bims-micgli Biomed News
on Microglia
Issue of 2026–02–08
fourteen papers selected by
Matheus Garcia Fragas, Universidade de São Paulo
  1. Microglial C5aR1 defines a pathogenic inflammatory axis driving cerebral edema.
  2. Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism.
  3. Loss of TREM2 impairs microglial function and exacerbates retinal neurodegeneration in glaucoma.
  4. Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimer's disease.
  5. The immunoproteasome as a neuroimmune hub in the central nervous system: from proteostasis stress to inflammatory pathology.
  6. Plastic microglia.
  7. A HIF1A variant impacts long-term disability and smoldering inflammation in multiple sclerosis.
  8. Microglial Metabolic Reprogramming in Alzheimer's Disease: Pathways, Mechanisms, and Therapeutic Implications.
  9. The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits.
  10. Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.
  11. Microglia sense fungal infections through capsular components from capillary-bound Cryptococcus neoformans via endothelial nucleotide signaling.
  12. THIK-1 channel mediates microglial glucose sensing and modulates AgRP neurons.
  13. MerTK-triggered TGFβ1 autocrine signal regulates microglial response to neurodegeneration.
  14. Mitochondria at the membrane provide a route to inflammatory cell death.
  1. Neuron. 2026 Feb 04. pii: S0896-6273(25)00992-4. [Epub ahead of print]114(3): 378-380
    Microglial C5aR1 defines a pathogenic inflammatory axis driving cerebral edema.
    Amnah Al-Sayyar, Rejane Rua.
      Zhou et al.1 identify a C5aR1+ microglial subtype that amplifies neuroinflammation after traumatic brain injury and intracerebral hemorrhage. The mechanism reveals microglial-astrocyte-neutrophil crosstalk driving cerebral edema, highlighting C5aR1 as a therapeutic target and raising new questions about complement-glial interactions.
    DOI:  https://doi.org/10.1016/j.neuron.2025.12.036
  2. J Neuroinflammation. 2026 Jan 31.
    Clinically advanced NLRP3 inhibitor modulates microglial transcriptome and alleviates α-synuclein-induced progression of parkinsonism.
    Maria Luque, Magdalena Matic, Antonio Heras-Garvin, Jesus Amo-Aparicio, Kelvin C Luk, Michaela Tanja Haindl, Michael Khalil, Damaris B Skouras, Charles A Dinarello, Nadia Stefanova.
      
    Keywords:  Biomarker; Disease-associated microglia; Multiple system atrophy; NLRP3; Neuroinflammation; Parkinson’s disease; Therapy; Transcriptome; α-synuclein
    DOI:  https://doi.org/10.1186/s12974-026-03716-3
  3. Am J Pathol. 2026 Feb 03. pii: S0002-9440(26)00034-9. [Epub ahead of print]
    Loss of TREM2 impairs microglial function and exacerbates retinal neurodegeneration in glaucoma.
    Gong Chen, Zhiruo Wang, Cong Zhao, Chun Wang, Yunping Li, Jingming Shi, Guochun Chen, Huihui Chen.
      Glaucoma is a leading cause of irreversible blindness, characterized by retinal ganglion cell (RGC) degeneration and neuroinflammation. Retinal microglia are key modulators of this pathology. Using single-cell transcriptomic analysis of human glaucomatous retinas, we identified a distinct population of disease-associated microglia (DAM), defined by elevated TREM2 and other neurodegeneration-related genes. DAM exhibited enriched transcriptional programs associated with phagocytosis, antigen presentation, and immune regulation, with TREM2high microglia predominating. In a mouse model of retinal ischemia-reperfusion (IR) injury, Trem2 knockout (Trem2-/-) mice exhibited exacerbated retinal neurodegeneration and neuroinflammation, impaired microglial phagocytosis and antigen presentation relative to WT controls. Furthermore, Trem2-/- microglia failed to acquire a DAM-like or anti-inflammatory (M2) phenotype, instead adopting a pro-inflammatory (M1)-skewed state. Flow cytometry and immunofluorescence analyses of cervical lymph nodes revealed increased frequencies of CD8+ T cells and CD19+ B cells, along with a reduction in FOXP3+ regulatory T cells (Tregs) in Trem2-/- mice. CD8+ T cells displayed heightened proliferation and diminished exhaustion, indicating sustained effector function. Transcriptomic profiling further confirmed enhanced lymphocyte activation, inflammasome signaling, and suppression of immunoregulatory pathways, including TGF-β and IL-2 signaling critical for Treg induction. Collectively, these findings establish TREM2 as a central regulator of disease-associated microglial activation and immune homeostasis in glaucoma. Loss of TREM2 compromises both innate and adaptive immune regulation, leading to sustained inflammation and exacerbated retinal neurodegeneration.
    Keywords:  Disease-associated microglia; Glaucoma; Immune homeostasis; Neuroinflammation; Regulatory T cells; TREM2
    DOI:  https://doi.org/10.1016/j.ajpath.2026.01.009
  4. Alzheimers Dement. 2026 Feb;22(2): e71083
    Reduced triacylglycerols and lipid droplets are associated with resilience to Alzheimer's disease.
    Daan van der Vliet, Luuk E de Vries, Xinyu Di, Dennis Wever, Brechtje de Jong, Marc T C van der Meij, Marielle van der Peet, Amy C Harms, Thomas Hankemeier, Dick F Swaab, Inge Huitinga, Joost Verhaagen, Mario van der Stelt.
       INTRODUCTION: Although it has become clear that alterations in lipid metabolism are associated with Alzheimer's disease (AD), it is unclear how they contribute to both cognitive decline and the pathophysiology of AD.
    METHODS: Lipidomics and activity-based protein profiling (ABPP) were performed in the frontal cortex of control, AD and resilient donors, that is, individuals with AD pathology without cognitive decline.
    RESULTS: The most pronounced alterations in lipids were in ω6-derived oxylipins, which were particularly increased in AD. Triacylglycerols (TAGs) and lipid droplets (LDs) were more abundant in the AD donors compared to the resilient donors. Multi-omics factor analysis (MOFA) showed that increased ω6-derived oxylipins and the loss of inhibitory neurons were associated with amyloid beta (Aβ) plaque load.
    DISCUSSION: Our multi-omics data show a molecular response associated with Aβ load shared among AD and resilient donors, but reduced LDs in resilient donors compared to AD.
    HIGHLIGHTS: Comprehensive lipidomics analysis of frontal cortex from controls, Alzheimer's disease (AD) patients and resilient individuals. ω6 Oxylipins, markers of neuroinflammation, are increased in both AD and resilience. Resilient donors have reduced triacylglycerols and lipid droplets compared to AD. Multi-omics integration shows a molecular response to amyloid beta plaques associated with ω6-derived oxylipins and loss of interneurons.
    Keywords:  Alzheimer's disease; lipid droplets; lipid metabolism; neuroinflammation; resilience
    DOI:  https://doi.org/10.1002/alz.71083
  5. J Neuroinflammation. 2026 Feb 05.
    The immunoproteasome as a neuroimmune hub in the central nervous system: from proteostasis stress to inflammatory pathology.
    Huiying Zhao, Yuexian Liu, Xingyong Chen.
      
    Keywords:  CNS; IP; Neuroinflammation; The ubiquitin proteasome system; Therapeutic target
    DOI:  https://doi.org/10.1186/s12974-026-03709-2
  6. Nat Immunol. 2026 Feb;27(2): 169
    Plastic microglia.
    Ioana Staicu.
      
    DOI:  https://doi.org/10.1038/s41590-026-02424-7
  7. Acta Neuropathol. 2026 Feb 04. 151(1): 12
    A HIF1A variant impacts long-term disability and smoldering inflammation in multiple sclerosis.
    Antonino Giordano, Pernilla Stridh, Paolo Preziosa, Marco Pisa, Celia Lerma-Martin, Melissa Sorosina, Elisabetta Mascia, Silvia Santoro, Kaalindi Misra, Ferdinando Clarelli, Laura Ferrè, Maria Needhamsen, Ali Manouchehrinia, Matteo Missaglia, Thomas Moridi, Klementy Shchetynsky, Russell Ouellette, Adil Harroud, Elisabeth de Vries, Subita Balaram Kuttikkatte, Fredrik Piehl, Lars Alfredsson, Jan Hillert, Tomas Olsson, Lars Fugger, Kathrine Attfield, Tobias Granberg, Lucas Schirmer, Martina Absinta, Maja Jagodic, Gabriele Carmine DeLuca, Maria A Rocca, Massimo Filippi, Ingrid Kockum, Federica Esposito.
      Multiple sclerosis (MS) shows a highly heterogeneous course, with some patients accumulating severe disability early while others remain relatively preserved even after decades. A key driver of disability progression is smoldering inflammation, a chronic, compartmentalized immune process at the edge of chronic active lesions. However, the factors driving smoldering inflammation in MS remain incompletely understood. We investigated the role of genetic variation in smoldering inflammation-related genes across two independent MS cohorts, using a discovery-replication design in a total of 2,817 patients. We identified a locus in the HIF1A (Hypoxia-Inducible Factor 1-alpha) gene that is associated with a more favorable disease course at over 20 years from disease onset. Using additional independent cohorts, we found that carriers of the HIF1A protective allele exhibited lower paramagnetic rim lesion volume on MRI, lower plasma and cerebrospinal fluid neurofilament levels, and reduced microglial/macrophage inflammation with less axonal injury in post-mortem progressive MS tissue. By integrating single-nucleus RNA sequencing and spatial transcriptomics, we showed that the HIF1A variant dynamically modulates gene expression in a cell-type specific and context-dependent manner in the MS brain. Collectively, these findings highlight a protective HIF1A variant associated with a more favourable long-term disease course and reduced smoldering inflammation, opening new avenues to translate this genetic discovery into new potential strategies to tackle disease progression.
    Keywords:  Disability; Hypoxia; Multiple sclerosis; Paramagnetic rim lesions; Progression; Smoldering inflammation
    DOI:  https://doi.org/10.1007/s00401-026-02984-w
  8. Ageing Res Rev. 2026 Feb 04. pii: S1568-1637(26)00042-5. [Epub ahead of print] 103050
    Microglial Metabolic Reprogramming in Alzheimer's Disease: Pathways, Mechanisms, and Therapeutic Implications.
    Feng-Ge Yang, He Yang, Sheng-Wang Han, Jun-Ting Wang, Wei Gao, Qiu-Yan Ye, Miao-Miao Zhang, Yu Yang, Hong-Lin Li.
      In recent years, the immune metabolism of central nervous system cells has gained increasing attention from researchers. Microglia (MG) are innate immune cells of the central nervous system. They can metabolize a wide range of energy substrates. The pathways and products generated through these processes play a critical role in the onset and progression of Alzheimer's disease (AD). This paper provides a comprehensive review of metabolic reprogramming in MG during AD. It focuses on the three primary energy substrates: glucose, fatty acids, and amino acids. It delves deeply into the molecular signaling pathways that regulate this reprogramming, including TREM2, PI3K-AKT-mTOR, HIF-1α, AMPK, PPARs, and LXRs. Additionally, the paper explores the potential of metabolomics as a tool for early diagnosis of AD, identifying biomarkers that could enhance detection in its early stages. Therapeutic strategies targeting the regulation of microglial phagocytic function, mitochondrial activity, and glycolysis are also examined, highlighting their potential to alleviate disease progression. This review article aims to uncover the dynamic network of microglial metabolic reprogramming. It also explores its causal relationship with the pathological cascade of AD. The findings provide theoretical support for developing innovative drugs that combine metabolic regulation and neuroprotective functions.
    Keywords:  Alzheimer's disease; Biomarkers; Drug targets; Metabolic reprogramming; Microglia; Signaling pathways
    DOI:  https://doi.org/10.1016/j.arr.2026.103050
  9. bioRxiv. 2026 Jan 23. pii: 2026.01.21.700784. [Epub ahead of print]
    The loss of Tau in the adult brain triggers neuroplastic, epigenetic and behavioral deficits.
    Joana Margarida Silva, Shibojyoti Lahiri, Daniela Monteiro-Fernandes, Carina Soares-Cunha, Victor Solis-Mezarino, Moritz Volker-Albert, Georgia Papadimitrou, Patrícia Gomes, Carlos Marques, Bárbara Coimbra, Inês Caetano Campos, Martina Samiotaki, George Panayotou, Nikolaos Kokras, Christina Dalla, Benjamin Wolozin, João Filipe Oliveira, Jose Francisco Abisambra, Axel Ihnof, Ana João Rodrigues, Nuno Sousa, Ioannis Sotiropoulos.
       INTRODUCTION: Accumulation of pathological Tau precipitates neuronal malfunction in Alzheimer's disease (AD). However, the impact of loss of normal Tau function in the adult brain, independently of Tau aggregates, remains unclarified.
    METHODS: We used a mouse model with conditional mapt knocking-down in forebrain of 5-7 months old animals (cTau-KO), a virus-driven selective Tau knockdown in wild-types (WT) and Tau re-expression approaches, accompanied by neurostructural, epigenetic, proteomic, electrophysiological, neurochemical and behavioral analyses.
    RESULTS: Loss of Tau in the adult brain of cTau-KOs triggers neuronal atrophy and malfunction, epigenetic as well cognitive and mood deficits. Importantly, these perturbations were confirmed by selective Tau loss in WT adult brain and reverted by Tau re-expression or pharmacologically-induced epigenetic correction in cTau-KOs.
    DISCUSSION: Our findings highlight the contribution of loss of normal Tau function in the adult brain malfunction that could be relevant in diverse brain pathologies beyond AD, associated to Tau and its dysfunction.
    DOI:  https://doi.org/10.64898/2026.01.21.700784
  10. medRxiv. 2026 Jan 28. pii: 2026.01.26.26344888. [Epub ahead of print]
    Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.
    Marc Carceles-Cordon, Eliza M Brody, Masen L Boucher, Michael D Gallagher, Robert T Skrinak, Travis L Unger, Cooper K Penner, Adama J Berndt, Sromona Das, Katie Lam, Rudolf Jaenisch, Vivianna Van Deerlin, Edward B Lee, Kurt Brunden, Kelvin Luk, Alice S Chen-Plotkin.
      Glycoprotein nonmetastatic melanoma B (GPNMB), encoded by the target gene ( GPNMB ) of a Parkinson's disease (PD) risk locus, acts as a secreted factor mediating inflammatory effects in the context of immunity and cancer. In a neurodegenerative disease context, GPNMB is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein that misfolds and accumulates in PD. Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB, shed into conditioned medium or added as recombinant protein, enables uptake of aSyn fibrils in a non-cell-autonomous manner. In human postmortem brain, GPNMB is widely expressed in neurons and microglia, with increased microglial expression in the setting of neurodegenerative disease. In microglial cell lines and induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increases with exposure to apoptotic neurons. In the aSyn-fibril seeded model of PD, iMicroglia-derived GPNMB allows for development of aSyn pathology in GPNMB knockout neurons, while conditioned medium from GPNMB knockout iMicroglia lacks this effect. Conversely, treatment with anti-GPNMB antibodies rescues neurons from development of aSyn pathology in this model. Finally, in 1675 human postmortem cases, GPNMB genotypes conferring higher GPNMB expression associate with more widespread aSyn pathology, without affecting beta-amyloid or tau pathology. Taken together, our data suggest a positive feedback model, where neuronal death triggers increased GPNMB expression and secretion by microglia, leading to increased uptake of pathological forms of aSyn by neurons, leading to more neuronal death. Importantly, this cycle can be interrupted by anti-GPNMB antibodies, offering an avenue for therapeutic development.
    One Sentence Summary: The extracellular domain of GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.
    Highlights: The extracellular domain of GPNMB confers capacity for uptake of alpha-synuclein fibrils to iPSC-derived neurons (iNeurons) lacking GPNMB expression. GPNMB is widely expressed in neurons and microglia in human brain, with more expression in microglia, particularly in Parkinson's disease brain.iPSC-derived microglia (iMicroglia) secrete GPNMB in response to neurodegeneration-related insults, and iMicroglia-derived GPNMB enhances development of alpha-synuclein pathology in iNeurons.Anti-GPNMB antibodies rescue iNeurons from development of synuclein pathology. Expression quantitative trait loci (eQTLs) for GPNMB associate with extent of alpha-synuclein pathology in human neurodegenerative disease.
    DOI:  https://doi.org/10.64898/2026.01.26.26344888
  11. PLoS Biol. 2026 Feb 06. 24(2): e3003642
    Microglia sense fungal infections through capsular components from capillary-bound Cryptococcus neoformans via endothelial nucleotide signaling.
    Chenxu Feng, Ge Wang, Yixuan Wang, Xiang Gao, Zhenqi Xu, Luyao Fang, Ziyi Ma, Suwei Zheng, Yuyan Xie, Yufeng Chu, Mei Meng, Angela Yang, Miriam Lu, Judd Denzel Garcia Mondina, Weiwei Zhu, Lisheng Zhang, Linqi Wang, Zongyan Chen, Donglei Sun.
      Macrophages are essential for host defense, yet how parenchyma-residing macrophages detect pathogens without direct contact remains unclear. Cryptococcus neoformans is an encapsulated fungal pathogen that infects the brain. Using in situ imaging of mouse model, we showed that brain-resident microglia vigilantly detect capillary-residing C. neoformans prior to its blood-brain barrier transmigration, but are less responsive to nonencapsulated fungi or parenchyma-injected C. neoformans. Microglia migrate to and enwrap leaky capillaries harboring fungi, leading to fungal uptake but not clearance, instead promoting fungal growth. Microglial response is triggered by released capsule components, rather than the assembled capsule. In particular, glucuronoxylomannan (GXM) plays a critical role by activating endothelial cells to release nucleotides which act on microglia P2Y12. Our findings revealed a novel paradigm by which microglia detect pathogens without direct contact, offering new insights for microglia-directed antifungal therapies.
    DOI:  https://doi.org/10.1371/journal.pbio.3003642
  12. bioRxiv. 2026 Jan 16. pii: 2026.01.15.699765. [Epub ahead of print]
    THIK-1 channel mediates microglial glucose sensing and modulates AgRP neurons.
    Qingzhuo Liu, Jonathan C Bean, Jinjing Jian, Tong Zhou, Yuxue Yang, Meixin Sun, Yongxiang Li, Kristine M Conde, Mengjie Wang, Yue Deng, Jiamin Qiu, Fuhui Wang, Xinming Liu, Yutian Liu, Jingjing Cheng, Xi Wu, Lamei Xue, Chunling Chen, Chenling Meng, Yi Zhu, Yongjie Yang, Longlong Tu, Hailan Liu, Yong Xu.
      Microglia play essential roles in maintaining energy homeostasis, and their dysfunction contributes to metabolic disease. Although high-fat diet (HFD) exposure induces microglial activation, the underlying mechanisms remain poorly defined. Here, we identified a previously unrecognized role for THIK-1 channel in mediating glucose sensing of microglia in arcuate nucleus of the hypothalamus (ARH), during HFD-induced obesity. Pharmacological inhibition of THIK-1 channel with tetrapentylammonium (TPA) suppresses feeding and attenuates body-weight gain in diet induced obese mice. Mechanistically, inhibition of agouti-related peptide (AgRP) neurons is indispensable for TPA-induced hypophagia. Moreover, THIK-1 inhibition promotes microglial phagocytosis of perineuronal nets (PNNs), leading to reduced AgRP neuronal activity and feeding suppression. Together, these findings establish THIK-1 as a critical glucose sensor in hypothalamic microglia and uncover a microglia-dependent pathway through which overnutrition modulates AgRP neuronal activity via PNN remodeling to regulate energy balance, highlighting THIK-1 as a potential therapeutic target for treatment of diet-induced obesity.
    DOI:  https://doi.org/10.64898/2026.01.15.699765
  13. Nat Commun. 2026 Feb 03.
    MerTK-triggered TGFβ1 autocrine signal regulates microglial response to neurodegeneration.
    Yingying Huang, Zhangyuzi Deng, Zhijie Zhou, Koukou Fu, Fuhai Liu, Haoyue Zhang, Jian Chen, Jing Yang, Ying Cao.
      Microglial phagocytosis exerts essential roles in neurodegeneration, but how phagocytic processes may reciprocally regulate microglia remains incompletely understood. Here, we report that microglial response in the mouse model of pathological axonal degeneration depends on the phagocytic receptor MerTK. The MerTK-triggered downstream phospholipase C signal is sufficient to induce the up-regulation of PU.1 and IRF8, the two central transcription factors governing microglial functions. Chromatin immunoprecipitation-sequencing analyses identify that PU.1 and IRF8 directly target the gene locus of TGFβ1, and disruption of this PU.1-IRF8 targeting site abolishes the induction of microglial TGFβ1 during neurodegeneration. Of importance, neurodegeneration-induced TGFβ1 acts in an autocrine manner, and the microglia-specific deletion of TGFβ1 or its receptors TGFβR1 or TGFβR2 blocks microglial response. Moreover, microglial TGFβ1 autocrine signaling similarly occurs in the 5×FAD mouse model of Alzheimer's disease and in human patients. These results have delineated an important mechanism underlying microglial response to neurodegeneration.
    DOI:  https://doi.org/10.1038/s41467-026-69189-3
  14. Cell Metab. 2026 Feb 03. pii: S1550-4131(25)00550-9. [Epub ahead of print]38(2): 260-262
    Mitochondria at the membrane provide a route to inflammatory cell death.
    Zezhao Chen, Daichao Xu.
      In a recent issue of Cell, Wang et al. identify "mitoxyperilysis," a previously unknown lytic cell death pathway where combined innate immune and metabolic stress triggers prolonged mitochondria-plasma membrane contact, causing local oxidative damage and membrane rupture. This mTORC2-regulated process identifies a therapeutic axis for inflammatory diseases and cancer.
    DOI:  https://doi.org/10.1016/j.cmet.2025.12.019
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