bims-microg 2025-10-05 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–10–05
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis.
From sentinels to engineers: The future of microglia in brain regeneration.
Microglial ADGRG1: AD glial resilience generator.
Treg-microglia partnership in the injured spinal cord preserves Treg cell function and regulates microglial cholesterol metabolism.
Heterogeneity of Extracellular Vesicles and Non-Vesicular Nanoparticles in Glioblastoma.
Intracortical microstimulation induces rapid microglia process convergence.
Demyelinated lesion associated compartmental inflammation in progressive multiple sclerosis brains.
Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.
Cholecystokinin ameliorates cognitive impairment via inhibiting microglia phagocytosis of excitatory synapses in sepsis-associated encephalopathy mice.
A novel electric field approach for improving cognitive function through ameliorating cell-specific pathology in P301S tauopathy mice.
Single-nucleus transcriptomics reveals sepsis-related neurovascular dysfunction in the human hippocampus.
Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits.
Intermittent fasting attenuates glial hyperactivation and photoreceptor degeneration in a NaIO3-induced mouse model of age-related macular degeneration.
Single nucleus RNA sequencing unveils relationship between microglia and endothelial cells in mixed Alzheimer's disease and vascular pathology.
S-ketamine relieves neuropathic pain by inhibiting microglia phagocytosis of the perineuronal nets.
Targeting RORγ to boost regulatory T cells and ameliorate diabetic retinopathy in mice.
Increased reactive astrocytes in hippocampal CA1 region mediated by decreased CXCR7 is involved in postoperative cognitive dysfunction in aged mice.
Distinct reduction in relative microglial glucose uptake compared to astrocytes and neurons upon isolation from the brain environment.
Retinitis pigmentosa elicits neurodegeneration within the visual pathway in REEP6 knockout mice.
Mechanisms of methyltransferase-like 3-mediated microglial pyroptosis in sepsis-associated encephalopathy.

Immunity. 2025 Oct 02. pii: S1074-7613(25)00418-2. [Epub ahead of print]

Notch3 destabilizes regulatory T cells to drive autoimmune neuroinflammation in multiple sclerosis.

Mehdi Benamar, Paola Contini, Klaus Schmitz-Abe, Olga Lanzetta, Feven Getachew, Corinne Bachelin, Juan Manuel Leyva Castillo, Muyun Wang, Fatma Betul Oktelik, Océane Perrot, Yvann Batamack, Sena Nur Arbag, Emmanuel Stephen-Victor, Hani Harb, Pankaj B Agrawal, Céline Louapre, Federico Ivaldi, Antonio Uccelli, Matilde Inglese, Claudia Angelini, Violetta Zujovic, Raffaele De Palma, Talal A Chatila.

  The immune regulatory defects that promote neuroinflammation in multiple sclerosis (MS) remain unclear. We show that a specific regulatory T (Treg) cell subpopulation expressing Notch3 was increased in individuals with MS and in mice with experimental autoimmune encephalomyelitis (EAE). Notch3+ Treg cells were induced by the gut microbiota via Toll-like receptor (TLR)-dependent mechanisms. They then translocated to the central nervous system (CNS) in EAE where they promoted disease severity. Notch3 interacted with delta-like ligand 1 (DLL1) on microglia to subvert Treg cells into T helper 17 (Th17) cells. Notch3 deletion in Treg cells prevented EAE onset by stabilizing Treg cells and by simultaneously promoting the expansion of a tissue-resident Treg cell population that expressed neuropeptide Y receptor 1 (NPY1R) and which suppressed pathogenic IFN-γ+ and GM-CSF+ T cells. Our studies thus identify altered Treg cell population dynamics as a fundamental pathogenic mechanism in autoimmune neuroinflammation.

Keywords:  DLL1; EAE; Hippo pathway; NPY1R; Notch3; central nervous system; ex-Treg cells; immune tolerance; multiple sclerosis; regulatory T cells

DOI:  https://doi.org/10.1016/j.immuni.2025.09.007
Cell Stem Cell. 2025 Oct 02. pii: S1934-5909(25)00335-2. [Epub ahead of print]32(10): 1487-1488

From sentinels to engineers: The future of microglia in brain regeneration.

Muzhen Qiao, Peng Jiang.

Recent studies highlight microglial replacement as a promising therapeutic approach for neurological disease. Wu et al.1 demonstrated that transplanted bone marrow-derived cells halted ALSP progression, while Mader et al.2 introduced a strategy that avoids systemic bone marrow ablation toxicity and reduces immune rejection, collectively validating this strategy's therapeutic potential.

DOI: https://doi.org/10.1016/j.stem.2025.09.004
Neuron. 2025 Oct 01. pii: S0896-6273(25)00669-5. [Epub ahead of print]113(19): 3070-3072

Microglial ADGRG1: AD glial resilience generator.

Kia M Barclay, Qingyun Li.

Microglial states underlying Alzheimer's disease (AD) have been well characterized in animal models and human samples, yet their regulation remains elusive. In this issue of Neuron, Zhu et al.1 uncover Adgrg1, which governs a protective microglia phenotype through MYC activation.

DOI: https://doi.org/10.1016/j.neuron.2025.09.003
Neuron. 2025 Sep 29. pii: S0896-6273(25)00667-1. [Epub ahead of print]

Treg-microglia partnership in the injured spinal cord preserves Treg cell function and regulates microglial cholesterol metabolism.

Tao Qin, Tao Jiang, Zihan Zhou, Mengyuan Wu, Yuanzhen Zhang, Zhenqi Yang, Ziyang Zheng, Jiang Yi, Xiaowei Wang, Mingran Luo, Peng Gao, Jiayun Liu, Yifan Huang, Hao Liu, Qingqing Li, Wei Zhou, Shujun Zhang, Xiaodong Guo, Baorong He, Yongxiang Wang, Jin Fan, Shujie Zhao, Jian Chen, Guoyong Yin.

  The spatiotemporal dynamics and specific roles of regulatory T (Treg) cells in spinal cord injury (SCI) remain unclear. Using single-cell RNA sequencing, flow cytometry, and immunofluorescence, we found that thymus-derived Treg cells infiltrate the injured spinal cord via peripheral blood around 3 days post-SCI. Treg cell depletion worsened SCI and impaired long-term recovery. Transcriptomic profiling revealed strong anti-inflammatory functions of Treg cells and the potential to regulate cholesterol metabolism in neighboring microglia. Further single-cell RNA sequencing uncovered the clonality of SCI-associated Treg cells. Major histocompatibility complex class II (MHC II) expression on microglia, not macrophages, was crucial for sustaining Treg cell numbers and neuroprotective function, with myelin-phagocytosing microglia-activated Treg cells showing significant neuroprotective effects. Treg cells mitigated microglial inflammation via CTLA-4 and upregulated the ATP-binding cassette transporter G1 (Abcg1) receptor in microglia, helping to manage myelin load and reduce lipid droplet formation. Our findings offer mechanistic insights into SCI-associated Treg cells and lay the groundwork for future Treg-based therapies in SCI treatment.

Keywords:  Abcg1; MHC II; cholesterol metabolism; microglia; regulatory T cell; spinal cord injury

DOI:  https://doi.org/10.1016/j.neuron.2025.09.001
J Extracell Vesicles. 2025 Oct;14(10): e70168

Heterogeneity of Extracellular Vesicles and Non-Vesicular Nanoparticles in Glioblastoma.

Tuoye Xu, Joao A Paulo, Piyan Zhang, Xinyue Liu, Alya Nguyen, Yuanhua Cheng, Clark Massick, Yanhong Zhang, Dennis K Jeppesen, Qin Zhang, James N Higginbotham, Oleg S Tutanov, Anna M Krichevsky, Daniel T Chiu, Steve P Gygi, Kasey C Vickers, Jeffrey L Franklin, Robert J Coffey, Al Charest.

  It is increasingly clear that intercellular communication is largely mediated by lipid-bilayer, membrane-bound extracellular vesicles (EVs) and amembranous, non-vesicular extracellular particles (NVEPs), including exomeres and the recently identified supermeres. To elucidate the cargo and functional roles of these carriers, we performed a comprehensive analysis of their lipid, protein and RNA content in the context of colorectal cancer and glioblastoma (GBM). Our results demonstrate that EVs exhibit distinct density profiles correlated with specific biomolecular signatures. Moreover, EVs and NVEPs display notable differences in their protein and RNA composition, which confer distinct functional attributes. Supermeres are notably enriched in components involved in extracellular matrix remodeling and possess the ability to cross the blood-brain barrier, a process dependent on their intact structure and RNA content. Once in the central nervous system (CNS), they preferentially engage with microglia and suppress TGFβ1 expression, suggesting a role in modulating microglial immune activity. Furthermore, systemically administered exogenous supermeres selectively accumulate in GBM tumors in vivo. Together, these findings highlight supermeres as a promising vehicle for delivering therapeutics to the CNS and brain tumors.

Keywords:  EGFR; exomeres; extracellular nanoparticles; extracellular vesicles; glioblastoma; supermeres

DOI:  https://doi.org/10.1002/jev2.70168
Biomaterials. 2025 Sep 24. pii: S0142-9612(25)00651-9. [Epub ahead of print]327 123732

Intracortical microstimulation induces rapid microglia process convergence.

Nathaniel P Williams, Anna M Kelly, X Sally Zheng, Alberto L Vazquez, X Tracy Cui.

Intracortical microstimulation (ICMS) has the potential to restore vision and hearing by stimulating relevant cortical regions in both animals and humans, offering significant clinical promise for sensory restoration. While the neuronal response to ICMS has been extensively studied at the cellular level through electrophysiology and two-photon (2P) imaging, the response of non-neuronal cells, particularly microglia, as well as the effects on blood-brain barrier (BBB) integrity remain poorly understood. In this study, we applied ICMS under 2P imaging in dual-reporter mice, with green fluorescent protein labeling microglia and a red fluorescent Ca2+ indicator labeling neurons. We also monitored vascular dye leakage to assess BBB integrity. Using clinically relevant waveforms, we tested a range of current amplitudes. Surprisingly, we found that microglia responded within 15 min of stimulation by converging their processes (MPC) on areas of high neural activity and the prevalence of MPC increased at higher current amplitudes. Additionally, vascular dye penetration into brain tissue was higher in stimulated animals and increased with current amplitude. This study reveals a rapid microglia and BBB response to ICMS that has not been reported previously, underscoring the need for further research to fully characterize the biological response to ICMS and establish improved safety standards.

DOI: https://doi.org/10.1016/j.biomaterials.2025.123732
Acta Neuropathol Commun. 2025 Sep 29. 13(1): 204

Demyelinated lesion associated compartmental inflammation in progressive multiple sclerosis brains.

Liane Najm, Anthony Chomyk, Kaitlyn Cyncynatus, Dimitrios Davalos, Kedar R Mahajan, Bruce D Trapp.

  The pathogenesis of progressive multiple sclerosis (PMS) involves aggregates of peripheral and innate immune cells that are collectively referred to as compartmental inflammation. Sites include the meninges, perivascular spaces of vessels, choroid plexus, and borders of demyelinated lesions. Iron-laden activated microglia/macrophages that border cerebral white matter (WM) lesions appear as paramagnetic rims (PRLs) on magnetic resonance imaging. PRLs have been associated with lesion expansion and are considered as a target of brain-penetrable therapies in people with MS. Less is known about inflammatory compartments Bordering cortical lesions. The objective of this retrospective study is to describe the location and morphology of MHC Class II-positive cells in 334 demyelinated lesions from 22 PMS brains. Activated microglia bordered Type III subpial lesions (cortical layers I through III demyelinated) and cortical portions of leukocortical lesions. Activated microglia/macrophages lined the border of chronic active WM lesions, WM portions of leukocortical lesions, and Type IV subpial lesions (all six cortical layers demyelinated). Type IV subpial lesions were lined by activated microglia/macrophages that resided in subcortical WM and were always contiguous with Type III subpial lesions. The location in WM or cortex, rather than lesion type, determined the cellular composition of inflammatory compartments. Since the majority of subpial lesions stop at cortical layer IV and Type IV subpial lesions do not invade subcortical WM, compartments bordering subpial lesions are often associated with lesion stability. Iron was enriched in a subpopulation of inflammatory compartments bordering WM and Type IV subpial lesions, as well as at the border of myelinated cortex and subcortical WM. These myelinated borders were not enriched in microglia and iron was diffusely distributed, providing evidence that iron enrichment is not always associated with lesion expansion nor compartmental inflammation. These data will aid in designing imaging outcome measures for clinical trials targeting inflammatory compartments in PMS.

Keywords:  Compartmental inflammation; Iron; Multiple sclerosis; Neuropathology

DOI:  https://doi.org/10.1186/s40478-025-02122-9
J Neuroinflammation. 2025 Oct 02. 22(1): 223

Microglial glycolytic reprogramming in alzheimer's disease: association with impaired phagocytic function and altered vascular proximity.

Ning Lu, Zhongman Jin, Nian Liu, Caiyun Zhu, Hui Wei, Qi Xu.

   BACKGROUND: Alzheimer's disease (AD) is characterized by chronic neuroinflammation alongside amyloid-beta plaque and phosphorylated tau (p-Tau) tangle accumulation. Microglia, as resident immune cells, undergo glycolytic reprogramming that may exacerbate inflammation and impede toxic protein clearance. Specifically, the glycolytic enzyme pyruvate kinase M2 (PKM2) drives proinflammatory microglial phenotypes linked to neurodegeneration. This study investigates how PKM2-mediated microglial glycolytic reprogramming and inflammatory responses alongside Aβ/p-Tau clearance in human AD brains.
METHODS AND RESULTS: Hippocampal-entorhinal cortex (HP-EC) tissues from 8 AD patients and 8 matched controls underwent multiplex immunohistochemistry and high-resolution spatial analysis. PKM2+Iba1+ microglia density significantly increased in AD versus controls (p < 0.001), predominantly displaying a disease-associated microglial (HAM-like) phenotype (ABCA7+) with concurrent lipid-droplet accumulation (PLIN3+; LDAM phenotype). Spatially, glycolytic PKM2+Iba1+ microglia accumulated near Aβ plaques, p-Tau tangles, and cerebral vasculature. Notably, their distribution around plaques/tau showed anomalous increasing density with distance (p < 0.001), suggesting impaired chemotaxis. Perivascular localization lacked clear chemotactic gradients. Functionally, overall phagocytic activity (CD68+) decreased significantly in AD (p = 0.001), primarily attributed to PKM2- subsets, whereas PKM2+Iba1+ microglia exhibited pronounced phagocytic exhaustion (PLIN2+; p < 0.001), consistent around both Aβ and p-Tau lesions (all p < 0.001).
CONCLUSION: Our study establishes that microglial glycolytic reprogramming via PKM2 promotes a proinflammatory HAM-like phenotype, phagocytic exhaustion, and peri-pathological accumulation with aggregates and cerebral vessels. Targeting glycolytic pathways represents a viable therapeutic strategy for alleviating microglial dysfunction and neuroinflammation in AD.

Keywords:  Alzheimer’s disease; Glycolysis; Microglia; Neuroinflammation; PKM2

DOI:  https://doi.org/10.1186/s12974-025-03546-9
J Neuroinflammation. 2025 Sep 29. 22(1): 217

Cholecystokinin ameliorates cognitive impairment via inhibiting microglia phagocytosis of excitatory synapses in sepsis-associated encephalopathy mice.

Lei Chen, Zhen Li, Yubo Gao, Guangxi Piao, Yitong Li, Jingshu Hong, Qian Wang, Kaixi Liu, Jie Wang, Ailian Du, Luhua Chen, Xiangyang Guo, Zhengqian Li, Taotao Liu.

   BACKGROUND: Sepsis-associated encephalopathy (SAE) is characterised by cognitive impairment and is a common complication in patients with sepsis. Microglia are involved in various cognitive impairment-related diseases through phagocytic synapses. Cholecystokinin (CCK), an abundant neuropeptide in the brain, is closely related to cognitive function. However, the role of CCK in SAE and the relationship between CCK and microglial phagocytosis of synapses are unknown.
METHODS: Lipopolysaccharide (LPS) was used to construct SAE models in 3-month-old male mice and BV2 microglial cells. To investigate the effects of CCK on cognitive impairment in SAE model mice, we used exogenous CCK injection into the dorsal hippocampal CA1 region or the chemogenetic activation of CCK-positive neurons to promote endogenous CCK release. Morris water maze and fear conditioning test were used to assess cognitive function in mice. RNA sequencing was performed to explore the potential signalling pathways involved in CCK-induced neuroprotection. Western blot and immunofluorescence were used to assess the effects of CCK on microglial phagocytosis of synapses, neurotoxic astrocytes, and excitatory synapses. Whole-cell recording was used to determine excitatory synaptic transmission.
RESULTS: LPS successfully established in vivo and in vitro models of SAE. Both exogenous CCK injection and activation of CCK-positive neurons in hippocampal CA1 region attenuated cognitive impairment in SAE mice. Mechanistically, CCK significantly alleviated excitatory synaptic plasticity damage via inhibiting complement 1q (C1q)-mediated microglial phagocytosis of synapses and neurotoxic astrocyte polarisation. Moreover, in vitro SAE model of BV2 cells demonstrated that CCK exerts neuroprotective effects through microglial CCK2-type receptor.
CONCLUSIONS: CCK may alleviate cognitive impairment by inhibiting microglia C1q-mediated phagocytosis of excitatory synapses, suggesting that both CCK drugs and specific activation of CCK-positive neurons are potential treatments for SAE.

Keywords:  Cholecystokinin; Complement 1q; Excitatory synapse; Microglia; Sepsis-associated encephalopathy

DOI:  https://doi.org/10.1186/s12974-025-03554-9
Alzheimers Res Ther. 2025 Sep 30. 17(1): 210

A novel electric field approach for improving cognitive function through ameliorating cell-specific pathology in P301S tauopathy mice.

Jinyun Zhou, Yan Zhong, Chentao Jin, La Dong, Rui Zhou, Yuxing Wang, Zhengbo Fan, Xuesheng Zheng, Xiaoqing Xing, Jing Wang, Mei Tian, Hong Zhang.

  Alzheimer's disease (AD) is a devastating neurodegenerative disorder, with no effective treatment currently available. Recently, non-pharmacological therapy, especially gamma frequency stimulation has shown promising therapeutic effects in Alzheimer's disease (AD) mouse models. Electric field (EF) is a non-invasive biophysical approach for neuronal protection. However, whether EF is beneficial in AD neuropathology remains unknown. In this study, we exposed the P301S tauopathy mouse model to EF at gamma frequency on the head. We demonstrated that EF treatment significantly improved the cognitive impairments in the P301S mice. This was accompanied by reduced tau pathologies, suppressed microglial activation, neuroinflammation and oxidative stress in the tauopathy mouse brain. Moreover, EF treatment induced cell-specific responses in neural cells, with neurons being more susceptible, followed by microglia and oligodendrocytes. EF also had favorable effects on synaptic protein in neurons, inflammatory response and complement signaling in microglia, and myelination in oligodendrocytes. This study provides strong evidence that EF at gamma frequency may have great potential to be a novel therapeutic intervention for P301S by attenuating neuropathology and offering neuroprotection.

Keywords:  Alzheimer’s disease (AD); Cognitive function; Electric field; Neurodegeneration; Positron emission tomography (PET); Single nuclei RNA sequencing (snRNA-seq)

DOI:  https://doi.org/10.1186/s13195-025-01859-8
Front Immunol. 2025 ;16 1648278

Single-nucleus transcriptomics reveals sepsis-related neurovascular dysfunction in the human hippocampus.

Liu Liu, Pengfei Li, Brent A Wilkerson, Yan Wu, Meng Liu, Wei Jiang, Eric D Hamlett, Steven L Carroll, Hongkuan Fan.

   Introduction: Sepsis is increasingly recognized as a major precipitant of long-term cognitive impairment, yet the cellular mechanisms underlying hippocampal vulnerability remain elusive.
Methods: We performed single-nucleus RNA sequencing of human hippocampal tissues from sepsis and control patients to profile neurovascular cell populations and their transcriptional changes.
Results: We identified profound neurovascular alterations involving 21 distinct cell populations. Astrocytes and microglia exhibited marked polarization: Astrocyte 2 showed simultaneous upregulation of neurotoxic A1 and neuroprotective A2 gene signatures in sepsis, whereas Astrocyte 1 displayed reduced A1 activity and a relatively quiescent profile. Microglia 2 demonstrated a prominent M1-like inflammatory signature, including elevated HLA-DRA, IL1B, and TNF, while Microglia 1 downregulated both M1 and M2 markers, suggesting a hypo-responsive state. Intercellular communication analysis revealed intensified astrocyte-microglia interactions in the septic hippocampus. Endothelial and mural cells exhibited transcriptional signatures of blood-brain barrier disruption, oxidative stress, and compromised vascular homeostasis. Key molecular pathways associated with antigen presentation, cytokine signaling, and vascular permeability were selectively activated across neurovascular compartments.
Discussion: These findings uncover a coordinated glial and vascular response to systemic inflammation, driven in part by dysfunctional astrocyte-microglia crosstalk and pro-inflammatory polarization. Such changes may underlie blood-brain barrier breakdown and contribute to sustained neuroinflammation and cognitive decline in sepsis survivors. Targeting glial-vascular signaling axes and modulating astrocyte or microglial polarization states may offer promising avenues for therapeutic intervention in post-sepsis neurological sequelae.

Keywords:  astrocytes; blood-brain barrier; hippocampus; microglia; neurovascular dysfunction; sepsis

DOI:  https://doi.org/10.3389/fimmu.2025.1648278
Neurotherapeutics. 2025 Sep 26. pii: S1878-7479(25)00237-5. [Epub ahead of print] e00759

Inhibition of microglial glutaminase alleviates chronic stress-induced neurobehavioral and cognitive deficits.

Meixiang Huang, Yannan Li, Ajit G Thomas, Anjali Sharma, Wathsala Liyanage, Tomáš Tichý, Lukáš Tenora, Yu Su, Jisu Ha, Niyada Hin, Mizuho Obayashi, Pavel Majer, Rangaramanujam M Kannan, Takashi Tsukamoto, Gianluca Ursini, Rana Rais, Barbara S Slusher, Xiaolei Zhu.

  Major depressive disorder (MDD) is a prevalent and debilitating psychiatric condition with significant societal and economic impacts. Many patients are resistant to current antidepressant therapies, underscoring the need for novel treatments targeting underlying mechanisms. We previously discovered that glutaminase (GLS1), an enzyme converting glutamine to glutamate, is upregulated specifically in activated microglia in mice exposed to Chronic Social Defeat Stress (CSDS). Importantly, GLS1 mRNA was also upregulated in microglia within postmortem brain tissue of MDD patients, highlighting a potential role for microglial GLS1 in MDD pathophysiology. However, existing GLS1 inhibitors lack brain penetrance and/or cause gastrointestinal toxicities, limiting their translational potential. To address this, we utilized a hydroxyl-terminated poly(amidoamine) dendrimer nanoparticle system to selectively target microglial GLS1. Using structurally distinct GLS1 inhibitors, we synthesized two hydroxyl-dendrimer-GLS1 inhibitor conjugates: dendrimer-TTM020 (D-TTM020) and dendrimer-JHU29 (D-JHU29). In the murine CSDS model, we evaluated their microglial target engagement, safety, and efficacy using immunofluorescence, GLS1 activity assays, gastrointestinal histopathology, and a battery of behavioral tests. Using a Cy5 fluorescently labeled hydroxyl-dendrimer (D-Cy5), we confirmed that systemically administered D-Cy5 crossed the blood-brain barrier and was selectively engulfed by activated microglia in mice after CSDS. D-TTM020 and D-JHU29 attenuated CSDS-induced microglial GLS1 activity elevation without affecting non-microglial cells. Furthermore, D-TTM020 and D-JHU29 both alleviated CSDS-induced social avoidance, and D-TTM020 additionally reduced anxiety-like behavior and improved recognition memory. Both conjugates were well tolerated, with no overt or gastrointestinal toxicities. Collectively, these findings suggest that microglia-targeted GLS1 inhibition is a promising therapeutic approach for chronic stress-associated depression.

Keywords:  Chronic social defeat stress; Dendrimer; Depression; Glutaminase; Microglia

DOI:  https://doi.org/10.1016/j.neurot.2025.e00759
Commun Biol. 2025 Oct 01. 8(1): 1408

Intermittent fasting attenuates glial hyperactivation and photoreceptor degeneration in a NaIO3-induced mouse model of age-related macular degeneration.

Jingzhen Li, Beibei Wang, Pinjie Liu, Xuecheng Qiu, Qiyun Bian, Congxin Shen, Yanyan Li, Mengwen Shao, Meng Li.

Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss, with limited treatments available. Recent studies suggest intermittent fasting (IF) may offer neuroprotective benefits for aging and age-related disorders, but its efficacy in AMD has not yet been established. Here, using a sodium iodate (NaIO3)-induced AMD model in male mice, we find that pretreatment with an IF diet regimen mitigates NaIO3-induced cellular damage and loss of both retinal pigment epithelium (RPE) and photoreceptors. Visual function tests indicate that IF preserves vision in NaIO3-treated mice. Transcriptome analyses show IF counteracts NaIO3-induced transcriptional dysregulation, affecting genes related to reactive oxygen species (ROS), inflammation, and photoreceptor structure. Further experimental results confirm that IF effectively reduces ROS levels and inhibits the activation of microglia and Muller cells in the retina. Collectively, these findings indicate that IF reduces ROS production and inflammation in NaIO3-induced retinal damage, providing a potential therapeutic strategy for oxidative stress-induced retinal degenerative diseases, including AMD.

DOI: https://doi.org/10.1038/s42003-025-08815-0
Neurobiol Dis. 2025 Sep 27. pii: S0969-9961(25)00345-6. [Epub ahead of print] 107128

Single nucleus RNA sequencing unveils relationship between microglia and endothelial cells in mixed Alzheimer's disease and vascular pathology.

Oluwatosin A Olayinka, Nicholas O'Neill, Jenny A Empawi, Payton Bock, Junming Hu, Hannah Rickner, Melissa Wong, Thor D Stein, Benjamin Wolozin, Lindsay A Farrer, Xiaoling Zhang.

  Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of cell type-specific transcriptional profiles. We evaluated differential gene expression using snRNAseq data generated from hippocampal region tissue donated by 11 Boston University Alzheimer's Disease Research Center (BU-ADRC) participants with neuropathologically confirmed Alzheimer's disease (AD) with or without co-existing pathology (AD only = 3, AD+vascular disease (Vas) = 6, AD+Lewy body disease (LBD) = 2). Expression of 19,893 genes was compared between AD+Vas and other AD groups for each cell type. Co-expression modules were identified in a set of 174 bulk RNAseq hippocampal samples from BU-ADRC. Modules enriched in differentially expressed genes (DEGs) were identified using Fisher's exact tests. The overlap between DEGs and co-expression modules was incorporated into quantitative gene set analysis. AD+Vas subjects showed decreased expression of genes related to immune activation in microglia (t = -2.67, p = 2.72 × 10-2). Expression of these genes was negatively associated with expression of receptors P2RY12 and CX3CR1 (r = -0.87, p = 1.70 × 10-2), which have been linked to microglial migration and activation, respectively. Expression of genes that negatively regulate angiogenesis in endothelial cells was decreased (t = -4.84, p = 1.49 × 10-3) and associated with expression of the microglial activation genes in the BU-ADRC dataset (r = 0.68, p = 1.63 × 10-2). This association and the finding of upregulation of P2RY12 in AD+Vas samples were replicated in 393 ROSMAP Study dorsolateral prefrontal cortex snRNAseq samples (r = 0.34, p = 8.37 × 10-12 and z = 5.82, pFDR = 8.73 × 10-6, respectively). In summary, we found an expression profile in brain tissue from individuals with AD+Vas pathology that is associated with reduced activation and increased migration in microglia and angiogenesis in endothelial cells.

Keywords:  Alzheimer's disease; Endothelial cells; Lewy body disease; Microglia; Single-nucleus RNA sequencing; Vascular disease

DOI:  https://doi.org/10.1016/j.nbd.2025.107128
Sci Rep. 2025 Sep 29. 15(1): 33596

S-ketamine relieves neuropathic pain by inhibiting microglia phagocytosis of the perineuronal nets.

Xuli Yang, Yu Wang, Li Jiang, Simin Huang, Yang Jiao, Qingzi Wu, Yuhao Zhang, Yulin Huang, Xiaoping Gu, Rui Xu, Wei Zhang, Zhengliang Ma.

  Perineurial network (PNN) is a special extracellular matrix structure in the central nervous system, and its alterations are associated with the pain hypersensitivity. Recent studies have suggested a potential interaction between abnormal activation of spinal microglia and PNN. This study investigates whether S-ketamine mitigates neuropathic pain via inhibiting degradation of PNNs by spinal microglia. C57BL/6 mice were utilized for CCI modeling to induce neuropathic pain. Subsequent to modeling, we assessed the expression changes of spinal microglia, PNN and inflammatory factors. Microglia colocalization with PNN was evaluated via 3D reconstruction to quantify spatial overlap. Minocycline was administered to target microglia. S-ketamine was subsequently administered to CCI mice, and its effects on pain behavior, microglial activation, and PNN were investigated. Microglia-PNN colocalization was evaluated via 3D reconstruction to quantify spatial overlap. CCI mice exhibited significant neuropathic pain, accompanied by increased microglia-mediated phagocytosis of PNN. Minocycline and S-ketamine treatment of CCI mice led to improved pain thresholds, suppression of neuroinflammation, and reduction in microglia-mediated phagocytosis of PNN. Increased microglial phagocytosis leading to PNNs degradation in the spinal dorsal horn plays a critical role in neuropathic pain pathogenesis. The analgesic effects of S-ketamine may be attributed to its modulation of this mechanism.

Keywords:  Microglia; Neuroinflammation; Neuropathic pain; Perineuronal nets; Phagocytosis; S-ketamine

DOI:  https://doi.org/10.1038/s41598-025-18834-w
Am J Pathol. 2025 Sep 30. pii: S0002-9440(25)00363-3. [Epub ahead of print]

Targeting RORγ to boost regulatory T cells and ameliorate diabetic retinopathy in mice.

Devy Deliyanti, Varaporn Suphapimol, Phoebe Ang, Abhirup Jayasimhan, Jennifer L Wilkinson-Berka.

Diabetic retinopathy, a leading cause of blindness, features damage to the retinal vasculature, where T cell-mediated inflammation is increasingly recognised as an important contributor. Retinoic acid receptor-related orphan receptor gamma (RORγ) plays a key role in regulating the balance between anti-inflammatory regulatory T cells (Tregs) expressing the transcription factor Foxp3 and pro-inflammatory Th17 cells. We hypothesised that inhibiting RORγ with SR2211, targeting both RORγ and its isoform RORγt, increases Tregs and reduces Th17 cells, resulting in reduced inflammation and vasculopathy in a streptozotocin-induced model of diabetic retinopathy. Mice expressing Foxp3 as a red fluorescent protein were treated with SR2211 for 26 weeks of diabetes, and comparisons made to diabetic mice administered vehicle and non-diabetic control mice. In blood and lymphoid tissues of diabetic mice, treatment with SR2211 restored the number of Tregs and reduced Th17 cells to the levels of diabetic mice + vehicle. In the retina of diabetic mice, treatment with SR2211 increased Tregs, and reduced the activation of microglia cells, the expression of pro-inflammatory factors including interleukin-17A, interleukin-6 and tumour necrosis factor, vascular leakage, vascular endothelial growth factor and acellular capillaries, compared to diabetic mice + vehicle. These findings indicate the ability of RORγ/RORγt inhibition to modulate specific T-cell responses and suppress microglia activation to reduce inflammation and vascular damage in diabetic retinopathy.

DOI: https://doi.org/10.1016/j.ajpath.2025.09.006
Cell Biol Toxicol. 2025 Oct 03. 41(1): 133

Increased reactive astrocytes in hippocampal CA1 region mediated by decreased CXCR7 is involved in postoperative cognitive dysfunction in aged mice.

Qiang Liu, Chen-Rui Zhou, Hai-Bi Wang, Yan-Ping Liu, Wei Dong, Jie Wan, Hui-Hui Miao, Cheng-Hua Zhou, Yu-Qing Wu.

  Postoperative cognitive dysfunction (POCD) is a prevalent neurological complication that significantly impairs recovery in elderly surgical patients. While astrocyte activation has been implicated in various neurodegenerative disorders, its dynamic changes and precise role in POCD pathogenesis remain poorly understood. In this study, we observed selective activation of astrocytes (but not microglia) in the hippocampal CA1 region of POCD model mice at postoperative day 3, accompanied by marked downregulation of the atypical chemokine receptor CXCR7. Notably, both astrocyte-specific CXCR7 overexpression in the hippocampal CA1 region and systemic administration of the CXCR7 agonist AMD3100 effectively attenuated astrocyte activation, reduced neuroinflammation, and significantly improved synaptic plasticity and cognitive performance in aged surgical mice. Furthermore, chemogenetic inhibition of hippocampal astrocytes during the perioperative period similarly ameliorated neuroinflammatory responses and cognitive deficits. Our findings demonstrate that surgery induces reactive astrogliosis in the hippocampal CA1 region through CXCR7 downregulation, ultimately leading to synaptic dysfunction and cognitive impairment. These results identify CXCR7 as a promising therapeutic target for POCD prevention.

Keywords:  CXCR7; Neuroinflammation; POCD; Reactive astrocytes; Synaptic plasticity

DOI:  https://doi.org/10.1007/s10565-025-10083-x
Front Cell Neurosci. 2025 ;19 1572431

Distinct reduction in relative microglial glucose uptake compared to astrocytes and neurons upon isolation from the brain environment.

Sebastian T Kunte, Johannes Gnörich, Philipp Beumers, Laura M Bartos, Stephan Wagner, Karin Wind-Mark, Adrien Holzgreve, Dennis Pötter, Rudolf A Werner, Sibylle Ziegler, Nathalie L Albert, Alessio Colombo, Sabina Tahirovic, Matthias Brendel.

   Introduction: Microglial energy metabolism has gained attention for the treatment of neurodegenerative diseases. In vitro methods provide important insights; however, it remains unclear whether the metabolism of highly motile microglia is preserved outside their regular environment. Therefore, we directly compared the microglial glucose uptake in vivo and in vitro in mice.
Methods: Microglia and astrocytes were isolated from the brain using immunomagnetic cell sorting following [18F]FDG injection in living mice, followed by gamma and single-cell radiotracing (scRadiotracing). Enriched cell fractions were incubated with excess [18F]FDG (50,000-fold) in vivo, washed, and measured equivalently. For all fractions, radioactivity per cell was normalized to the injected or incubated radioactivity, and ratios of microglialuptake were calculated relative to astrocytes and the microglia/astrocyte-negative fraction. The experiment was repeated using a glucose-free buffer and validated by in vitro incubation without prior in vivo [18F]FDG injection to exclude the influence of fasting and glucose injection.
Results: scRadiotracing results were compared against cell culture [18F]-FDG incubation. The in vivo glucose uptake of microglia was higher when compared to astrocytes (50.4-fold, p < 0.0001) and non-microglia/ non-astrocyte cells (10.6-fold, p < 0.0001). Microglia still exhibited the highest glucose uptake in vitro, but with a distinct reduction in microglia-to-astrocyte (5.7-fold, p < 0.0015) and microglia-to-microglia/astrocyte-negative ratios (1.7 fold, p < 0.0001). Fasting and in vitro incubation were used to validate the results. Cell culture indicated low microglial uptake compared to that in neurons (1:100) or astrocytes (1:10).
Discussion: Compared to astrocytes and other cells, microglia show a distinct reduction in uptake in vitro compared to in vivo uptake. Our results emphasize that in vitro experiments should be interpreted with caution when studying microglial energy metabolism.

Keywords:  glucose uptake; in vitro; in vivo; microglia; scRadiotracing

DOI:  https://doi.org/10.3389/fncel.2025.1572431
Neural Regen Res. 2025 Sep 29.

Retinitis pigmentosa elicits neurodegeneration within the visual pathway in REEP6 knockout mice.

Yin Yang, Maoxia Lv, Binbin Qiao, Zhengjiang Yang, Houbin Zhang, Zhengzheng Wu, Yang Xia, Dezhong Yao, Ke Chen.

   ABSTRACT: While degenerative diseases of the central nervous system are commonly linked to age-related macular degeneration and glaucoma, they have also been infrequently associated with retinitis pigmentosa, a condition defined by retinal degeneration that can be caused by an isoform of receptor expression enhancing protein 6 (REEP6) expressed in rod photoreceptors. In this study, we used REEP6 knockout mice (REEP6-/-) and wild-type mice (REEP6+/+) to examine neurodegenerative pathology within the visual pathways and neural activity in the primary visual cortex (V1) at three specific time points (1, 6, and 10 months) during retinitis pigmentosa progression. Microglial activation was observed in both the retina and the primary visual cortex starting at 1 month of age, but no such activation was detected in the lateral geniculate nucleus at any time point. Not only was increased microglial activation observed at 6 and 10 months within the primary visual cortex of REEP6-/- mice, but also coinciding with elevated levels of phosphorylated Tau expression. At 6 and 10 months of age, primary visual cortex neurons in REEP6-/- mice exhibited reduced responses to grating stimuli and increased spontaneous activity compared with neurons in the primary visual cortex of mice in the control group. Our findings show that retinitis pigmentosa induces neurodegenerative pathology within the visual pathway of mice, particularly in the primary visual cortex, suggesting that ocular disease contributes substantially to central nervous system degeneration. It may provide new clues for the selection of treatment opportunities and the development of therapeutic measures for the subsequent treatment of retinitis pigmentosa or even other retinal degenerative diseases.

Keywords:  ; microglial activation; nerve regeneration; neurodegeneration; phosphorylated Tau; photoreceptor degeneration; primary visual cortex (V1); retinitis pigmentosa; rod photoreceptors; visual pathway

DOI:  https://doi.org/10.4103/NRR.NRR-D-25-00168
Neuroreport. 2025 Nov 05. 36(16): 949-959

Mechanisms of methyltransferase-like 3-mediated microglial pyroptosis in sepsis-associated encephalopathy.

Dandan Chi, Feng Li, Zhimin Wang.

   OBJECTIVE: Sepsis-associated encephalopathy (SAE) is a common and serious neurological complication of sepsis. This study aimed to investigate the mechanism of methyltransferase-like 3 (METTL3) in SAE-induced microglial pyroptosis and to identify new therapeutic targets for SAE treatment.
METHODS: A SAE cell model was established using lipopolysaccharide (LPS)-treated BV-2 cells. The expression of interleukin-1β, interleukin-18, cleaved caspase-1, gasdermin D (GSDMD)-N, NOD-like receptor protein 3 (NLRP3), transforming growth factor beta receptor 3 (TGFBR3), and METTL3 was detected by. METTL3 was silenced in LPS-treated BV-2 cells to validate the role of METTL3 in microglial pyroptosis. Total N6-methyladenosine (m6A) content was measured. The binding of primary miRNA (pri-miR)-101-3p to DGCR8 and the m6A level of pri-miR-101-3p were analyzed by methylated RNA immunoprecipitation-qPCR. The expression of pri-miR-101-3p and miR-101-3p was measured by reverse transcription quantitative PCR. The downstream targets of miR-101-3p were predicted by databases, and the binding relationship between miR-101-3p and TGFBR3 was verified. Rescue experiments were performed to verify the role of METTL3/miR-101-3p/TGFBR3 axis in microglial pyroptosis.
RESULTS: LPS treatment decreased cell viability and promoted interleukin-1β, interleukin-18, METTL3, cleaved caspase-1, GSDMD-N, and NLRP3. Silencing METTL3 inhibited microglial pyroptosis. Mechanistically, METTL3 promoted the binding of pri-miR-101-3p to DGCR8 through m6A modification and increased mature miR-101-3p expression. miR-101-3p targeted TGFBR3 and inhibited TGFBR3 expression. miR-101-3p overexpression or TGFBR3 downregulation partially reversed the inhibitory effect of silencing METTL3 on LPS-induced microglial pyroptosis.
CONCLUSION: METTL3 is upregulated in SAE, enhances miR-101-3p expression through m6A modification, and inhibits TGFBR3 expression, finally leading to microglial pyroptosis in SAE.

Keywords:  METTL3; N6-methyladenosine; SAETGFBR3; lipopolysaccharide; miR-101-3p; microglia; pyroptosis

DOI:  https://doi.org/10.1097/WNR.0000000000002215