bims-microg 2026-09-06 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–09–06
eighteen papers selected by
Marcus Karlstetter, Universität zu Köln

Somatic mutations reveal the ontogeny of microglia in human ageing.
Photo-Driven Asymmetric Nanopore Electrode Enables Endogenous ROS Monitoring in Single Neuroimmune Cells.
Neonatal inflammation disrupts a temporally restricted postnatal Numb-enriched microglial state in mice.
Longitudinal analysis reveals myeloid cell contributions to murine neuroPASC pathogenesis.
Activation of transposable elements is linked to a region- and cell type-specific interferon response in Parkinson's disease.
Cancer-intrinsic SIRPα Signaling Triggers Mitochondrial Fission and Immune Tolerance to Promote TNBC Breast-to-Brain Metastasis.
Targeting microglial glutaminase 1 protects against ferroptosis-driven cognitive impairment in perioperative neurocognitive disorders.
Spatial synaptic pruning mechanism of NAC microglia in differential regulation of PTSD- and depression-like behaviors.
APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.
Effect of MALT1 inhibition by MI‑2 on the microglial phenotype switch, inflammatory cytokine secretion, neuronal loss and oxidative stress in Alzheimer's disease.
SIRT1 deacetylates GAPDH to drive microglial glycolysis and neuroinflammation.
LILRB4 Attenuates Ischemic Brain Injury by Inhibiting Microglial Necroptosis via a RIPK3-Dependent Mechanism.
Single-cell multiome landscape reveals elovanoid-mediated suppression of inflammatory glial states and induction of homeostatic signaling after ischemic stroke.
miR-124 alleviates behavioral deficits via inhibiting hippocampal microglial pyroptosis by targeting P2X7R in PTSD model rats.
Protective effect of miR-642b-3p against brain injury after intracerebral hemorrhage by targeting SERPINE1.
sAPPα acts as an endogenous ligand for TREM2 to regulate microglial survival and inflammatory responses in Alzheimer's disease.
Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.
Regulators of interferon-responsive microglia uncovered by Genome-wide CRISPRi screening.

Nature. 2026 Jul 30.

Somatic mutations reveal the ontogeny of microglia in human ageing.

Julia A Belk, Yaowen Zhang, Emily E Reilly, Quanming Shi, Daniel Dan Liu, Nicole Womack-Gambrel, Maarten van der Linde, Lisa Ma, Debasmita Paul, Alejandro Medina Enciso, Raja Kalluru, Jacob Weiss, Rui Li, Anna E Eastman, Chunfang Zhu, Arnav Chakravarthy, Syed Bukhari, Dipabarna Bhattacharya, Suyash Raj, Daniel Richard, Simone Brioschi, Matthew R Chrostek, Daniel C Nachun, Christopher M Arends, Jayakrishnan Gopakumar, Isak W Tengesdal, Ademar Bynum, Shaneice Mitchell, Katalin Sandor, Wenxi Zhang, Badri N Vardarajan, Inma Cobos, Donald E Born, Robert B West, Anne Brunet, Marco Colonna, Krishna L Bharani, Hannes Vogel, Thomas J Montine, Caitlin S Latimer, Irving L Weissman, Magdalena Matusiak, Jody E Hooper, C Dirk Keene, Howard Y Chang, Siddhartha Jaiswal.

Microglia are the resident macrophages of the central nervous system1. In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult haematopoiesis2-4. The origins of human microglia are less clear, but recent evidence suggests that bone-marrow-derived cells contribute to the human microglial pool in certain individuals5-9. Here, to investigate the ontogeny of human microglia, we develop an approach that uses the collection of accumulated somatic mutations that uniquely labels each clone of cells to track the infiltration of bone-marrow-derived cells into the human brain. Applying this approach to 20 older individuals, we find evidence of an influx of bone-marrow-derived cells into the brain in all examined individuals. Single-cell analysis, including single-cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are similar to microglia and can comprise a large fraction of the microglial pool. Analysis of human cohort data demonstrates a protective association between most types of clonal haematopoiesis and Alzheimer's disease. Together, we identify a widespread influx of myeloid cells into the healthy human brain that contributes to the pool of human microglia and becomes common with ageing.

DOI: https://doi.org/10.1038/s41586-026-10939-0
Angew Chem Int Ed Engl. 2026 Aug 31. e7149031

Photo-Driven Asymmetric Nanopore Electrode Enables Endogenous ROS Monitoring in Single Neuroimmune Cells.

Hui-Jun Wei, Chen-Xi Zhang, Ke-Le Chen, Ting-Jing Huang, Yi-Lun Ying, Yi-Tao Long.

  Reactive oxygen species (ROS) play central roles in neuroinflammatory signaling and neuroimmune function. However, quantitative detection of ROS in living neuroimmune cells remains challenging due to their low abundance and high sensitivity to electrical and chemical perturbations. While conventional nanoelectrodes can monitor ROS in cancer cells and macrophages, they require high operation potentials that may disrupt membrane integrity and redox homeostasis, limiting their use in sensitive neuroimmune cells. Here, we report a photo-driven asymmetric nanopore electrode (PNE) that enables zero-bias (0 mV) detection of intracellular H2O2. By integrating photo-responsive g-C3N4 quantum dots within an asymmetric quartz nanopipette, pulsed light excitation generates an ionic photocurrent that decreases quantitatively with increasing H2O2 concentration. The PNE delivers a linear detection range from 10 nM to 5 µM with a detection limit down to 10 nM. Further cellular imaging characterization confirms that this platform minimizes cellular perturbation, enabling in situ monitoring of intracellular H2O2 dynamics in single microglial cells under oxidative stress stimulation. By virtue of this minimal perturbation, this study represents the first real-time observation of a concentration-dependent transition in ROS scavenging dynamics in single microglial cells, providing a previously inaccessible view of neuroinflammatory redox regulation under undisturbed physiological conditions.

Keywords:  ROS; nanoelectrode; nanopore; photo‐driven; single microglial cell

DOI:  https://doi.org/10.1002/anie.7149031
Nat Commun. 2026 08 04. pii: 9385. [Epub ahead of print]17(1):

Neonatal inflammation disrupts a temporally restricted postnatal Numb-enriched microglial state in mice.

Jinjin Zhu, Yiran Xu, Liubo Sun, Ziwei Huang, Wenkai Yu, Shan Zhang, Xiaoli Zhang, Tiantian He, Yiwen Chen, Yanan Wu, Bingbing Li, Huifang Dong, Xiaoyang Wang, Changlian Zhu.

Early-life microglia are diverse and support brain development beyond immune surveillance, but the transient states associated with postnatal maturation remain poorly understood. Here we show, using a time-resolved single-cell atlas of neonatal mouse brain immune cells, that a postnatal Numb-enriched microglial state emerges during early postnatal development, expands during the second postnatal week and subsequently declines. This state is characterized by neurodevelopment-related gene expression programs and distinct metabolic features. Trajectory inference, cross-atlas mapping and RNAscope validation support its temporal pattern. During the period when this state expands, microglial depletion preserves gross myelination but alters synaptic protein composition and disrupts dendritic and cortical layer maturation, particularly in the primary somatosensory cortex. Neonatal lipopolysaccharide challenge impairs the establishment of the Numb-enriched state and induces an early glycolytic response followed by recovery-phase inflammatory states. These findings identify a developmentally timed microglial state associated with cortical maturation and vulnerable to neonatal inflammation in mice.

DOI: https://doi.org/10.1038/s41467-026-76341-6
Nat Commun. 2026 07 30. pii: 9259. [Epub ahead of print]17(1):

Longitudinal analysis reveals myeloid cell contributions to murine neuroPASC pathogenesis.

Lu Tan, Abhishek K Verma, Shea Lowery, Andrew Thurman, Alan Sariol, Cori Fain, Zhaoyuan Liu, Florent Ginhoux, John Harty, David K Meyerholz, Stanley Perlman.

Neurological and neuropsychiatric symptoms, collectively termed neuroPASC, are among the most prevalent Post-Acute Sequelae of COVID-19 (PASC). Neuroinflammation - particularly microglia reactivity - has been implicated in neuroPASC. We previously established a PASC model in which SARS-CoV-2-infected mice developed persistent behavior alterations and prolonged neuroinflammation for up to 120 days post-infection (dpi). Here, we extend these results to a longitudinal single-cell RNA sequencing analysis of brain immune cells collected at 0, 6, 30, and 100 dpi. We identify a coordinated contribution of infiltrating and resident myeloid cells to the initiation and persistence of neuroinflammation. In specific, microglia display sustained expansion of subclusters characterized by inflammatory, stress response, and metabolic signatures. Border-associated macrophages upregulate monocyte attractants during acute infection. Concurrently, peripherally derived monocytes and neutrophils mount transient inflammatory responses, potentially triggering long-term microglial reactivity. Together, these findings provide a high-resolution atlas of brain myeloid immune dynamics during neuroPASC and highlight a central role for microglia in sustaining chronic neuroinflammation.

DOI: https://doi.org/10.1038/s41467-026-76156-5
Sci Adv. 2026 Sep 04. 12(36): eaed2952

Activation of transposable elements is linked to a region- and cell type-specific interferon response in Parkinson's disease.

Raquel Garza, Anita Adami, Arun Thiruvalluvan, Sasvi Wijesinghe, Annabel Curle, Oliver Tam, Talitha Forcier, Danai A Lagka, Nina L Kazakou, Diahann A M Atacho, Yogita Sharma, Vivien Horvath, Sara Bermudez, Jenny Johansson, Daniel B Rainbow, Laura Castilla-Vallmanya, Joanne L Jones, Annelies Quaegebeur, Molly Gale Hammell, Agnete Kirkeby, Roger A Barker, Johan Jakobsson.

Parkinson's disease (PD) is a neurodegenerative disorder involving a neuroinflammatory response, the cause of which remains unclear. Transposable elements (TEs) have been linked to inflammation, but their potential role in PD remains unexplored. Using bulk- and single-nuclei RNA-seq of postmortem brain tissue from four brain regions, we studied TE transcription and its correlation with PD neuroinflammation. Over a thousand TEs, including LINE-1 s and ERVs, were expressed in a cell type- and region-specific manner in the human brain. Increased TE expression was found in microglia and neurons in the substantia nigra and putamen of PD brains, but not amygdala or prefrontal cortex, compared to controls. This TE activation correlated with an innate immune response in the same brain regions. The link between an interferon response and TE activation was mechanistically confirmed using human pluripotent stem cell-derived microglia and neurons. Our findings provide insights into TE transcription in the PD brain and suggest that TEs may contribute to neuroinflammation and pathological progression in PD.

DOI: https://doi.org/10.1126/sciadv.aed2952
Neuro Oncol. 2026 Aug 31. pii: noag202. [Epub ahead of print]

Cancer-intrinsic SIRPα Signaling Triggers Mitochondrial Fission and Immune Tolerance to Promote TNBC Breast-to-Brain Metastasis.

Yu-Ting Tsai, Jessica D Mackert, Adam Wilson, Mitra Kooshki, Valerie Payne, Jamie J Sagastume, Ashley Szymonski, Brian Westwood, Lance D Miller, Pierre L Triozzi, Dawen Zhao, Linda Metheny-Barlow, Masaki Terabe, Katherine L Cook, Glenn J Lesser, David R Soto-Pantoja.

   BACKGROUND: Triple negative breast cancer (require) new treatment strategies due to poor responses to current therapies. While myeloid SIRPα mediates immunosuppression, its cancer intrinsic role remains poorly understood.
METHODS: Human breast cancer scRNAseq profiles were used to examine SIRPα expression across different cell populations and subtypes. TNBC brain-tropic cells were injected into the mouse mammary fat pad for the orthotopic tumor model, and intracardiac-injected for brain metastasis models. Bulk RNA sequencing was used to determine SIRPα-regulated pathway. Stably SIRPα overexpressed and knockout TNBC cell lines were established to determine SIRPα intracellular regulation. Digital spatial profiling was utilized to investigate the orthotopic and brain metastasis tumor immune microenvironment.
RESULTS: Human single-cell data showed that SIRPα levels increased in malignant TNBC epithelial cells. We observed that SIRPα is upregulated in patient breast-to-brain metastatic lesions. SIRPα is overexpressed in TNBC brain-tropic cells compared to parental cells. Bulk RNA-Seq showed that targeting SIRPα affects genes involved in mitochondrial dynamics, and that SIRPα upregulates mitochondrial fission and induces metastasis through the SHP2/Erk/Drp1 signaling pathway. In vivo, overexpression of SIRPα in cancer cells significantly increases TNBC systemic metastasis. Next, spatial proteomics revealed changes in the immune microenvironment associated with the SIRPα-regulated ECM protein fibronectin. Fibronectin induces microglial tolerance by impairing inflammatory signaling and metabolic reprogramming, allowing cancer to escape microglial immunosurveillance. Most importantly, SIRPα inhibition reduced TNBC brain metastatic lesions in mouse metastasis models.
CONCLUSION: : Cancer-intrinsic SIRPα promotes TNBC brain metastasis through increased mitochondria fission and triggering microglia tolerance, and targeting SIRPα reduces brain metastasis.

Keywords:  TNBC brain metastasis; cancer-intrinsic SIRPα; microglia tolerance; mitochondria fission

DOI:  https://doi.org/10.1093/neuonc/noag202
Cell Death Differ. 2026 Sep 01.

Targeting microglial glutaminase 1 protects against ferroptosis-driven cognitive impairment in perioperative neurocognitive disorders.

Yiyan Sun, Yun Li, Fengping Zhang, Zhongli Wan, Xiaoming Zhang, Ping Xu, Yi Wang, Congcong Li, Yuanyuan Zuo, Jiehui Liu, Ying Wu, Changqi Chen, Xuanran Feng, Xiaohuan Xia, Jialin C Zheng, Jianhui Liu.

Perioperative neurocognitive disorders (PND) are common neurological complications in elderly surgical patients, for which effective mechanism-based therapies remain lacking. This study identifies ferroptosis, an iron-dependent lipid peroxidation-driven cell death, as a key pathological process in PND, and pharmacological inhibition of ferroptosis with ferrostatin-1 significantly ameliorated cognitive deficits in a surgery and anesthesia-induced mouse model of PND. Moreover, accumulation of glutamate has been observed in the brains of PND mice, which competitively inhibits the neuronal cystine/glutamate antiporter system Xc- (via SLC7A11) to trigger glutathione depletion and ferroptotic cell death. Excessive glutamate production and release are driven by hyperexpression of glutamate-producing enzyme glutaminase 1 (GLS1) in activated microglia via STAT1-dependent transcriptional activation. Pharmacological inhibition of GLS1 with the selective inhibitors CB839 and BPTES suppressed ferroptosis, preserved synaptic plasticity, and improved cognitive performance in PND mice, indicating GLS1 as a potential therapeutic target of PND. Notably, elevated plasma GLS1 levels in PND patients correlated negatively with cognitive test scores (R2 = 0.479, p < 0.001) and exhibited moderate diagnostic value across two independent cohorts (AUCs = 0.77 and 0.84), underscoring its clinical relevance as a potential biomarker. Collectively, our findings establish microglial GLS1 as a critical mediator of ferroptosis in PND and highlight its dual promise as a therapeutic target and diagnostic indicator.

DOI: https://doi.org/10.1038/s41418-026-01833-3
Brain Behav Immun. 2026 Aug 30. pii: S0889-1591(26)00733-6. [Epub ahead of print] 106985

Spatial synaptic pruning mechanism of NAC microglia in differential regulation of PTSD- and depression-like behaviors.

Mingyue Zhao, Wenyu Tian, Xinyu Hu, Jiajie Dai, Haimou Ye, Linan Zhuo, Wei Zhang, Hang Xu, Jiesi Wang, Xingshun Xu, Weiwen Wang.

   BACKGROUND AND AIMS: Post-traumatic stress disorder (PTSD) comorbid with depression is a prevalent, treatment-refractory clinical syndrome. Emerging evidence indicates shared microglial alterations in PTSD and depression, suggesting it may represent a common pathological substrate. However, the underlying neuroimmune mechanisms remain unclear.
METHODS: PTSD- and depression-like behaviors were induced in rats by using single prolonged stress combined with foot shock (SPS&S). Cellular activity, spatial distribution, and morphology were assessed using qPCR, immunofluorescence, and Golgi-Cox staining. Microglial activity was inhibited using clodronate liposomes (CDSlip) and minocycline. Bulk RNA sequencing was performed to profile neuroimmune-related signaling molecules.
RESULTS: Stress induced PTSD- and depression-like behaviors, accompanied by region-specific enhanced microglial activity in the anterior-medial NAC core (amNACc) and lateral NAC shell (LNACsh). Selective depletion of microglia in amNACc and LNACsh via CDSlip specifically alleviated stress induced PTSD- and depression-like behaviors, respectively. Morphological and functional analyses in each region revealed that microglia reshaped the spatial pattern of neuronal structure and function, manifested by enhanced in amNAC and inhibited in LNACsh, via differentially pruning adjacent inhibitory synapses in corresponding region. Further transcriptomic analysis of synaptic pruning relevant signaling pathway showed upregulated expression of "Eat me" signal molecules (particularly Mertk) in the amNAC and downregulated expression of "Find me" signal molecules (particularly Cx3cr1) in the LNACsh, consistent with the observed spatial synaptic pruning profiles. Minocycline administration reversed stress-induced PTSD and depression-like behaviors while normalizing the region-specific alterations in synaptic pruning signaling molecules.
CONCLUSION: Stress may elicit two regionally heterogeneous microglial subpopulations within NAC: phagocytosis-enhanced and recognition-impaired, which remodel the structure and function of local neural networks by differential pruning of inhibitory synapses, thereby driving the manifestation of PTSD- and depression-like behaviors, separately. These findings deepen our understanding of the neuroinflammatory mechanisms underlying trauma-related psychiatric disorders and identify novel targets for immunomodulation-based targets for transdiagnostic interventions .

Keywords:  Comorbidity; Depressive disorder; Microglia; Neuroplasticity; Nucleus accumbens; Post-traumatic stress disorder; Synaptic pruning

DOI:  https://doi.org/10.1016/j.bbi.2026.106985
Free Radic Biol Med. 2026 Aug 29. pii: S0891-5849(26)01056-7. [Epub ahead of print]256 312-322

APOE4-AGE axis is linked to mtDNA release and cGAS-STING-mediated neuroinflammation in the aging brain.

Firoz Akhter, Asma Akhter, Jasmine Zhou, Michelle Xi, Donghui Zhu.

  Advanced glycation end products (AGEs) accumulate with aging and have been implicated in neurodegeneration, yet their relationship with the APOE4 genotype and downstream inflammatory signaling remains poorly understood. Here, we show that APOE4 is associated with greater age-dependent AGE accumulation and APOE glycation in the aging brain compared with APOE3 in animal models. These changes are accompanied by mitochondrial dysfunction and increased release of mitochondrial DNA (mtDNA) into the cytosol, providing a potential trigger for innate immune activation. Consistent with enhanced innate immune signaling, APOE4 brains exhibit increased cGAS expression and phosphorylation of STING, TBK1, and IRF3, together with elevated type I interferon and pro-inflammatory responses. This activation is particularly prominent in microglia, as demonstrated by increased cGAS-DNA interactions and greater colocalization of cGAS signaling with Iba1-positive cells. APOE4 mice further display increased levels of cGAMP and IFN-β, as well as enhanced expression of pro-inflammatory cytokines and interferon-stimulated genes. Mechanistically, exposure of primary microglia to AGEs induces cytosolic mtDNA release and activates cGAS-STING signaling, whereas pharmacological inhibition of the receptor for advanced glycation end products (RAGE) attenuates these responses. Together, these findings identify an association between the APOE4-AGE axis, mitochondrial dysfunction, mtDNA release, and enhanced cGAS-STING-related inflammatory signaling in the aging brain, while the in vitro studies support a functional contribution of AGE-RAGE signaling to these responses in primary microglia.

Keywords:  APOE4; Advanced glycation end products (AGEs); Microglia; Mitochondrial DNA; Neuroinflammation; cGAS-STING signaling

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.08.054
Int J Mol Med. 2026 Nov;pii: 302. [Epub ahead of print]58(5):

Effect of MALT1 inhibition by MI‑2 on the microglial phenotype switch, inflammatory cytokine secretion, neuronal loss and oxidative stress in Alzheimer's disease.

Yuanlong Li, Hua Fan, Xiong Han, Ming Ni, Xiaodan Hou, Hailan Xia, Yinzhu Shi, Lin Zhang, Jun Sun.

  Mucosa‑associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is a key paracaspase enzyme regulating immune responses, inflammation and oxidative stress. The present study aimed to investigate the effect of MALT1 inhibition on neuroinflammation, neuronal loss and oxidative stress in Alzheimer's disease (AD). A co‑culture system involving microglia and neuron cells under β‑amyloid (Aβ) intervention was used to establish AD cellular models using human microglia HMC3 cells and neuroblastoma SH‑SY5Y cells and mouse microglia BV‑2 and hippocampal neuron HT‑22 cells. The inhibition of MALT1 proteolytic activity was achieved by MALT1 inhibitor 2 (MI‑2) treatment, and the NF‑κB pathway was activated by phorbol 12‑myristate 13‑acetate (PMA) treatment in HMC3 and BV‑2 cells. Western blotting, ELISA, Cell Counting Kit‑8, EdU staining, reactive oxygen species (ROS) detection and reduced glutathione (GSH) assays were performed to evaluate molecular changes, inflammatory responses, neuronal viability and oxidative stress. MALT1 expression was upregulated following Aβ treatment in HMC3 and BV‑2 cells. MALT1 inhibition by MI‑2 suppressed the microglial M1 phenotype but enhanced the M2 phenotype, reduced the levels of the proinflammatory cytokines TNF‑α and IL‑1β and inactivated the NF‑κB pathway in HMC3 and BV‑2 cells. Moreover, microglial MALT1 inhibition elevated cell viability (verified by Cell Counting Kit‑8 and EdU assays), increased the level of reduced glutathione and decreased the levels of reactive oxygen species in SH‑SY5Y and HT‑22 cells. NF‑κB activation by PMA attenuated the effects of MALT1 inhibition on the microglial phenotype switch and proinflammatory cytokine secretion in HMC3 and BV‑2 cells, as well as cell viability and oxidative stress in SH‑SY5Y and HT‑22 cells. The present study reveals that MALT1 inhibition may suppress microglial M1 phenotype, neuroinflammation, neuronal loss and oxidative stress by inactivating the NF‑κB pathway in AD.

Keywords:  Alzheimer's disease; MALT1 inhibition; NF‑κB; inflammation; microglial phenotype; neuronal loss

DOI:  https://doi.org/10.3892/ijmm.2026.5973
Front Immunol. 2026 ;17 1883095

SIRT1 deacetylates GAPDH to drive microglial glycolysis and neuroinflammation.

Chou-Yi Hsu, Ibrokhim Sapaev, Ozodbek Nematov, Rustam Turakulov, Sarmad S Abdullah, Zeina T Khaleel, Enas R Alwaily, Majid S Jabir.

   Introduction: Microglial activation drives neuroinflammation through a metabolic switch from oxidative phosphorylation to aerobic glycolysis; however, the molecular mechanisms governing this transition remain poorly defined. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), sirtuin 1 (SIRT1), lipopolysaccharide (LPS), and interferon-gamma (IFN-γ) are central to this study; GAPDH plays plays a key regulatory role in this switch, and its activity is modulated by reversible acetylation at lysine 254 (K254). It remains unclear whether sirtuin deacetylases regulate this modification in microglia.
Methods: Here, we demonstrate that SIRT1 physically associates with GAPDH in murine microglia and deacetylates K254 under basal conditions. Inflammatory activation using LPS/IFN-γ reduced SIRT1 protein levels and deacetylase activity by approximately 50%, leading to a 2.5-fold increase in K254 acetylation. Pharmacological activation of SIRT1 (SRT1720) reversed this modification and enhanced glycolytic output, mimicking the effects of the deacetylation-mimetic K254R mutant. To isolate the causal role of K254, we replaced endogenous GAPDH with K254R or acetylation-mimetic (K254Q) mutant proteins.
Results: K254R microglia exhibited approximately 35% higher GAPDH enzymatic activity, 40% greater glycolytic flux, and 1.6- to 2.2-fold higher secretion of TNF-α, IL-1β, IL-6, and IL-12p70 than K254Q cells. Glycolytic inhibition with 2-deoxyglucose reduced most of the excess cytokines, confirming enhanced flux as the causal factor in K254-driven inflammatory amplification.
Discussion: Thus, SIRT1-GAPDH signaling represents a post-translational axis linking sirtuin activity directly to glycolytic enzyme function, distinct from SIRT1's traditional transcriptional roles and serving as a viable molecular checkpoint in microglial immunometabolism.

Keywords:  Sirtuin 1; glyceraldehyde-3-phosphate dehydrogenase; glycolysis; lysine acetylation; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1883095
Glia. 2026 Nov;74(11): e70215

LILRB4 Attenuates Ischemic Brain Injury by Inhibiting Microglial Necroptosis via a RIPK3-Dependent Mechanism.

Jinglong Hu, Meijuan Zhang, Pinyi Liu, Yanting Chen, Hailan Meng, Shengnan Xia, Xinyu Bao, Yun Xu, Yan Chen.

  Microglia are central mediators of neuroinflammation following ischemic stroke. Our previous multi-omics data revealed significant upregulation of leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4) in microglia after transient middle cerebral artery occlusion (tMCAO), but its functional role remains unclear. This study demonstrates that LILRB4 expression peaks at 3 days post-tMCAO and is predominantly localized to microglia. Microglia-specific Lilrb4 knockout (Lilrb4-cKO) displayed worse neurological functions, larger infarct volumes, and more significant microglial activation. Transcriptomic analysis in vitro and functional experiments further revealed that microglial LILRB4 knockdown promoted the release of proinflammatory factors and enhanced necroptosis. Mechanistically, deletion of LILRB4 mainly drives receptor-interacting protein 3 (RIPK3) and mixed lineage kinase domain-like (MLKL) expression and phosphorylation, without affecting receptor-interacting protein 1 (RIPK1). Pharmacologic inhibition of RIPK3 can relieve the brain damage caused by LILRB4 knockout after stroke. Additional analysis showed that LILRB4 negatively regulates the stimulator of interferon genes (STING)/RIPK3 axis to limit microglial necroptosis. STING suppression blocked the hyperactivation of RIPK3 induced by LILRB4 deficiency. In conclusion, LILRB4 attenuates ischemic brain injury by suppressing STING/RIPK3-mediated microglial necroptosis and neuroinflammation, emphasizing its significance as a potential neuroprotective therapy.

Keywords:  LILRB4; ischemic stroke; microglia; necroptosis; neuroinflammation

DOI:  https://doi.org/10.1002/glia.70215
Exp Neurol. 2026 Aug 29. pii: S0014-4886(26)00364-X. [Epub ahead of print]406 115998

Single-cell multiome landscape reveals elovanoid-mediated suppression of inflammatory glial states and induction of homeostatic signaling after ischemic stroke.

Jeff X Ji, Surjyadipta Bhattacharjee, Brian L Giles, Ludmila Belayev, Nicolas G Bazan.

  Ischemic stroke is a leading cause of death and disability. Administration of the lipid mediators elovanoids (ELVs) is protective in human neuronal-glia cultures and in experimental ischemic stroke. We now report using a single-cell multiome approach that intranasally-delivered (IN) ELV34 or its precursor reduced the loss of neuronal markers and upregulated homeostatic microglia signatures after stroke. Thus, ELV reduces disease-associated microglia (expressing Spp1, Gpnmb, Lgals3, Clec7a) and the expression of neuroinflammatory signaling genes. In astrocytes, ELV decreased reactive astrocytes (expressing Gfap, Vim, Nes, Lcn2) and upregulated genes involved in synaptic organization. Also, ELV reduced abundance of oligodendrocytes and OPCs expressing immune markers. ELV induced a phenotype shift from pro-inflammatory microglia, astrocytes, oligodendrocytes, and OPCs in response to ischemic stroke damage. ELV upregulated gene pathways promoting synaptic integrity, reducing immune cell activation and neuronal loss.

Keywords:  Astrocytes; Glial activation; Microglia; Neuron subtypes; Neuroprotection; Oligodendrocytes; Single-cell; Synaptic integrity

DOI:  https://doi.org/10.1016/j.expneurol.2026.115998
Arch Biochem Biophys. 2026 Sep 04. pii: S0003-9861(26)00266-3. [Epub ahead of print] 110994

miR-124 alleviates behavioral deficits via inhibiting hippocampal microglial pyroptosis by targeting P2X7R in PTSD model rats.

Yi-Long Lin, Yan-Li Chen, Xin-Yu Ji, Zi-Hang Zhang, Cheng-Hao Piao, Lei Tong, Li-Li Ji.

  Post-traumatic stress disorder (PTSD) is a refractory psychiatric disorder with limited effective treatments. Emerging evidence indicates that abnormal microglial activation and pyroptosis in the hippocampus trigger persistent neuroinflammation, neuronal synaptic damage and progressive behavioral disorders. MicroRNA-124 (miR-124) is a brain-enriched miRNA with anti-inflammatory and neuroprotective functions. In the present study, we identified P2X7R as a direct target of miR-124 via bioinformatics prediction and dual-luciferase reporter assay. Using an mSPS-established rat PTSD model, we found that hippocampal miR-124 was markedly decreased in model animals, accompanied by upregulated P2X7R, enhanced NLRP3 inflammasome activation and excessive microglial pyroptosis. Lentivirus-mediated miR-124 overexpression downregulated P2X7R, reduced the levels of pyroptosis-related proteins and pro-inflammatory cytokines, and effectively rescued multiple PTSD-like behavioral phenotypes. Pharmacological blockade of P2X7R with A438079 recapitulated the protective effects of miR-124. Further in vitro co-culture experiments demonstrated that P2X7R-mediated microglial pyroptosis impaired neuronal synaptic function, while suppressing P2X7R restored the expression of synaptic proteins. This study demonstrates that miR-124 modulates microglial pyroptosis and hippocampal neuroinflammation through directly targeting P2X7R, thereby improving neuronal synaptic function and alleviating PTSD symptoms. Our findings provide novel mechanistic insights into PTSD pathogenesis and offer potential molecular targets for clinical intervention.

Keywords:  P2X7R; Post-traumatic stress disorder; miR-124; microglia; pyroptosis

DOI:  https://doi.org/10.1016/j.abb.2026.110994
J Stroke Cerebrovasc Dis. 2026 Sep 04. pii: S1052-3057(26)00202-8. [Epub ahead of print] 108739

Protective effect of miR-642b-3p against brain injury after intracerebral hemorrhage by targeting SERPINE1.

Zhijuan Rao, Jiarong Li.

   INTRODUCTION: The pathological mechanism of post-intracerebral hemorrhage (ICH) brain injury remains incompletely clarified. This study aims to clarify the role and molecular mechanism of miR-642b-3p in ICH, thereby providing a potential candidate target for clinical treatment.
MATERIAL AND METHODS: We enrolled 66 ICH patients and 70 matched healthy controls with strict inclusion/exclusion criteria, and used multivariable linear regression to analyze independent correlates of miR-642b-3p and SERPINE1. Collagenase-induced rat ICH models with pre-calculated sample size, random grouping and blinded tests were established, followed by intracerebroventricular injection of 5 nmol/rat miR-642b-3p agomir. Neurological function, brain edema and inflammatory cytokines were detected via mNSS, mLPT and ELISA. LPS-stimulated BV-2 microglia, dual-luciferase assay and SERPINE1 overexpression rescue experiments were adopted to validate the miRNA-target regulatory cascade. NLRP3 inflammasome components and microglial polarization markers were further assessed by qPCR.
RESULTS: miR-642b-3p decreased while SERPINE1 increased in patient serum and rat brain tissue; hematoma volume and GCS score independently predicted their expression. miR-642b-3p overexpression suppressed SERPINE1, relieved edema, improved neurofunction and lowered proinflammatory cytokines in vivo. In LPS-treated BV-2 cells, miR-mimic reversed abnormal SERPINE1 elevation and inflammation, whereas SERPINE1 overexpression abolished such protective effects. Dual-luciferase assay verified direct binding between miR-642b-3p and SERPINE1 3'UTR. Moreover, miR-642b-3p inhibited NLRP3 inflammasome activation and promoted microglial M2 polarization by targeting SERPINE1.
CONCLUSION: Our findings support that restoration of miR-642b-3p alleviates post-ICH cerebral edema and neurological deficits via targeted inhibition of SERPINE1-mediated inflammation, involving suppression of NLRP3 inflammasome and promotion of M2 polarization. The miR-642b-3p/SERPINE1 axis may serve as a promising therapeutic target for ICH.

Keywords:  SERPINE1; brain injury; inflammatory response; intracerebral hemorrhage; miR-642b-3p

DOI:  https://doi.org/10.1016/j.jstrokecerebrovasdis.2026.108739
Neuroreport. 2026 Aug 20.

sAPPα acts as an endogenous ligand for TREM2 to regulate microglial survival and inflammatory responses in Alzheimer's disease.

Zongqi Wang, MiHua Liu, Jing Xu, Yihong Liu, Ting Liu.

   BACKGROUND: Triggering receptor expressed on myeloid cells 2 (TREM2) regulates microglial functions in Alzheimer's disease, whereas soluble amyloid precursor protein alpha (sAPPα) has neuroprotective effects. Whether sAPPα directly interacts with TREM2 remains unclear.
METHODS: Single-cell RNA sequencing data from wild-type and APP/PS1 mouse cortices and bulk RNA-seq data (GSE18309) were analyzed. Solid-phase binding, pull-down, and co-immunoprecipitation assays were used to examine TREM2-sAPPα binding and map the interacting regions. LPS-stimulated BV-2 cells were used to assess the effects of TREM2 knockdown and sAPPα supplementation on viability, apoptosis, invasion, phagocytosis, cytokine production, and polarization.
RESULTS: A TREM2-positive microglial subpopulation was more abundant in the APP/PS1 dataset and showed relatively restrained inflammatory signaling. Cell-cell communication analysis predicted enhanced APP-(TREM2+TYROBP) signaling. Biochemical assays confirmed direct binding between TREM2 and sAPPα. The TREM2 51-71 amino acid region and the APP E1+Ac fragment contributed to this interaction, whereas TREM2 variants Y38C, R47H, R62H, and T66M reduced binding affinity. TREM2 knockdown aggravated LPS-induced loss of viability, apoptosis, inflammatory cytokine production, and M1-like polarization in BV-2 cells. Exogenous sAPPα reversed these changes.
CONCLUSION: sAPPα directly binds TREM2 and may limit excessive inflammatory activation of microglia under LPS stimulation. The TREM2-sAPPα interaction may represent a regulatory pathway relevant to Alzheimer's disease.

Keywords:  APP; Alzheimer’s disease; TREM2; bulk RNA sequencing; microglia; sAPPα; single-cell RNA sequencing

DOI:  https://doi.org/10.1097/WNR.0000000000002307
NPJ Dement. 2026 ;2(1): 83

Matrix and intermembrane space-specific mitochondrial stress response in Alzheimer's disease.

Shatakshi Shukla, Devin Kolmetzky, Shanikumar Goyani, Kunal Samantaray, Anupriya Sinha, Philip A Kramer, Dhanendra Tomar, Pooja Jadiya.

  Alzheimer's disease (AD) lacks effective therapies, partly due to an incomplete understanding of mitochondrial dysfunction, a key driver of neurodegeneration. Mitochondria activate the unfolded protein response (UPRmt) to maintain proteostasis, but the roles of matrix- and intermembrane space (IMS)-associated stress responses in AD remain unclear. Here, we used human microglial-like cells expressing mutant amyloid precursor protein together with compartment-targeted mitochondrial proteotoxic stressors to investigate matrix (UPRmt-MM) and IMS (UPRmt-IMS) stress responses. RNA-seq revealed activation of mitochondrial stress pathways and suppression of synaptic and lipid signaling in AD-like cells. UPRmt-MM promoted robust immune activation, severe oxidative phosphorylation defects, increased mitochondrial reactive oxygen species, and cell death. In contrast, UPRmt-IMS preferentially induced interferon signaling and suppressed antioxidant pathways. Notably, suppression of ATF5-dependent UPRmt signaling rescued mitochondrial dysfunction and reduced Aβ release. Together, these findings demonstrate that matrix- and IMS-targeted mitochondrial stress elicit distinct microglial responses and identify mitochondrial proteostasis as a potential therapeutic target in AD.

Keywords:  Cell biology; Molecular biology; Neuroscience

DOI:  https://doi.org/10.1038/s44400-026-00137-0
NPJ Dement. 2026 ;2(1): 75

Regulators of interferon-responsive microglia uncovered by Genome-wide CRISPRi screening.

Amanda McQuade, Vincent Cele Castillo, Venus Hagan, Weiwei Liang, Thomas Ta, Reet Mishra, Olivia Teter, Layla Gomes, Bianca Gonzalez, Noam Teyssier, Kun Leng, Martin Kampmann.

  Microglia dynamically support brain health through the induction of specialized activation states in response to injury or disease. Activation of the interferon-responsive microglia (IRM) state has been identified across neurodevelopmental windows, age-related cognitive decline, and neurodegenerative diseases. Functionally, IRM have been linked to synaptic pruning, dead cell removal, and neuroinflammation, making this state critical to brain homeostasis. While the functional importance of this state is becoming increasingly clear, our understanding of the regulatory networks that govern IRM induction remain incomplete. To systematically identify genetic regulators of the IRM state, we conducted a genome-wide CRISPR interference screen in human iPSC-derived microglia using IFIT1 as a representative IRM marker. We identified 772 genes that modulate IRM, including canonical type I interferon signaling genes (IFNAR2, TYK2, STAT1/2, USP18) and newly described regulators. We uncovered a non-canonical role for the CCR4-NOT transcription complex subunit 10, CNOT10, in IRM activation. This work provides a comprehensive resource that can be applied to dissect the functions of interferon-responsive microglia and highlights both established and novel targets for modulating microglial interferon signaling in health and disease.

Keywords:  Computational biology and bioinformatics; Immunology; Neurology; Neuroscience

DOI:  https://doi.org/10.1038/s44400-026-00125-4