bims-microg 2026-02-08 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–02–08
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln

Live Imaging and Characterization of Microglia Dynamics and Interactions with Synapses in Diseased Murine Retina.
Glial and Neuronal Alzheimer's Disease-Related Alterations Reproduced in Human Induced Pluripotent Stem Cells With Presenilin-1 Mutation.
Multi-omics characterized the effects of Akkermansia muciniphila and fecal microbiota transplant on the microglial activation after traumatic brain injury.
Early and progressive retinal microglial changes in APPNL-F/NL-F mouse model of Alzheimer's disease revealed by an automated image analysis software.
Loss of TREM2 impairs microglial function and exacerbates retinal neurodegeneration in glaucoma.
Retinal glial cells in glaucoma and age-related retinal diseases: Inflammatory responses, disease transitions, and translational perspectives.
Inflammation-targeted single-atom nanozymes drive microglial depolarization and inhibit ferroptosis via Sirt-6-xCT-GPX4 axis to attenuate early brain injury following subarachnoid hemorrhage.
Natural killer cells aggravate neuroinflammation through microglial type I interferon pathway activation after traumatic brain injury.
Microglia sense fungal infections through capsular components from capillary-bound Cryptococcus neoformans via endothelial nucleotide signaling.
PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling.
The C3-C3aR axis drives rotenone-induced cognitive damage via synaptic engulfment, dark microglia and PANoptosis.
Ythdf2 loss in microglia aggravates ischemic retinopathy by increasing microglia activation and microvascular anomalies.
Spatial heterogeneity in microglia-complement crosstalk: Implications for synaptic pruning in Alzheimer's disease.
Generation and characterization of iPSC-derived microglia for in vitro modeling of stimuli-specific neuroimmune responses.
ACSL1-Dependent Microglial Lipoimmunometabolic Reprogramming Underlies Cognitive Deficits in Alcohol Use Disorder.
Disengaging the Engine: Histone Deacetylases 1 and 2-Mediated Acetylation of Hexokinase-2 Regulates Energy Metabolism in Microglia Following Intracerebral Hemorrhage.
MerTK-triggered TGFβ1 autocrine signal regulates microglial response to neurodegeneration.
Microglial C5aR1 defines a pathogenic inflammatory axis driving cerebral edema.
Plastic microglia.

J Vis Exp. 2026 Jan 16.

Live Imaging and Characterization of Microglia Dynamics and Interactions with Synapses in Diseased Murine Retina.

Camille Fang, Subramanian Dharmarajan, Colin Germer, Jeanette Hyer, Yvonne Ou.

Microglia are the resident macrophages of the central nervous system (CNS) that respond to tissue infection and injury. In addition to their role in inflammation, microglia play a developmental role in circuit refinement through synaptic pruning. However, the mechanisms of synaptic pruning in neuroinflammation and neurodegeneration remain unknown. In this protocol, we use a mouse retina explant model to study microglia dynamics ex vivo. To examine microglia motility and their interactions with postsynaptic proteins, we label synapses with AAV-PSD95-RFP and record timelapse videos of motile microglia colocalized with postsynaptic proteins using spinning disk confocal microscopy. We then create surface and spot reconstructions of microglia and PSD95 using image analysis software. Data such as microglia displacement length, process speed, and contact with postsynaptic puncta can then be extracted from these surfaces to understand microglia behavior both in homeostatic states and after neuronal injury. This protocol can be useful in examining the role of microglia in synaptic pruning in retinal neurodegenerative diseases.

DOI: https://doi.org/10.3791/68420
Res Sq. 2026 Jan 19. pii: rs.3.rs-8549806. [Epub ahead of print]

Glial and Neuronal Alzheimer's Disease-Related Alterations Reproduced in Human Induced Pluripotent Stem Cells With Presenilin-1 Mutation.

Davide Comolli, Elisa Murari, Milica Cerovic, Liviu Soltuzu, Wenjie Liao, Aurora Bianchi, Serena Seminara, Ilaria Craparotta, Stefano Fumagalli, Claudia Balducci, Gianluigi Forloni, Massimiliano De Paola.

Background A pathogenetic role of glial cells has been established virtually in all neurodegenerative disorders. In Alzheimer's disease (AD), together with β-amyloid deposition and the formation of fibrillary tangles, neuroinflammation contributes to neuronal dysfunction associated with the disease. Thus, selective control of glial cell activation becomes part of the multifactorial therapeutic strategies in AD. Astrocytes and microglia are highly heterogeneous in their morphology and physiology, and this diversity underlies their distinct functional states in the central nervous system. In AD, they exhibit dynamic and stage-dependent pathological phenotypes during disease onset and progression. In this context, investigating the disease-associated glia signature would provide significant progress in understanding pathological mechanisms and in the development of beneficial treatments. The use of human induced pluripotent stem cells (iPSCs) to study CNS cell alterations during brain pathologies greatly improves the possibility of identifying human- and cell-specific changes likely contributing to AD progression. Methods Here we used isolated glia cultures and neuron/glia cocultures derived from iPSC carrying a mutation in the presenilin-1 (PSEN1) gene to investigate AD-related microglia and astrocyte impairments and their contribution to neuronal degeneration. Results Microglia from AD iPSCs showed compromised functional properties while astrocytes exhibited a predominant fibroblast-like phenotype and increased expression of inflammatory markers. Consistently, transcriptomic derangement for reactive phenotype-related genes, correlating with cell morphology, allowed to well distinguish AD astrocytes from control cells. We finally observed that glia-specific AD-related changes affected some neuronal properties in mixed neuron/glia cocultures, while the presence of the mutation in both cell population triggered a dramatic neuronal damage, involving neuronal network degradation, synaptic alterations and impaired electrophysiological properties. On the other hand, the replacement of AD with healthy glia was not sufficient to protect from neurodegeneration, suggesting the pivotal role of mutated PSEN1 in neurons. Conclusions We herein succeeded in reproducing crucial AD-related changes in iPSC-derived in vitro models providing new insights in the neuropathological communication amongst brain cells, thus representing a promising tool to deepen disease mechanisms and develop neuroprotective treatments.

DOI: https://doi.org/10.21203/rs.3.rs-8549806/v1
BMC Microbiol. 2026 Jan 30.

Multi-omics characterized the effects of Akkermansia muciniphila and fecal microbiota transplant on the microglial activation after traumatic brain injury.

Shuai Wang, Xuemei Fan, Zhipeng Zheng, Qiao Gu, Shurui Xu, Ying Zhu, Fangjie Zhang, Mengyuan Diao, Wei Hu.



Keywords:  Akkermansia; Fecal microbiota transplantatio; Intestinal flora; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1186/s12866-026-04775-5
Front Aging Neurosci. 2025 ;17 1712480

Early and progressive retinal microglial changes in APPNL-F/NL-F mouse model of Alzheimer's disease revealed by an automated image analysis software.

Lidia Sánchez-Puebla, Inés López-Cuenca, Miguel A Sánchez-Puebla, Ana Granados, Ana I Ramírez, Juan Llorens, Takaomi C Saido, Takashi Saito, Carmen Nieto-Vaquero, María A Moro, Valentín Moreno, José M Ramírez, Rosa de Hoz.

  Alzheimer's disease (AD) is characterized by the accumulation of misfolded proteins that trigger neuroinflammation and neuronal loss. The retina, as an extension of the central nervous system, mirrors these pathological processes and represents a potential biomarker. Microglial activation, a key component of neuroinflammation, can be morphologically assessed through automated image analysis. This study performed a quantitative and morphological analysis of retinal microglia in the APPNL-F/NL-F mouse model of AD across aging (6-20 months) and comparing them with age-matched C57BL/6 J controls using an automated image analysis software. A cross-sectional design was applied to 72 mice (36 APPNL-F/NL-F and 36 WT). Retinas samples were processed by Iba-1 immunohistochemistry. Quantified parameters included cell number, soma size, arborization area, skeletonization, fluorescence intensity, and Feret's Diameter Ratio across OS, OPL, IPL, and NFL/GCL layers. Image analysis was performed using a custom automated system, called MorphoSomas, specifically developed for the comprehensive morphological assessment of microglia. Age-dependent changes were observed in both groups. WT mice showed a later and more gradual activation pattern, whereas APPNL-F/NL-F mice exhibited early activation from 6 months, characterized by increased cell number and soma size, followed by reductions in arborization and skeletonization, indicating progressive activation. The automated system allowed precise and reproducible assessment, highlighting significant differences between groups and retinal layers. In conclusion, retinal microglia in APPNL-F/NL-F mice exhibit early and biphasic activation followed by signs of dysfunction, reflecting AD neuropathology. Automated analysis enhances objectivity and efficiency in morphological studies. These findings support the retina as a promising, non-invasive biomarker for early AD detection.

Keywords:  APPNL-F/NL-F mouse model; Alzheimer’s disease; automated image analysis; morphological quantification; neuroinflammation; retinal microglia

DOI:  https://doi.org/10.3389/fnagi.2025.1712480
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
Neural Regen Res. 2026 Feb 05.

Retinal glial cells in glaucoma and age-related retinal diseases: Inflammatory responses, disease transitions, and translational perspectives.

Akanksha Salkar, Viswanthram Palanivel, Devaraj Basavarajappa, Benjamin Heng, Angela Schulz, Vivek Gupta, Stuart Graham, Mehdi Mirzaei, Yuyi You.

   ABSTRACT: Microglia, Müller cells, and astrocytes play a crucial role in maintaining retinal structure, homeostasis, and neuronal function. In disease, they undergo reprogramming that drives chronic inflammation and neurodegeneration. Unique to the retina, these glial cells occupy specialized niches and interact closely with the blood-retinal barrier, creating distinct vulnerabilities. We summarized the glial activation mechanisms, shared triggers, including oxidative stress, metabolic dysfunction, aging, and systemic inflammation, as well as key pathways, such as nuclear factor kappa-B, mitogen-activated protein kinase, Janus kinase/signal transducer and activator of transcription, the inflammasome, and the complement system. Disease-specific responses in glaucoma, age-related macular degeneration, diabetic retinopathy, and vascular occlusions were compared, highlighting the heterogeneity of gliosis and its impact on neuronal and vascular pathology. We also discussed emerging human-derived platforms alongside proteomics approaches, highlighting their utility for mechanistic insights and discovering biomarkers. Despite advances, critical gaps remain in understanding glial-glial interactions and in developing robust models focused on glia. Despite these advances, major gaps remain in our understanding of glial-glial communication, state transitions, and their temporal relationship to neurodegeneration. Moreover, the lack of experimental models explicitly designed to interrogate glial biology continues to limit translational progress. Addressing these challenges will be essential to reposition glial cells as central drivers of retinal disease rather than secondary responders. A strategic shift toward glia-centered models, integrative multi-omics analyses, and human-relevant systems holds promise for advancing biomarker discovery and developing targeted therapeutic strategies that aim to modulate glial dysfunction and preserve vision.

Keywords:  biomarker; blood–retinal barrier; cytokine; glaucoma; gliosis; humanized model; neurodegeneration; neuroinflammation; oxidative stress; proteomics; retina

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-01905
Mater Today Bio. 2026 Apr;37 102829

Inflammation-targeted single-atom nanozymes drive microglial depolarization and inhibit ferroptosis via Sirt-6-xCT-GPX4 axis to attenuate early brain injury following subarachnoid hemorrhage.

Boliang Liu, Chao Xiang, Xiaodan Zhang, Wei Guo, Haitao Wu, Fandi Hou, Yueyang Ba, Xiulei Zhang, Zhongcan Chen, Guang Feng, Yuan Dang, Yang Zhu, Jianjun Gu.

  Early brain injury (EBI) has been identified as a key factor leading to the poor prognosis of patients with subarachnoid hemorrhage (SAH). At present, apart from surgical treatment, there is a lack of effective neuroprotective drugs. In this study, a biomimetic nanozyme V-MDL-800 was constructed by coordinating Vanadium Single-atom enzymes (V/SAE) and the allosteric activator MDL-800 of Sirt6, and encapsulated into NM@V-MDL-800 with neutropenia cell membrane (NM). By clearing ROS, the xCT/GPX4 pathway was activated, blocking the pathophysiological process of EBI after SAH can improve prognosis. NM@V-MDL-800 recruits through the blood-brain barrier (BBB) at the site of hemorrhagic injury by relying on the chemotactic property of neutrophils. Among them, the catalase-like, superoxide dismutase-like, and hydroxyl radical scavenging effects of V/SAE can eliminate excessive reactive oxygen species (ROS) within cells and inhibit oxidative stress; at the same time, as an allosteric activator of Sirt6, it activates the downstream xCT/GPX4 pathway, improving lipid metabolism abnormalities. Regulating the key core pathway of lipid peroxidation on ferroptosis promotes the polarization of microglia from the pro-inflammatory M1 form to the anti-inflammatory M2 morphology to inhibit the pathophysiological process of neuroinflammation in EBI. In addition, in vivo imaging of mice confirmed the targeted effect of NM@V-MDL-800 through the blood-brain barrier and recruited at the site of bleeding injury. The therapeutic effect of NM@V-MDL-800 on the SAH model has also been confirmed in vivo and in vitro experiments. This provides new ideas for SAH drug therapy regimens of SAH targeting microglial ferroptosis.

Keywords:  Early brain injury; Ferroptosis; Reactive oxygen species; Single-atom nanozyme; Subarachnoid hemorrhage

DOI:  https://doi.org/10.1016/j.mtbio.2026.102829
J Neuroinflammation. 2026 Feb 02. 23(1): 52

Natural killer cells aggravate neuroinflammation through microglial type I interferon pathway activation after traumatic brain injury.

Meng Nie, Jiangyuan Yuan, Shiying Dong, Zhitao Gong, Zhuang Sha, Tao Liu, Liang Mi, Xuanhui Liu, Jinhao Huang, Weiwei Jiang, Mingqi Liu, Chuang Gao, Rongcai Jiang.



Keywords:  Microglia; NK cells; Neuroinflammation; Traumatic brain injury; Type I interferon

DOI:  https://doi.org/10.1186/s12974-026-03715-4
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
Proc Natl Acad Sci U S A. 2026 Feb 10. 123(6): e2521944123

PTP1B inhibition promotes microglial phagocytosis in Alzheimer's disease models by enhancing SYK signaling.

Yuxin Cen, Steven R Alves, Dongyan Song, Christy Felice, Jonathan B Preall, Linda Van Aelst, Nicholas K Tonks.

  Amyloid β (Aβ) accumulation is a hallmark of Alzheimer's disease (AD). Emerging evidence suggests that impaired microglial Aβ phagocytosis is a key feature in AD, highlighting the therapeutic potential of enhancing this innate immune function. Here, we demonstrate that genetic deletion or pharmacological inhibition of protein tyrosine phosphatase 1B (PTP1B) ameliorated memory deficits and reduced Aβ burden in APP/PS1 mice. Moreover, we show that PTP1B was highly expressed in microglia, and its deficiency promoted a transcriptional shift toward immune activation and phagocytosis. Consistently, PTP1B deletion in microglia enhanced phagocytosis and energy metabolism, supported by increased AKT-mTOR signaling, a pathway essential for meeting the energy demands of activation. Mechanistically, we identified spleen tyrosine kinase (SYK), a key regulator of microglial phagocytosis, as a direct substrate of PTP1B. Inhibition of SYK showed that PTP1B modulates microglial activation in a SYK-dependent manner. These findings established PTP1B as a critical modulator of microglial activation and a potential therapeutic target for AD.

Keywords:  Alzheimer’s disease; PTP1B; microglia; signal transduction; therapeutic target

DOI:  https://doi.org/10.1073/pnas.2521944123
Redox Biol. 2026 Jan 30. pii: S2213-2317(26)00060-1. [Epub ahead of print]90 104062

The C3-C3aR axis drives rotenone-induced cognitive damage via synaptic engulfment, dark microglia and PANoptosis.

Jianing Liu, Liyan Hou, Yu Ma, Lu Tian, Jau-Shyong Hong, Jie Zhao, Qingshan Wang.

  Cognitive impairment, a common non-motor symptom of Parkinson's disease (PD), is a key factor in reducing the life quality of patients, but its pathogenesis remains unclear. Recent studies highlighted the role of Complement C3 in regulating neuroinflammation and cognitive function. This study aimed to elucidate the mechanisms through which C3 contributed to PD-related cognitive dysfunction, using a rotenone-induced mouse model. Rotenone exposure led to pronounced upregulation of astrocytic C3, while C3 deficiency significantly ameliorated neurodegeneration and α-synuclein Ser129 phosphorylation, accompanied by marked improvements in cognitive performance. Notably, the expression of C3a receptor (C3aR) was elevated in both microglia and neurons, and inhibition of C3aR with SB290157 effectively mitigated neuronal injury and cognitive decline. Mechanistically, blockade of the C3-C3aR axis suppressed microglial activation, reduced aberrant phagocytosis and synaptic engulfment, and restored synaptic plasticity. Subsequently, dark microglia characterized by activation of PKR-PERK-eIF2α-ATF4 pathways and abnormal lipid metabolism and release were also mitigated by C3 deletion or C3aR inhibition. Furthermore, inhibition of the C3-C3aR axis restored blood-brain barrier integrity, decreased TUNEL-positive cell numbers, and suppressed the expression or activation of PANoptosis-related markers in rotenone-exposed mice. In vitro experiments revealed that C3-C3aR axis promoted PANoptosome formation and PANoptosis through z-DNA and ZBP-1 interaction via mitochondrial ROS. Collectively, our findings uncovered the C3-C3aR axis as a critical mediator linking neuroinflammation, abnormal synaptic pruning, dark microglia, BBB impairments and neuron PANoptosis to cognitive decline in PD, providing new mechanistic insights and a potential therapeutic target for combating PD-related cognitive impairment.

Keywords:  Apoptosis; C3aR; Complement C3; Necroptosis; Neuroinflammation; Parkinson's disease

DOI:  https://doi.org/10.1016/j.redox.2026.104062
J Adv Res. 2025 Oct 24. pii: S2090-1232(25)00777-5. [Epub ahead of print]

Ythdf2 loss in microglia aggravates ischemic retinopathy by increasing microglia activation and microvascular anomalies.

Hong-Jing Zhu, Yi-Chen Zhang, Ye-Ran Zhang, Bing Qin, Xin Cao, Jia-Nan Wang, Ying Wang, Zi-Qin Ding, Meidong Zhu, Jiang-Dong Ji, Qing-Huai Liu, Biao Yan, Song-Tao Yuan, Xue Chen.

   INTRODUCTION: Microvascular dysfunction is a key contributor to life-threatening diseases, with retinal microvascular diseases being a leading cause of blindness. Aberrant microglia activation is critical in microvasculopathies, but the underlying molecular mechanisms remain unclear. Post-transcriptional modifications, such as N6-methyladenosine (m6A) modification, are key in these processes, yet their role in retinal vasculopathy is unexplored.
OBJECTIVES: We aimed to investigate the role of the m6A reader, YTH domain-containing family protein 2 (Ythdf2), in microglia and its involvement in retinal vasculopathy, and to uncover its underlying regulatory mechanisms.
METHODS: We assessed the expression of microglial Ythdf2 in the retinas of oxygen-induced retinopathy (OIR) mice using single-cell RNA sequencing (scRNA-seq). To investigate its function, we generated a microglia-specific Ythdf2 knockout mouse model and analyzed retinal microglial and vascular phenotypes under both physiological and pathological conditions. Additionally, RNA-seq and selective inhibitors were employed to explore the underlying signaling pathways.
RESULTS: Down-regulation of Ythdf2 was observed in microglia from mice with microvascular diseases. Microglial Ythdf2 knockout in developing retinas caused aberrant microglial activation, disrupting capillary function, delaying sprouting, and accelerating vascular remodeling, thereby affecting physiological angiogenesis. In OIR retinas, Microglial Ythdf2 knockout intensified microglial activation and aggravated pathological angiogenesis. Mechanistically, Ythdf2 directly regulated the mRNA stability of Ace and Bmp4 as an m6A reader. Captopril (an Ace inhibitor) or noggin (a Bmp4 antagonist) alleviated microvascular retinopathy exacerbated by Ythdf2 insufficiency.
CONCLUSION: Loss of Ythdf2 in retinal microglia increased their activation and caused microvascular anomalies through Ace and Bmp4, providing insights into microvascular development and disease mechanisms. These findings suggest potential therapeutic approaches targeting the Ythdf2-Ace/Bmp4 network for microvascular diseases.

Keywords:  Microglia; Microvascular dysfunction; N(6)-methyladenosine (m(6)A) modification; Ythdf2

DOI:  https://doi.org/10.1016/j.jare.2025.10.024
Alzheimers Dement. 2026 Feb;22(2): e71185

Spatial heterogeneity in microglia-complement crosstalk: Implications for synaptic pruning in Alzheimer's disease.

Qiuyan Ye, Wei Gao, Jiaping Feng, Xue Li, Jianhui Li, Fengge Yang, Linqing Li, Mingsheng Zi, Xinkai Wu, Hainan Gao, Honglin Li.

  Alzheimer's disease (AD) is a neurodegenerative disorder characterized by synaptic loss, as a key pathological feature in its early stages. Recent studies have highlighted the central role of microglia-complement interactions in synaptic pruning. This interaction exhibits significant spatial heterogeneity in AD, with activation patterns and functional manifestations varying across different brain regions and stages of disease. Therefore, this article systematically reviews the synergistic mechanisms of microglia and the complement system in physiological synaptic pruning. Additionally, the dynamic evolution of the complement-immune network during disease progression is analyzed, and the amplifying effect of genetic factors on the spatial heterogeneity of synaptic pruning is explored. Furthermore, current treatment strategies from both Western medicine and traditional Chinese medicine are discussed, emphasizing the potential value of combining these approaches for intervening in synaptic loss in AD.

Keywords:  Alzheimer's disease; complement; microglia; spatial heterogeneity; synaptic pruning

DOI:  https://doi.org/10.1002/alz.71185
Alzheimers Dement. 2026 Feb;22(2): e71117

Generation and characterization of iPSC-derived microglia for in vitro modeling of stimuli-specific neuroimmune responses.

Angela K Haskell, Joshua A Kulas, William E Carter, June Javens-Wolfe, Raven Dance Hinkel, Mustapha Moussaif, Jacob S Smiley, Olivia Lazaro, Sylvia Robertson, Alan D Palkowitz, Bruce T Lamb, Timothy I Richardson, Jeffrey L Dage, Shaoyou Chu, Travis Johnson, Louis F Stancato, Abdul Qadir Syed.

   INTRODUCTION: Microglia are macrophage-like brain resident immune cells known to express numerous Alzheimer's disease risk genes. Here we generated a human induced pluripotent stem cell (iPSC) derived microglia cell culture model for use in neuroimmune modeling and therapeutic testing.
METHODS: We generated iPSC lines using episomal reprogramming for subsequent stepwise differentiation of iPSC-derived microglia (iMG) without commercial kits. We characterized the responses of this model to immunogenic stimuli and recombinant TREM2 antibodies.
RESULTS: The iMG expressed several key microglia signature genes and are morphologically and transcriptionally dynamic. iMG rapidly phagocytosed myelin debris and strongly changed expression of lipid homeostasis genes. iMG expressed TREM2 and increased TREM2 levels in response to IL-4. Recombinant TREM2 antibody treatment impaired iMG myelin phagocytosis and upregulated chemokines.
DISCUSSION: We validated our iMG model system for the evaluation of biological responses of human microglia-like cells to stimuli and pharmacological agents for their transcriptional and functional impacts.

Keywords:  immune response; induced pluripotent stem cells; microglia; myelin; phagocytosis; triggering receptor on myeloid cells 2

DOI:  https://doi.org/10.1002/alz.71117
Adv Sci (Weinh). 2026 Feb 05. e19760

ACSL1-Dependent Microglial Lipoimmunometabolic Reprogramming Underlies Cognitive Deficits in Alcohol Use Disorder.

Liang Hao, Xing-Rui Cao, Bai-Qiang Li, Fu-Ying Zhao, Jia-Mei Wang, Rui-Kang Gao, Zhi-Peng Cao, Zhen-Xian Du, Hua-Qin Wang.

  Alcohol use disorder (AUD) leads to cognitive impairment dependent on prefrontal cortex (PFC) dysfunction, yet the underlying cellular and molecular mechanisms, particularly the role of microglia, remain poorly understood. Through re-analysis of single-cell RNA sequencing data from AUD patients, we identified aberrant activation of lipid metabolic pathways in microglia and pinpointed acyl-CoA synthetase long-chain family member 1 (ACSL1) as a central regulator. In animal and cellular models, chronic ethanol exposure induced ACSL1 upregulation, triggering lipid droplet accumulation, neuroinflammatory activation, and aberrant microglia-neuron interactions mediated via PTPRM signaling. Pharmacological inhibition of ACSL1 reversed these pathological phenotypes. We further developed a dual-targeted lipid nanoparticle system for microglia-specific ACSL1 silencing, which effectively ameliorated ethanol-induced cognitive deficits in mice. Our study unveils ACSL1-mediated lipoimmunity reprogramming of microglia as a core mechanism underlying cognitive impairment in AUD and proposes a novel targeted therapeutic strategy.

Keywords:  ACSL1; alcohol use disorder (AUD); cognitive deficits; lipoimmunometabolic reprogramming; microglia

DOI:  https://doi.org/10.1002/advs.202519760
Adv Sci (Weinh). 2026 Feb 03. e00194

Disengaging the Engine: Histone Deacetylases 1 and 2-Mediated Acetylation of Hexokinase-2 Regulates Energy Metabolism in Microglia Following Intracerebral Hemorrhage.

Zhiwen Jiang, Heng Yang, Xinjie Gao, Zengyu Zhang, Ruiyuan Weng, Yuchao Fei, Jiabin Su, Hanqiang Jiang, Wei Ni, Yuxiang Gu.

  Microglia-mediated neuroinflammation is closely associated with the pathogenesis of secondary brain injury following spontaneous intracerebral hemorrhage (ICH). However, the relationship between immune response regulation and metabolic patterns in microglia remains unclear. Histone Deacetylases 1 and 2, a class of lysine deacetylases, regulates gene transcription by modulating histone acetylation modifications and is widely involved in various cellular activities of microglia. In this study, we observed that knockout of HDAC1/2 in microglia alleviated neurological deficits caused by ICH, preserved white matter integrity, and accelerated hematoma clearance post-ICH. Mechanistically, we found that after ICH, microglia exhibited increased expression of hexokinase 2 (HK2) and enhanced glycolysis. HDAC1/2 knockout/pharmacological inhibition affected the acetylation level of HK2, inhibited its glycolytic activity, and promoted a metabolic shift in activated microglia from glycolysis to fatty acid oxidation. This shift was associated with reduced pro-inflammatory responses and enhanced phagocytic activity in microglia. Enhanced fatty acid oxidation may have a detrimental effect on mitochondrial function, and HDAC1/2 inhibition simultaneously promoted mitophagy in microglia. Additionally, HDAC1/2 inhibition triggered microglial apoptosis and suppressed proliferation, ultimately leading to a reduction in microglial cell numbers. Overall, this study reveals the potential mechanisms by which targeting HDAC1/2, through acetylation modifications and transcriptional regulation, modulates microglial function and metabolism after ICH, thereby exerting protective effects.

Keywords:  HK2; acetylation; autophagy; fatty acid oxidation; glycolysis; histone deacetylase 1/2; intracerebral hemorrhage; microglia; mitochondrial

DOI:  https://doi.org/10.1002/advs.202500194
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
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
Nat Immunol. 2026 Feb;27(2): 169

Plastic microglia.

Ioana Staicu.

DOI: https://doi.org/10.1038/s41590-026-02424-7