorder with high morbidity and mortality. PAR4 has been implicated in ICH and neuroinflammation.
    METHODS: The rat model of intracerebral hemorrhage (ICH) was established by injecting collagenase into the brain. TTC staining, H&E staining, and immunofluorescence were used to evaluate the brain tissue. In vitro, rat primary microglia (RPMCs) were isolated and the rat microglial cell line HAPI and the hippocampal neuronal cell line H19-7 were cultured. RNA-seq analysis, Western blot, co-immunoprecipitation, cell immunofluorescence, RIP assay, m6A Dot Blot Analysis were performed to investigate the role of PAR4 and its downstream signaling pathways.
    RESULTS: In the ICH rat model, treatment with the PAR4 antagonist inhibited neuronal death and reversed the M1-dominant shift of microglia. PAR4 regulated m6A methylation in microglia via KIAA1429-mediated recruitment of methyltransferase complexes. PAR4AP increased JAK2 mRNA m6A modification, mRNA and protein levels, and enhanced STAT3 protein phosphorylation. It also increased the expression of inflammatory factors and inflammasome components, with a stronger effect on AIM2 expression. PAR4AP enhanced AIM2 expression in microglial cells through mechanisms dependent on the JAK2/STAT3 signaling pathway and m6A modification. PAR4AP-activated microglia induce neuronal PANoptosis via exosome-mediated transfer of AIM2, promoting Pyrin-ZBP1 complex formation. In a rat model of ICH, lentivirus-delivered shRNAs targeting KIAA1429, FMR1, and AIM2, as well as PAR4 inhibition, suppressed PANoptosis in neuronal cells.
    CONCLUSION: This study provides insights into the role of PAR4 in ICH and its downstream signaling pathways, suggesting potential therapeutic targets for ICH treatment.
    Keywords:  Intracerebral hemorrhage; JAK2/STAT3 signaling; M6A methylation; Microglial polarization; PANoptosis; PAR4
    DOI:  https://doi.org/10.1007/s10565-026-10237-5
This page is being maintained by Thomas Krichel. It was last updated on 2026‒11‒08 at 9:44.