bims-microg 2025-06-01 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–06–01
twenty-two papers selected by
Marcus Karlstetter, Universität zu Köln

Microglia eliminate inhibitory synapses and drive neuronal hyperexcitability in epilepsy.
GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy.
The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia xenografted into a mouse model of Alzheimer's disease.
STING deletion protects against amyloid β-induced Alzheimer's disease pathogenesis.
Inactivation of the PHD3-FOXO3 axis blunts the type I interferon response in microglia and ameliorates Alzheimer's disease progression.
Nanoimmunomodulation of the Aβ-STING feedback machinery in microglia for Alzheimer's disease treatment.
Semaglultide targets Spp1+ microglia/macrophage to attenuate neuroinflammation following perioperative stroke.
FOXA2/miR-148a-3p/SMURF2 signaling feed-forward loop alleviates spinal cord ischemia-reperfusion injury-induced neuropathic pain by modulating microglia polarization in rats.
Acetylcholine from tuft cells promotes M2 macrophages polarization in Hirschsprung-associated enterocolitis.
Microglial Histaminergic Signaling Promotes Interleukin-10 Production and Ameliorates Motor Dysfunction in Parkinson's Disease.
Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling.
Integrative single-cell and bulk transcriptomics with Mendelian randomization reveals NAD-related biomarkers in diabetic retinopathy: Insights and experimental validation.
Spatial Transcriptomic Analysis Reveals HDAC Inhibition Modulates Microglial Dynamics to Protect Against Ischemic Stroke in Mice.
Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains.
Adrb2 Expression in Ocular-Infiltrating Macrophages Is Necessary for Interleukin-6 Expression and Choroidal Neovascularization.
Brain region and sex differences in human microglia morphology and function.
Aging-induced alterations in microglial cells and their impact on neurodegenerative disorders.
Transcription factors that define the epigenome structures and transcriptomes in microglia.
OGT-Mediated O-GlcNAcylation of ATF2 Protects Against Sepsis-Associated Encephalopathy by Inhibiting Microglial Pyroptosis.
Lycium barbarum glycopeptide alleviates retinal inflammation by suppressing microglial M1 polarization via NF-κB/MAPK pathways.
Perfluoroalkyl substance pollutants disrupt microglia function and trigger transcriptional and epigenomic changes.
Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1.

Nat Neurosci. 2025 May 30.

Microglia eliminate inhibitory synapses and drive neuronal hyperexcitability in epilepsy.

DOI: https://doi.org/10.1038/s41593-025-01983-6
Nat Neurosci. 2025 May 27.

GABA-dependent microglial elimination of inhibitory synapses underlies neuronal hyperexcitability in epilepsy.

Zhang-Peng Chen, Xiansen Zhao, Suji Wang, Ruolan Cai, Qiangqiang Liu, Haojie Ye, Meng-Ju Wang, Shi-Yu Peng, Wei-Xuan Xue, Yang-Xun Zhang, Wei Li, Hua Tang, Tengfei Huang, Qipeng Zhang, Liang Li, Lixia Gao, Hong Zhou, Chunhua Hang, Jing-Ning Zhu, Xinjian Li, Xiangyu Liu, Qifei Cong, Chao Yan.

Neuronal hyperexcitability is a common pathophysiological feature of many neurological diseases. Neuron-glia interactions underlie this process but the detailed mechanisms remain unclear. Here, we reveal a critical role of microglia-mediated selective elimination of inhibitory synapses in driving neuronal hyperexcitability. In epileptic mice of both sexes, hyperactive inhibitory neurons directly activate surveilling microglia via GABAergic signaling. In response, these activated microglia preferentially phagocytose inhibitory synapses, disrupting the balance between excitatory and inhibitory synaptic transmission and amplifying network excitability. This feedback mechanism depends on both GABA-GABAB receptor-mediated microglial activation and complement C3-C3aR-mediated microglial engulfment of inhibitory synapses, as pharmacological or genetic blockage of both pathways effectively prevents inhibitory synapse loss and ameliorates seizure symptoms in mice. Additionally, putative cell-cell interaction analyses of brain tissues from males and females with temporal lobe epilepsy reveal that inhibitory neurons induce microglial phagocytic states and inhibitory synapse loss. Our findings demonstrate that inhibitory neurons can directly instruct microglial states to control inhibitory synaptic transmission through a feedback mechanism, leading to the development of neuronal hyperexcitability in temporal lobe epilepsy.

DOI: https://doi.org/10.1038/s41593-025-01979-2
Nat Commun. 2025 May 27. 16(1): 4883

The APOE isoforms differentially shape the transcriptomic and epigenomic landscapes of human microglia xenografted into a mouse model of Alzheimer's disease.

Kitty B Murphy, Di Hu, Leen Wolfs, Susan K Rohde, Gonzalo Leguía Fauró, Ivana Geric, Renzo Mancuso, Bart De Strooper, Sarah J Marzi.

Microglia play a key role in the response to amyloid beta in Alzheimer's disease (AD). In this context, the major transcriptional response of microglia is the upregulation of APOE, the strongest late-onset AD risk gene. Of its three isoforms, APOE2 is thought to be protective, while APOE4 increases AD risk. We hypothesised that the isoforms change gene regulatory patterns that link back to biological function by shaping microglial transcriptomic and chromatin landscapes. We use RNA- and ATAC-sequencing to profile gene expression and chromatin accessibility of human microglia xenotransplantated into the brains of male APPNL-G-F mice. We identify widespread transcriptomic and epigenomic differences which are dependent on APOE genotype and are corroborated across the profiling assays. Our results indicate that impaired microglial proliferation, migration and immune responses may contribute to the increased risk for late-onset AD in APOE4 carriers, while increased phagocytic capabilities and DNA-binding of the vitamin D receptor in APOE2 microglia may contribute to the isoform's protective role.

DOI: https://doi.org/10.1038/s41467-025-60099-4
Alzheimers Dement. 2025 May;21(5): e70305

STING deletion protects against amyloid β-induced Alzheimer's disease pathogenesis.

Jessica M Thanos, Olivia C Campbell, Maureen N Cowan, Katherine R Bruch, Katelyn A Moore, Hannah E Ennerfelt, Nick R Natale, Aman Mangalmurti, Nagaraj Kerur, John R Lukens.

   INTRODUCTION: While immune dysfunction has been increasingly linked to Alzheimer's disease (AD) progression, many major innate immune signaling molecules have yet to be explored in AD pathogenesis using genetic targeting approaches.
METHODS: To investigate a role for the key innate immune adaptor molecule, stimulator of interferon genes (STING), in AD, we deleted Sting1 in the 5xFAD mouse model of AD-related amyloidosis and evaluated the effects on pathology, neuroinflammation, gene expression, and cognition.
RESULTS: Genetic ablation of STING in 5xFAD mice led to improved control of amyloid beta (Aβ) plaques, alterations in microglial activation status, decreased levels of neuritic dystrophy, and protection against cognitive decline. Moreover, rescue of neurological disease in STING-deficient 5xFAD mice was characterized by reduced expression of type I interferon signaling genes in both microglia and excitatory neurons.
DISCUSSION: These findings reveal critical roles for STING in Aβ-driven neurological disease and suggest that STING-targeting therapeutics may offer promising strategies to treat AD.
HIGHLIGHTS: Stimulator of interferon genes (STING) deficiency in the 5xFAD mouse model of Alzheimer's disease-related amyloidosis results in decreased amyloid beta (Aβ) deposition and altered microglial activation status. Protection against amyloidosis in STING-deficient 5xFAD mice is associated with decreased expression of genes involved in type I IFN signaling, improved neuronal health, and reduced levels of oxidative stress. Loss of STING in 5xFAD mice leads to improved spatial learning and memory.

Keywords:  Alzheimer's disease; STING; amyloid beta; amyloidosis; innate immunity; microglia; neurodegenerative disease; neuroimmunology

DOI:  https://doi.org/10.1002/alz.70305
Sci Adv. 2025 May 30. 11(22): eadu2244

Inactivation of the PHD3-FOXO3 axis blunts the type I interferon response in microglia and ameliorates Alzheimer's disease progression.

Manuel A Sanchez-Garcia, Nieves Lara-Ureña, Rosana March-Diaz, Clara Ortega-de San Luis, Silvia Quiñones-Cañete, Bella Mora-Romero, Juan M Barba-Reyes, Daniel Cabello-Rivera, Carmen Romero-Molina, Antonio Heras-Garvin, Victoria Navarro, Jose Lopez-Barneo, Marisa Vizuete, Javier Vitorica, Ana M Muñoz-Cabello, Ana B Muñoz-Manchado, Matthew E Cokman, Alicia E Rosales-Nieves, Alberto Pascual.

Microglia respond to Alzheimer's disease (AD) with varied transcriptional responses. We show that oligomeric Aß (oAß) induces the expression of Hif1a and Egln3 in microglia in vitro, together with the transcription of the type I interferon signature (IFNS) genes in a PHD3-dependent manner. We identify FOXO3 as a repressor of IFNS, whose abundance decreases upon PHD3 induction in response to oAß. In vivo, loss of PHD3 correlates with abrogation of the IFNS and activation of the disease-associated microglia signature, an increase in microglia proximity to Aß plaques and phagocytosis of both Aß and small plaques. PHD3 deficiency mitigated the Aß plaque-associated neuropathology and rescued behavioral deficits of an AD mouse model. Last, we demonstrate that microglial PHD3 overexpression in the absence of Aß pathology is sufficient to induce the IFNS and behavioral alterations. Together, our data strongly indicate that the inactivation of the PHD3-FOXO3 axis controls the microglial IFNS in a cell autonomous manner, improving AD outcome.

DOI: https://doi.org/10.1126/sciadv.adu2244
Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2427257122

Nanoimmunomodulation of the Aβ-STING feedback machinery in microglia for Alzheimer's disease treatment.

Limin Tian, Guangyu Long, Siqi Zhu, Yuelong Wang, Pengcheng Xu, Lifeng Liu, Hong Yao, Shentong Fang, Shuqing Chen, Suxin Li.

  Imbalanced production and clearance of amyloid-β (Aβ) is a hallmark pathological feature of Alzheimer's disease (AD). While several monoclonal antibodies targeting Aβ have shown reductions in amyloid burden, their impact on cognitive function remains controversial, with the added risk of inflammatory side effects. Dysregulated stimulator of interferon genes (STING) signaling is implicated in neurodegenerative disorders, yet the biological interaction between this pathway and Aβ, as well as their combined influence on AD progression, is poorly understood. Here, we show that while microglia play a protective role in clearing extracellular Aβ, excessive Aβ engulfment triggers the cytosolic leakage of mitochondrial DNA for cGAS-STING cascade. This creates a negative feedback loop that not only exacerbates neuroinflammation but also impairs further Aβ clearance. To address this, we present a nanomedicine approach termed "Aβ-STING Synergistic ImmunoSilencing Therapy (ASSIST)". ASSIST comprises STING inhibitors encapsulated within a blood-brain barrier (BBB)-permeable polymeric micelle that also serves as an Aβ scavenger. Through a multivalent interaction mechanism, ASSIST efficiently destabilizes Aβ plaques and prevents monomer aggregation, subsequently promoting the engulfment of the dissociated Aβ by microglia rather than neurocytes. Furthermore, the STING signaling induced by excessive Aβ uptake is blocked, reducing inflammation and restoring microglial homeostatic functions involved in Aβ clearance. Intravenous administration of ASSIST significantly reduces Aβ burden and improves cognition in AD mice, with minimal cerebral amyloid angiopathy or microhemorrhages. We provide a proof-of-concept nanoengineering strategy to target the maladaptive immune feedback loop arising from conventional immunotherapy for AD treatment.

Keywords:  Alzheimer’s disease; Aβ clearance; cGAS-STING; immune feedback; nanomedicine

DOI:  https://doi.org/10.1073/pnas.2427257122
J Neuroinflammation. 2025 May 27. 22(1): 143

Semaglultide targets Spp1+ microglia/macrophage to attenuate neuroinflammation following perioperative stroke.

Yan Li, Qiuyue Fan, Rui Pang, Ling Cai, Jie Qi, Weijie Chen, Yueman Zhang, Chen Chen, Weifeng Yu, Peiying Li.

  Peripheral surgery evokes neuroimmune activation in the central nervous system and modulates immune cell polarization in the ischemic brain. However, the phenotypic change of microglia and myeloid cells within post-surgical ischemic brain tissue remain poorly defined. Using an integrated approach that combines single-cell RNA sequencing with comprehensive biological analysis in a perioperative ischemic stroke (PIS) model, we identified a distinct Spp1-positive macrophage/microglia (Spp1+ Mac/MG) subgroup that exhibit enriched anti-inflammatory pathways with distinct lipid metabolic reprogrammed profile. Moreover, using immunofluorescence staining, we identified the expression of Glucagon-like peptide-1 receptor (GLP1R) in Spp1+F4/80+ cells and Spp1+Iba-1+ cells. Intraperitoneal administration of semaglutide, a GLP1R agonist clinically approved for the treatment of type 2 diabetes mellitus, resulted in a significant reduction of cerebral infarct volume in PIS mice compared to that in ischemic stroke (IS) mice. Meanwhile, semaglutide treatment also increased the proportion of Spp1+Edu+Iba-1+ cells 3 days after PIS. Using high-parameter flow cytometry, immunofluorescence staining and RNA sequencing, we demonstrated that semaglutide treatment significantly attenuated the expression of neuroinflammatory markers in mice following PIS. We also found that semaglutide treatment significantly ameliorated sensorimotor dysfunction up to 3 days after PIS in mice. Our current finding reveal a novel protective Spp1+Mac/MG subset after PIS and demonstrated that it can be upregulated by semaglutide. We propose that targeting Spp1+Mac/MG subsets using semaglutide could serve as a promising strategy to attenuate the exacerbated neuroinflammation in PIS.

Keywords:  Neuroinflammation; Perioperative ischemic stroke; Semaglutide; Spp1+ Mac/MG

DOI:  https://doi.org/10.1186/s12974-025-03465-9
Front Immunol. 2025 ;16 1563377

FOXA2/miR-148a-3p/SMURF2 signaling feed-forward loop alleviates spinal cord ischemia-reperfusion injury-induced neuropathic pain by modulating microglia polarization in rats.

Xiaotong Hao, Linyan Cao, Jinshi Li, Qian Lei, Xuan Liu, Yuanyuan Li, Yiting Fan, Jingjing Xu, Bo Fang.

   Background: Microglia polarization is crucial in mediating neuropathic pain. However, the role of microglia polarization in regulating spinal cord ischemia-reperfusion injury (SCIRI)-induced neuropathic pain is largely unknown. This study aimed to elucidate the relationship between SCIRI-induced neuropathic pain and microglia polarization, as well as the underlying mechanisms, with the objective of identifying potential therapeutic targets.
Methods: A rat model of SCIRI was established by aortic arch clamping, then pain thresholds were measured. In vitro, oxygen-glucose deprivation/reperfusion (OGD/R) of HAPI microglia was performed. The expressions of sirtuin1 (SIRT1), SMAD specific E3 ubiquitin protein ligase 2 (SMURF2), and markers of microglial polarization (CD206, iNOS) were quantitated by Western blot and immunofluorescence, and the levels of cytokines (TNF-α, IL-4) were assessed by Enzyme-linked immunosorbent assay (ELISA). Real-time quantitative reverse transcription PCR (RT-qPCR) experiments were conducted to quantify the levels of miR-148a-3p and FOXA2. Dual-luciferase reporter assay was employed to identify the targeted regulation of SMURF2 by miR-148a-3p and the transcriptional regulation of miR-148a-3p by FOXA2. The regulatory role of FOXA2 in the transcription of miR-148a-3p was validated using chromatin immunoprecipitation (ChIP). In addition, co-immunoprecipitation (Co-IP) assays were performed to confirm the binding relationship between SMURF2 and FOXA2. And the ubiquitination levels of FOXA2 and SIRT1 were measured. Subsequently, rats were administered miR-148a-3p to assess pain thresholds. Western blot and immunofluorescence quantitative analysis was conducted to assess the expression of markers associated with microglia polarization.
Results: SCIRI significantly reduced mechanical and thermal pain thresholds in rats and promoted microglial polarization, with a concomitant decrease in SIRT1 expression and an increase in SMURF2 expression in microglial cells. Further analysis revealed that upregulation of miR-148a-3p promoted microglia polarization toward M2 by targeting SMURF2, which in turn inhibited ubiquitination of SIRT1. FOXA2 was an upstream transcription factor of miR-148a-3p and SMURF2 bound to FOXA2, resulting in its ubiquitination. Finally, in vivo experiments demonstrated that miR-148a-3p effectively promoted microglia transformation from M1 to M2 and reduced neuropathic pain following SCIRI.
Conclusions: The FOXA2/miR-148a-3p/SMURF2 signaling feed-forward loop regulates SIRT1 levels and thereby exerts control over microglia polarization and the regulation of SCIRI-induced neuropathic pain.

Keywords:  SIRT1; foxa2; miR-148a-3p; microglia polarization; neuropathic pain; smurf2; spinal cord ischemia-reperfusion injury

DOI:  https://doi.org/10.3389/fimmu.2025.1563377
Front Immunol. 2025 ;16 1559966

Acetylcholine from tuft cells promotes M2 macrophages polarization in Hirschsprung-associated enterocolitis.

Ziyi Zheng, Lin Lin, Huifang Lin, Jie Zhou, Zhe Wang, Yang Wang, Jianxin Chen, Caimin Lai, Renfu Li, Zhiyong Shen, Ming Zhong, Cheng Xie, Yinjian Chen, Xuechao Zhang, Zhongjie Guo, Rui Dong, Shiwei He, Feng Chen.

   Background: Hirschsprung-associated enterocolitis (HAEC) is one of the most severe complications in patients with Hirschsprung's disease (HSCR). Previous research has indicated that acetylcholine (ACH) plays an anti-inflammatory role during inflammation by acting on the α7 nicotinic acetylcholine receptor(α7nAchR) to promote the secretion of anti-inflammatory factors. However, the specific role of ACH in HAEC remains unclear. This experiment aims to explore the sources of ACH in HSCR and its anti-inflammatory mechanisms, thereby identifying new directions for the prevention and treatment of HAEC.
Methods: We analyzed single-cell transcriptome data from HSCR to identify cells that secrete ACH and observed their distribution using immunofluorescence. In Ednrb-/- mice, F4/80, iNOS, ARG-1 and CD206 were used to identify and locate M1 and M2 macrophages in different intestinal segments. Western blot, reverse transcription-quantitative polymerase chain reaction, and enzyme-linked immunosorbent assay were used to test the levels of IκBα, tumor necrosis factor-α, interleukin-10, and the macrophage activation pathway proteins JAK2 and STAT3 in different intestinal segments of Ednrb-/- mice. Organoid and cell culture techniques were used to verify the anti-inflammatory mechanism of ACH in vitro models.
Results: scRNA-seq analysis revealed that tuft cells expressed the CHAT protein. In HSCR, aganglionic segments exhibited heightened cholinergic activity compared with dilated ganglionic segments. In HAEC, inflammation was mainly concentrated in the dilated ganglionic segment and was associated with an increase in M1 macrophages, whereas the aganglionic segment showed less inflammation and was associated with an increase in M2 macrophages. Furthermore, in vitro experiments showed that intestinal organoids containing tuft cells promoted an increase in M2 macrophage markers, and ACH promoted M2 macrophage polarization.
Conclusions: Differences in inflammation among various intestinal segments in HAEC may be linked to ACH secreted by tuft cells. Drugs targeting tuft cells have the potential to become important components of HAEC treatment in the future.

Keywords:  Ednrb-/-; Ednrb-/- mice; Hirschsprung-associated enterocolitis; Hirschsprung’s disease; acetylcholine; macrophages; tuft cells

DOI:  https://doi.org/10.3389/fimmu.2025.1559966
Aging Dis. 2025 May 12.

Microglial Histaminergic Signaling Promotes Interleukin-10 Production and Ameliorates Motor Dysfunction in Parkinson's Disease.

Yining Wang, Minglai Zhao, Lingjuan Li, Xiaoying Liu, Liqin Lang, Xin Zhang, Zengxin Qi.

Histamine functions as a neurotransmitter regulating multiple neural processes, whereas interleukin-10 (IL-10) is an anti-inflammatory cytokine with recognized neuroprotective properties. Previous research suggests that histamine can stimulate the release of various inflammatory mediators, including IL-10. However, the precise molecular mechanisms governing the interaction between histamine and IL-10, particularly their role in safeguarding dopaminergic neurons in Parkinson's disease (PD), have not been fully elucidated. The current findings suggest that, within the context of PD, histamine levels are elevated in the substantia nigra pars compacta (SNc) microglia, leading to an upregulation of IL-10 expression through activation of the H2 receptor and the downstream cAMP/PKA/p38β/CREB signaling cascade. However, the increased histamine concentration was negatively regulated by the IL-10 expression, allowing a limited increase in its concentration. Furthermore, the H2R-IL-10 pathway activation inhibited microglial activation and the production of inflammatory factors. Moreover, the H2R-IL-10 signaling axis modulated both membrane resistance and the expression of cleaved caspase-3 mRNA in dopaminergic neurons, contributing to the improvement of motor deficits in LPS-induced mouse models. These observations suggest that, in the pathological context of PD, microglia in the SNc exhibit increased production of histamine and IL-10 in a mutually regulatory manner. Elevated histamine levels further enhance IL-10 expression, which confers neuroprotection to dopaminergic neurons through its anti-inflammatory actions, ultimately alleviating motor impairments associated with PD.

DOI: https://doi.org/10.14336/AD.2025.0088
Int Immunopharmacol. 2025 May 26. pii: S1567-5769(25)00930-0. [Epub ahead of print]159 114940

Psilocybin and psilocin regulate microglial immunomodulation and support neuroplasticity via serotonergic and AhR signaling.

Salma Laabi, Claire LeMmon, Callie Vogel, Mariana Chacon, Victor M Jimenez.

   BACKGROUND: Psilocybin, a serotonergic psychedelic, has demonstrated therapeutic potential in neuropsychiatric disorders. While its neuroplastic and immunomodulatory effects are recognized, the underlying mechanisms remain unclear. This study investigates how psilocybin and its active metabolite, psilocin, influence microglial inflammatory responses and neurotrophic factor expression through serotonergic and AhR signaling.
METHODS: Using in vitro models of resting and LPS-activated microglia, we evaluated the effects of psilocybin and psilocin on the expression of pro-inflammatory cytokines (TNF-α), anti-inflammatory cytokines (IL-10), and neuroplasticity-related markers (BDNF). Receptor-specific contributions were assessed using selective antagonists for 5-HT2A, 5-HT2B, 5-HT7, TrkB, and AhR.
RESULTS: Psilocybin and psilocin significantly suppressed TNF-α expression and increased BDNF levels in LPS-activated microglia. These effects were mediated by 5-HT2A, 5-HT2B, 5-HT7, and TrkB signaling, while AhR activation was required for psilocin-induced BDNF upregulation but not TNF-α suppression. IL-10 levels remained unchanged under normal conditions but increased significantly when serotonergic, TrkB, or AhR signaling was blocked, suggesting a compensatory shift in anti-inflammatory pathways.
CONCLUSION: Psilocybin and psilocin promote a microglial phenotype that reduces inflammation and supports neuroplasticity via receptor-specific mechanisms. Their effects on TNF-α and BDNF depend on distinct serotonergic and neurotrophic pathways, with AhR playing a selective role in psilocin's action. These findings clarify the receptor-mediated dynamics of psilocybin's therapeutic effects and highlight alternative anti-inflammatory pathways that may be relevant for clinical applications.

Keywords:  5-HT2A; 5-HT2B; 5-HT7; AhR; BDNF; IL-10; Microglia; Neuroinflammation; Psilocin; Psilocybin; TNF-α; TrkB

DOI:  https://doi.org/10.1016/j.intimp.2025.114940
Int Immunopharmacol. 2025 May 27. pii: S1567-5769(25)00939-7. [Epub ahead of print]159 114949

Integrative single-cell and bulk transcriptomics with Mendelian randomization reveals NAD-related biomarkers in diabetic retinopathy: Insights and experimental validation.

Xudong Wen, Fei Han, Hengdi Zhang, Tao Luo, Jun Jiang, Zaiyuan Zhang, Tingrui Zhang, Yubo Li, Ling Yang, Weiming Yan, Mengshan He, Pan Long.

   BACKGROUND: Metabolic dysregulation involving nicotinamide adenine dinucleotide (NAD) has been implicated in the pathogenesis of various diseases; however, its role in diabetic retinopathy (DR) remains poorly understood. This study aimed to identify NAD-associated biomarkers and elucidate their molecular mechanisms in DR.
METHODS: DR-related data were retrieved from public databases. NAD-associated biomarkers were identified through differential expression analysis, NAD-related gene (NAD-RG) score comparison, Mendelian randomization (MR) analysis, and experimental validation. Functional enrichment and immune microenvironment analyses were conducted to explore the mechanisms underlying biomarker involvement in DR. Single-cell RNA sequencing (scRNA-seq) was employed to identify key cell types, and pseudo-temporal trajectory analysis was performed to assess dynamic biomarker expression during cellular differentiation. Reverse transcription quantitative PCR (RT-qPCR) was used to validate biomarker expression levels.
RESULTS: CCDC88A and GPD2 were identified as DR potential biomarkers and risk factors for disease progression. These genes were co-enriched in key pathways, including oxidative phosphorylation. CCDC88A exhibited the strongest positive correlation with monocytes (cor = 0.35, p < 0.05). scRNA-seq analysis highlighted microglia as key cells in DR. During microglia differentiation, CCDC88A expression initially decreased before rising, while GPD2 expression increased initially, declined, and then slowly increased in later stages. RT-qPCR confirmed significantly elevated expression of CCDC88A and GPD2 in the DR group (P < 0.05).
CONCLUSION: This study integrates bulk and single-cell transcriptomic analyses to identify CCDC88A and GPD2 as DR potential biomarkers and microglia as key cellular players, providing new insights into DR pathogenesis and potential diagnostic strategies.

Keywords:  Biomarkers; Diabetic retinopathy; Mendelian randomization; Nicotinamide adenine dinucleotide; Single-cell sequencing analysis

DOI:  https://doi.org/10.1016/j.intimp.2025.114949
Glia. 2025 May 26.

Spatial Transcriptomic Analysis Reveals HDAC Inhibition Modulates Microglial Dynamics to Protect Against Ischemic Stroke in Mice.

Kevin Jayaraj, Ritesh Kumar, Sukanya Shyamasundar, Thiruma V Arumugam, Jai S Polepalli, S Thameem Dheen.

  Ischemic stroke significantly contributes to global morbidity and disability through a cascade of neurological responses. Microglia, the immune modulators within the brain, exhibit dual roles in exacerbating and ameliorating ischemic injury through neuroinflammatory and neuroprotective roles, respectively. Despite emerging insights into microglia's role in neuronal support, the potential of epigenetic intervention to modulate microglial activity remains largely unexplored. We have previously shown that sodium butyrate, a histone deacetylase inhibitor (HDACi) epigenetically regulates the inflammatory response of microglia after ischemic stroke, and this study was aimed at characterizing the transcriptomic profiles of microglia and their spatial distribution in the stroke brain following HDACi administration. We hypothesized that the administration of HDACi epigenetically modulates microglial activation and a region-specific microglial phenotype in the stroke brain, shifting their phenotype from neurotoxic to neuroprotective and facilitating neuronal repair in the ischemic penumbra. Utilizing a rodent model of stroke, spatial transcriptomics and 3D morphometric reconstruction techniques were employed to investigate microglial responses in critical penumbral regions following HDACi administration. We found HDACi significantly altered the microglial transcriptomic landscape involving biological pathways of neuroinflammation, neuroprotection, and phagocytosis, as well as morphological phenotype, promoting a shift toward reparative, neurotrophic profiles within the ischemic penumbra. These changes were associated with enhanced neuronal survival and reduced neuroinflammation in specific regions in the ischemic brain. By elucidating the mechanisms through which HDACi influences microglial function, our findings propose therapeutic avenues for neuroprotection and rehabilitation in ischemic stroke, and possibly other neurodegenerative conditions that involve microglia-mediated neuroinflammation.

Keywords:  HDAC inhibitor; microglia; neuroinflammation; neuroprotection; spatial transcriptomics; stroke

DOI:  https://doi.org/10.1002/glia.70035
Neurobiol Dis. 2025 May 26. pii: S0969-9961(25)00192-5. [Epub ahead of print]212 106976

Imbalanced mitochondrial dynamics in human PD and α-synuclein mouse brains.

Harry J Brown, Rebecca Z Fan, Riley Bell, Said S Salehe, Carlos Martínez Martínez, Yanhao Lai, Kim Tieu.

  Emerging studies have shown that dysregulation in mitochondrial dynamics has a major negative impact on mitochondria. Partial genetic and pharmacological inhibition of the mitochondrial fission dynamin-related protein 1 (DRP1) has been demonstrated to be beneficial in models of neurodegenerative disorders, including Parkinson's disease (PD). However, the expression of DRP1 and other mitochondrial fission/fusion mediators have not been investigated in the brains of Parkinson's patients. This information is critical to strengthening mitochondrial dynamics as a potential therapeutic target for PD. We report in this study that significant increases in the levels of both DNM1L, which encodes DRP1, as well as the DRP1 protein were detected in Parkinson's patients. Immunostaining revealed increased DRP1 expression in dopamine (DA) neurons, astrocytes, and microglia. In addition to DRP1, the levels of other fission and fusion genes/proteins were also altered. To complement these human studies and given the significant role of α-synuclein in PD pathogenesis, we performed time-course studies using transgenic mice overexpressing human wild-type SNCA. As early as six months old, we detected an upregulation of DRP1 in the nigral DA neurons of the SNCA mice as compared to their wild-type littermates. Furthermore, these mutant animals exhibited more DRP1 phosphorylation at serine 616, which promotes its translocation to mitochondria to induce fragmentation. Together, this study shows an upregulation of DRP1 and alterations in other fission/fusion proteins in both human and mouse PD brains, leading to a pro-fission phenotype, providing additional evidence that blocking mitochondrial fission or promoting fusion is a potential therapeutic strategy for PD.

Keywords:  Dynamin-related protein 1; Mitochondrial dynamics; Neurodegeneration; Parkinson's disease; Protein aggregation; α-synuclein

DOI:  https://doi.org/10.1016/j.nbd.2025.106976
Invest Ophthalmol Vis Sci. 2025 May 01. 66(5): 43

Adrb2 Expression in Ocular-Infiltrating Macrophages Is Necessary for Interleukin-6 Expression and Choroidal Neovascularization.

Joyce Gong, Kyle S Chan, Amrita Rajesh, Steve Droho, Jeremy A Lavine.

Purpose: Effective therapies for treatment resistant neovascular age-related macular degeneration (nAMD) remain an unmet need. Beta-adrenergic receptor (AR) blockers can decrease laser-induced choroidal neovascularization (CNV) size in mice. We have shown that monocyte-derived macrophages (MDMs) and interleukin-6 (IL-6) are necessary for beta-AR blockers to inhibit CNV. However, the specific beta-AR and the mechanism of this pathway are not fully elucidated. We hypothesized that beta2-AR (Adrb2) signaling on MDMs increases IL-6 production and stimulates CNV.
Methods: Previously published single-cell RNA-sequencing data was reanalyzed to determine which mononuclear phagocytes express beta-ARs. Adrb2flox/flox: Cx3cr1CreER/+ mice (Adrb2ΔMacs) or Adrb2flox/flox (Adrb2flox) controls were given tamoxifen injections at either four weeks before or at the time of laser-induced CNV to knockout Adrb2 in tissue resident or all macrophages, respectively. Mice underwent laser induced-CNV, and eyes were collected for choroidal wholemount immunofluorescence imaging to measure CNV area, multiparameter flow cytometry to analyze macrophage heterogeneity, and ELISAs to quantitate IL-6 levels.
Results: Adrb2 was the predominantly expressed beta-AR and was found on microglia, macrophages, and monocytes. Adrb2 deletion in tissue resident macrophages had no effect upon CNV area. Adrb2 deletion in all macrophages decreased CNV area by 1.4-fold. Adrb2ΔMacs posterior eye cups demonstrated similar levels of pro-angiogenic CD11c+ macrophages compared to Adrb2flox controls, but Ly6CnegCD11cneg macrophages were significantly increased. IL-6 levels increased with laser in Adrb2flox controls, but IL-6 levels in Adrb2ΔMacs posterior eye cups were unchanged.
Conclusions: Beta2-AR deletion in ocular-infiltrating macrophages decreases laser-induced CNV area. Beta2-AR expression regulates IL-6 expression in monocyte-derived macrophages.

DOI: https://doi.org/10.1167/iovs.66.5.43
Cereb Cortex. 2025 May 01. pii: bhaf120. [Epub ahead of print]35(5):

Brain region and sex differences in human microglia morphology and function.

Andrew R Yoblinski, Jyoti Dubey, Tyler Myers, Nitya Sathees, David W Volk, Kenneth N Fish, Marianne L Seney.

  Microglia exhibit complex and dynamic morphology that is linked to function. Altered microglia function has been implicated in multiple diseases of the brain, including elevated phagocytosis of neuronal dendritic spines in schizophrenia. However, understanding the relationship between altered microglia and pathophysiology first requires a clearer picture of microglia morphology in the non-diseased brain, which has yet to be fully established. Here, we deploy immunostaining and confocal microscopy to sample over 1,300 microglia from two prefrontal cortex (PFC) subregions in postmortem human brain (3 males, 3 females). We use Neurolucida 360 to trace the 3-dimensional structure of these microglia and quantify interactions with dendritic spines. We find that PFC microglia in male subjects display overall more complex branching than in female subjects, and subgenual anterior cingulate cortex (sgACC) microglia are more complexly branched with more round somas than those in the dorsolateral PFC (DLPFC), irrespective of sex. Furthermore, a lower proportion of phagocytic burden in sgACC microglia involves engulfment of dendritic spines compared to DLPFC. Overall, our results paint a detailed and nuanced picture of microglia morphology and function in subjects unaffected by psychiatric or neurologic illness that can be used as a benchmark for future studies of the diseased brain.

Keywords:  DLPFC; dendritic spines; phagocytosis; postmortem; sgACC

DOI:  https://doi.org/10.1093/cercor/bhaf120
Mol Biol Rep. 2025 May 29. 52(1): 515

Aging-induced alterations in microglial cells and their impact on neurodegenerative disorders.

Hridaya Singh, Rahul Gupta, Madhu Gupta, Ausaf Ahmad.

  Senescence causes deterioration in the functioning and physiology of an organism. Microglia, the standing resident immune brain cells transform from neuroprotective to neurotoxic with age. Rapid process motility and cellular migration of microglia in the developing brain, and other characteristics are regarded to be crucial for immunological defense and tissue repair. As they mature, microglia not only differ in their morphology but also in their functioning. However, the exact mechanism related to the atrophies caused by aged microglia or their role in neurodegenerative diseases is still uncertain. The aim of this updated review is to provide insights of how aging microglial cells change and how this influences the development of neurodegenerative diseases. As life expectancy rises, there is an increase in the accumulation of iron, ROS/NOS, protein misfolding and insufficient clearing of debris. This is attributed to the age-dependent alterations in the genes linked to energy metabolism, mitochondrial and lysosome function, and neuroinflammation. Aging microglia often shifts towards a pro-inflammatory state with a reduction of anti-inflammatory cytokines. Aging microglia fail to clear amyloid-beta plaques, accelerates tau-pathology and enhances the chronic neuroinflammation, exacerbating the α-synuclein aggregation. These changes significantly impacted the onset of various neurogenerative disorders such as amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease etc. However, it is important to note that these microglial aging effects might not be perceived as absolute, due to various limitations such as microglial heterogeneity, intercellular complexity across brain regions and variability in human aging owing to genetic and epigenetic variations. Regardless of this the future perspective of such insights are of immense relevance as novel therapeutic approaches can be formulated if the molecular and cellular mechanisms of aging microglial perturbations are understood. Future research should focus on restoring microglial homeostasis to mitigate the effects of aging on the brain and slowing the progression of neurodegenerative diseases.

Keywords:  Aging; Microglial cells; Neurodegenerative diseases; Neuroinflammation

DOI:  https://doi.org/10.1007/s11033-025-10623-y
Exp Hematol. 2025 May 25. pii: S0301-472X(25)00105-5. [Epub ahead of print] 104814

Transcription factors that define the epigenome structures and transcriptomes in microglia.

Keita Saeki, Keiko Ozato.

  Microglia, the resident macrophages of the brain, play critical roles in maintaining brain health. Recent genome-wide analyses, including ATAC-seq, ChIP-seq/CUT&RUN, and single-cell RNA-seq, have identified key transcription factors that define the transcriptome programs of microglia. Four transcription factors-PU.1, IRF8, SALL1, and SMAD4-form enhancer complexes and act as lineage-determining factors, shaping microglial identity. These factors co-bind with other lineage-determining transcription factors, directing one towards designated regions that program microglia while inhibiting the other from binding to DNA. Other transcription factors, such as BATF3 and MAFB, contribute to transcriptional cascades in microglia. TGF-β is a crucial cytokine driving these transcription factors to bind DNA and maintain homeostatic microglia. These findings provide insights into the physiological aspects of microglia and their roles in neuroinflammatory and neurodegenerative diseases. TEASER ABSTRACT: eTOC blurb: In this article, we compiled more than 100 transcription factors expressed in microglia. Our analysis illustrates that some transcription factors are under a distinct hierarchical rank and are sequentially activated to achieve microglia specific transcriptome programs. This article offers a new scope on the mechanistic foundation underlying microglia's complex activity.

Keywords:  DNA methylation; Epigenome; Homeostatic microglia; TGF-β; Transcription factor cascades; Transcription factors

DOI:  https://doi.org/10.1016/j.exphem.2025.104814
Neurosci Bull. 2025 May 24.

OGT-Mediated O-GlcNAcylation of ATF2 Protects Against Sepsis-Associated Encephalopathy by Inhibiting Microglial Pyroptosis.

Huan Yao, Caixia Liang, Xueting Wang, Chengwei Duan, Xiao Song, Yanxing Shang, Mingyang Zhang, Yiyun Peng, Dongmei Zhang.

  Microglial pyroptosis and neuroinflammation have been implicated in the pathogenesis of sepsis-associated encephalopathy (SAE). OGT-mediated O-GlcNAcylation is involved in neurodevelopment and injury. However, its regulatory function in microglial pyroptosis and involvement in SAE remains unclear. In this study, we demonstrated that OGT deficiency augmented microglial pyroptosis and exacerbated secondary neuronal injury. Furthermore, OGT inhibition impaired cognitive function in healthy mice and accelerated the progression in SAE mice. Mechanistically, OGT-mediated O-GlcNAcylation of ATF2 at Ser44 inhibited its phosphorylation and nuclear translocation, thereby amplifying NLRP3 inflammasome activation and promoting inflammatory cytokine production in microglia in response to LPS/Nigericin stimulation. In conclusion, this study uncovers the critical role of OGT-mediated O-GlcNAcylation in modulating microglial activity through the regulation of ATF2 and thus protects against SAE progression.

Keywords:  Activation transcription factor 2 (ATF2); Microglia; O-GlcNAc transferase (OGT); Pyroptosis; Sepsis-associated encephalopathy (SAE)

DOI:  https://doi.org/10.1007/s12264-025-01418-z
Exp Eye Res. 2025 May 23. pii: S0014-4835(25)00223-4. [Epub ahead of print]257 110452

Lycium barbarum glycopeptide alleviates retinal inflammation by suppressing microglial M1 polarization via NF-κB/MAPK pathways.

Yiwen Ou, Yinhua Huang, Xu Yang, Lian Li, Rangsheng Mei, Zhexiong Yu, Kwok-Fai So, Jiansu Chen, Jacey Hongjie Ma, Shibo Tang.

  Lycium barbarum glycopeptide (LBGP) is a known glycoconjugate with various pharmacological benefits, notably anti-inflammatory properties, though its impact on retinal inflammatory conditions is not fully understood. This research evaluated the impact of LBGP on retinal inflammation using a diabetic retinopathy (DR) mouse model induced by streptozotocin (STZ), along with LPS/IFN-γ (L/I)-stimulated BV2 microglia and primary retinal microglia. In vivo, administration of LBGP effectively enhances retinal thickness, structure, and function in diabetic mice. Additionally, it prevents microglial activation and inflammation. In vitro, LBGP pretreatment significantly reversed L/I-induced morphological alterations in microglial area, perimeter, Feret's diameter, and roundness. LBGP significantly alleviated L/I-induced microglial activation in primary and BV2 microglia. LBGP shifted M1 pro-inflammatory phenotype to M2 anti-inflammatory phenotype by downregulating M1 markers (IL-6, IL-1β, iNOS, COX2, CD86, and CD16) and upregulating M2 markers (CD206 and arginase 1). Additionally, LBGP reduced the upregulation of NF-κB and MAPK pathways in L/I-stimulated BV2 microglial cells. Our study suggests that LBGP protects against microglial overactivation and diminishes the secretion of inflammatory molecules from microglia in vivo and vitro, potentially through attenuation of the NF-κB and MAPK signaling pathways.

Keywords:  DR; LBGP; MAPK; Microglia; NF-κB; Polarization; Retinal inflammatory diseases

DOI:  https://doi.org/10.1016/j.exer.2025.110452
Toxicology. 2025 May 24. pii: S0300-483X(25)00157-X. [Epub ahead of print] 154198

Perfluoroalkyl substance pollutants disrupt microglia function and trigger transcriptional and epigenomic changes.

Yating Cheng, Jian-Rong Li, Hangjin Yu, Shuang Li, Boranai Tychhon, Chao Cheng, Yi-Lan Weng.

  Per- and polyfluoroalkyl substances (PFAS), commonly referred to as "forever chemicals", are widely utilized in various industries and consumer products worldwide. Their exposure has been associated with numerous diseases and malignancies, including neurodevelopmental and neurodegenerative disorders. However, the molecular mechanisms underlying PFAS-induced adverse effects on the central nervous system (CNS) remain poorly understood. In this study, we investigated the transcriptomic and epigenetic changes in microglia exposed to perfluorooctane sulfonate (PFOS), a prevalent PFAS compound. Our findings demonstrate that 24-hour PFOS exposure (25 and 50µM) disrupts the microglial transcriptome and compromises their homeostatic state, marked by increased inflammation and impaired actin cytoskeleton remodeling. Comparative analysis with in vivo transcriptional states revealed that PFOS-exposed microglia exhibit gene expression profiles resembling those of aged microglia. Additionally, profiling of active chromatin regions uncovered significant alterations in the H3K27ac landscape in PFOS-exposed microglia. Notably, these epigenetic disruptions persisted even after PFOS withdrawal, with a subset of H3K27ac-enriched regions remaining altered, suggesting the presence of lasting epigenetic scars. Furthermore, transcription factor analysis implicated the AP-1 and TEAD families as potential upstream regulators connecting the altered chromatin landscape to transcriptomic changes. Collectively, these findings provide mechanistic insights into how PFOS exposure disrupts microglial function and highlight its potential role in exacerbating neurodegenerative processes.

Keywords:  PFAS; aged microglia; epigenetic scars; inflammation; neurodegeneration

DOI:  https://doi.org/10.1016/j.tox.2025.154198
Int J Mol Sci. 2025 May 14. pii: 4698. [Epub ahead of print]26(10):

Fingolimod Prevents Neuroinflammation but Has a Limited Effect on the Development of Ataxia in a Mouse Model for SCA1.

Chen Yang, Nienke Gravendeel, Amy Chin On, Laura Post, Ryan van Bergen, Catarina Osorio, Martijn Schonewille.

  Spinocerebellar ataxia type 1 (SCA1) is a neurodegenerative disorder that predominantly affects the Purkinje cells (PCs) of the cerebellum, leading to cerebellar degeneration, motor dysfunction, and cognitive impairment. Sphingosine-1-phosphate (S1P) signaling, known to modulate neuroinflammation, has been identified as a potential therapeutic target in SCA1. To investigate the therapeutic efficacy of the S1P modulator fingolimod, we treated a mouse model for SCA1, ATXN1[82Q]/+ mice during three different periods with fingolimod and assessed the effects. Potential therapeutic effects were monitored by tracking locomotion during the treatment period and examining PC morphology, connectivity, and markers for neuroinflammation post-mortem. Fingolimod treatment reduced astrocyte and microglial activation during all three treatment periods. We found no effect on calbindin levels or the thickness of the molecular layer, but fingolimod did improve the extent of the synaptic input of climbing fibers to PCs. While fingolimod improved important aspects of cellular pathology, we could only detect signs of improvement in the locomotion phenotype when treatment started at a later stage of the disease. In conclusion, fingolimod is able to mitigate neuroinflammation, preserve aspects of PC function in SCA1, and remediate part of the ataxia phenotype when treatment is appropriately timed. Although behavioral benefits were limited, targeting S1P pathways represents a potential therapeutic strategy for SCA1. Further studies are needed to optimize treatment regimens and assess long-term outcomes.

Keywords:  fingolimod; microglia; neuroinflammation; sphingosine-1-phosphate pathway; spinocerebellar ataxia type 1

DOI:  https://doi.org/10.3390/ijms26104698