bims-microg 2025-11-02 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–11–02
seventeen papers selected by
Marcus Karlstetter, Universität zu Köln

The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.
Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.
Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.
Galectin-9 activates the TLR4-NLRP3 inflammasome pathway and promotes tau pathology in Alzheimer's disease.
Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology.
Microglia-mediated Perineuronal nets loss contributes to social memory deficit in male mice after repeated neonatal sevoflurane exposure.
Microglial Rack1 Deficiency Alleviates Alzheimer's Disease Pathology through Enhancing IGF1-Mediated Astrocytic Phagocytosis.
Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology.
Anxiety induced by systemic inflammation involves microglial engulfing of nucleus accumbens inputs and diminished excitability of D1 receptor neurons.
The border-associated macrophage marker MRC1 contributes to an early neuroprotective inflammatory response to traumatic brain injury in mice.
Genome-wide consensus transcriptional signatures identify synaptic pruning linking Alzheimer's disease and epilepsy.
Microglia from patients with multiple sclerosis display a cell-autonomous immune activation state.
STING activates ZBP1-mediated PANoptosis to defend against HSV-1 retinal infection.
FGF21 confers neuroprotection in Parkinson's disease by activating the FGFR1-sirt1 pathway.
Semaglutide attenuates Alzheimer's disease model progression by targeting microglial NLRP3 inflammasome-mediated neuroinflammation and ferroptosis.
miR-21-5p Alleviates Retinal Ischemia-Reperfusion Injury by Inhibiting M1 Polarization of Microglia via Suppression of STAT3 Signaling.
epDevAtlas: mapping GABAergic cells and microglia in the early postnatal mouse brain.

J Neuroinflammation. 2025 Oct 27. 22(1): 244

The Parkinson's disease-associated LRRK2-G2019S variant restricts serine metabolism, leading to microglial inflammation and dopaminergic neuron degeneration.

Henry Kurniawan, Sarah L Nickels, Alise Zagare, Elisa Zuccoli, Isabel Rosety, Gemma Gomez-Giro, Enrico Glaab, Jens C Schwamborn.

  A growing body of evidence implicates inflammation as a key hallmark in the pathophysiology of Parkinson's disease (PD), with microglia playing a central role in mediating neuroinflammatory signaling in the brain. However, the molecular mechanisms linking microglial activation to dopaminergic neuron degeneration remain poorly understood. In this study, we investigated the contribution of the PD-associated LRRK2-G2019S mutation to microglial neurotoxicity using patient-derived induced pluripotent stem cell (iPSC) models. We found that LRRK2-G2019S mutant microglia exhibited elevated activation markers, enhanced phagocytic capacity, and increased secretion of pro-inflammatory cytokines such as TNF-α. These changes were associated with metabolic dysregulation, including upregulated glycolysis and impaired serine biosynthesis. In 3D midbrain organoids, these overactivated microglia resulted in dopaminergic neuron degeneration. Notably, treating LRRK2-G2019S microglia with oxamic acid, a glycolysis inhibitor, attenuated microglial inflammation and reduced neuronal loss. Our findings underscore the link between metabolic targeting in microglia and dopaminergic neuronal loss in LRRK2-G2019S mutation, and highlight a potential strategy that warrants further preclinical evaluation.

Keywords:  Glycolysis; IPSC; LRRK2-G2019S; Metabolism; Microglia; Organoids; Parkinson’s disease; Serine

DOI:  https://doi.org/10.1186/s12974-025-03577-2
Immunity. 2025 Oct 29. pii: S1074-7613(25)00433-9. [Epub ahead of print]

Single-cell spatial transcriptomic profiling defines a pathogenic inflammatory niche in chronic active multiple sclerosis lesions.

Ruoqing Feng, Lena Spieth, Lu Liu, Stefan Berghoff, Jonas Franz, Qian Liu, Zhen Wang, Vini Tiwari, Simona Vitale, Simon Frerich, Sergi Florensa, Niklas Junker, Ludwig Huber, Marco Keller, Christoph Müller, Franz Bracher, Xiaoke Ge, Patrick C N Rensen, Gijs Kooij, Leon Hosang, Serhii Chornyi, Martin Dichgans, Ozgun Gokce, Gesine Saher, Christine Stadelmann, Martin Giera, Janos Groh, Mikael Simons.

  Compartmentalized inflammation is a key driver of multiple sclerosis (MS) progression, but the mechanisms sustaining its persistence remain unclear. A hallmark of this persistent and slowly evolving inflammatory process is chronic active MS lesions. We generated a high-resolution, single-cell molecular and spatial atlas of such lesions by combining single-nucleus RNA sequencing (snRNA-seq) with multiplexed error-robust fluorescence in situ hybridization (MERFISH). Within lesion rims, we identified CD8+ T cell niches associated with inflamed microglia displaying an interferon response and upregulated lipid metabolism. To investigate their function, we deleted ATP-binding cassette transporters A1 and G1 (ABCA1/G1) in the microglia of mice with experimental autoimmune encephalomyelitis (EAE), which increased the formation of lipid-storing phagocytes that amplified inflammation. Moreover, pharmacologically targeting sterol metabolism mitigated foam cell formation and inflammatory demyelination in EAE. Thus, our high-resolution map of immune niches in chronic active MS lesions identifies a role for lipid-storing, dysfunctional microglia in persistent neuroinflammation.

Keywords:  CD8+ T cells; CD8+ tissue-resident memory T cells; glia; lipids; microglia; multiple sclerosis; myelin; neuroinflammation; spatial transcriptomics

DOI:  https://doi.org/10.1016/j.immuni.2025.10.003
Nat Aging. 2025 Oct 29.

Loss of MFE-2 impairs microglial lipid homeostasis and drives neuroinflammation in Alzheimer's pathogenesis.

Min Gao, Jing Bai, Fangzhou Lou, Yang Sun, Zhikai Wang, Xiaojie Cai, Yan Li, Fengjiao Zhang, Jihuan Liang, Xiangxiao Li, Yue Wu, Ziyang Zhang, Li Fan, Xinping Jin, Honglin Wang.

Dysregulated lipid metabolism promotes persistent microglial activation and neuroinflammation in Alzheimer's disease (AD), but the underlying pathogenic mechanisms remain to be elucidated, and druggable targets remain to be identified. Here we found that multifunctional enzyme type 2 (MFE-2), the key enzyme regulating fatty acid β-oxidation in the peroxisome, was downregulated in the microglia of humans with AD and AD model mice. Microglia-specific ablation of MFE-2 drove microglial abnormalities, neuroinflammation and Aβ deposition in AD models. Mechanistically, MFE-2 deficiency facilitated lipid accumulation, resulting in excessive arachidonic acid, mitochondrial reactive oxygen species and proinflammatory cytokine production by microglia. The compound 3-O-cyclohexane carbonyl-11-keto-β-boswellic acid (CKBA) bound to MFE-2 and restored MFE-2 levels, ameliorating AD pathology by inhibiting microglial overactivation. Collectively, our data revealed a pathogenic role of microglia with impaired lipid metabolism in AD and identified MFE-2 as a druggable target of CKBA, which restores its expression and has therapeutic potential for treating AD.

DOI: https://doi.org/10.1038/s43587-025-00976-1
Brain Behav Immun. 2025 Oct 26. pii: S0889-1591(25)00400-3. [Epub ahead of print]131 106158

Galectin-9 activates the TLR4-NLRP3 inflammasome pathway and promotes tau pathology in Alzheimer's disease.

Xiaodi Guo, Guoxin Zhang, Qinyu Peng, Hui Liu, Keqiang Ye, Tingting Xiao, Chaoyang Liu, Xiangyan Zhang, Sheng Li, Hualong Wang, Jin Feng, Zhentao Zhang.

  Tau deposition, microglial activation, and neuroinflammation are prominent features of Alzheimer's disease (AD). Galectin-9 (Gal-9), one of the most abundant beta-galactosidase-binding proteins secreted by active microglia, is elevated in brain tissue and cerebrospinal fluid in patients with AD, associating with cognitive impairments. However, whether Gal-9 is involved in the onset of AD pathology remains unclear. Here, we report that the expression and secretion of Gal-9 are increased in microglia exposed to tau fibrils and in the brain tissue of tau P301S transgenic mice. Gal-9 binds to toll-like receptor 4 (TLR4) on microglia and activates the NLR family, pyrin domain containing 3 (NLRP3) inflammasome, promoting the secretion of interleukin-1β (IL-1β) and IL-18, which are toxic to neurons. Genetic ablation of Gal-9 in tau P301S mice diminishes microglial activation and tau deposition, preserves synaptic integrity, and improves cognitive function. Furthermore, Gal-9 knockout also halted the spread of tau pathology induced by the intracerebral injection of tau fibrils, whereas the intracerebral injection of Gal-9 promoted tau pathology. Overall, our findings demonstrate that microglial activation facilitates tau pathology through Gal-9 and support the therapeutic potential of targeting the Gal-9-TLR4-NLRP3 axis to treat AD.

Keywords:  Interleukin-1β; Microglia; NLRP3; Neuroinflammation; Tauopathy

DOI:  https://doi.org/10.1016/j.bbi.2025.106158
Brain Behav Immun. 2025 Oct 23. pii: S0889-1591(25)00391-5. [Epub ahead of print]131 106149

Delta-opioid receptor ameliorates microglia-induced synapse loss by regulating C1q in Alzheimer disease pathology.

Yuan Xu, Ya Peng, Feng Zhi, Yilin Yang, Jiahui Li, Ligang Fan, Ying Xia, Naiyuan Shao.

  While previous studies have well established δ-opioid receptor (DOR)-mediated neuroprotection against Alzheimer's pathology, the underlying mechanisms remain poorly understood. Our present work reveals a strong negative correlation between DOR and the classical complement pathway (CCP) initiator C1q, confirming their direct binding both in vitro and in APP/PS1 transgenic mice. Activating DOR with the specific agonist UFP-512 in aged APP/PS1 mice reduced cerebral C1q levels, while increasing DOR-C1q binding affinity. This interaction subsequently suppressed CCP activation, ameliorated complement-dependent synaptic engulfment by microglia, prevented synaptic protein loss, and consequently improved cognitive performance of these Alzheimer's disease (AD) mice. Consistent with these findings, overexpressing microglial DOR effectively inhibited its shift towards a phagocytotic phenotype and protected co-cultured neurons from lipopolysaccharide (LPS) -induced injury. Collectively, our findings demonstrate a critical role of DOR in restricting complement-mediated synaptic elimination during neurodegeneration, highlighting its potential as a new therapeutic target for AD.

Keywords:  Alzheimer’s disease; C1q; Delta-opioid receptor; Microglia; Synaptic pruning

DOI:  https://doi.org/10.1016/j.bbi.2025.106149
Brain Behav Immun. 2025 Oct 23. pii: S0889-1591(25)00390-3. [Epub ahead of print] 106148

Microglia-mediated Perineuronal nets loss contributes to social memory deficit in male mice after repeated neonatal sevoflurane exposure.

Ziwen Shi, Jingwen Qin, Lin Gao, Fa Huang, Wei Wei, Tianyun Zhao, Xingrong Song, Xinying Guo.

   BACKGROUND: Repeated early-life exposure to general anesthetics might affect social behavior. Perineuronal nets (PNNs), which enwrap around parvalbumin (PV) interneurons and support their function, are crucial for social memory. Given that microglia contribute to PNN remodeling and are responsive to anesthetic exposure, we hypothesized that repeated neonatal sevoflurane exposure impairs social memory via microglia-mediated PNN degradation.
METHODS: Mice were exposed to 2.5 % sevoflurane for 2 h daily during postnatal days 7-9. At postnatal day 28, we evaluated social behavior, PNN integrity, patch-clamp recordings, and conducted analyses of microglia and PV interneurons. Subsequently, we explored the effects of microglia depletion by PLX5622 (CSF1R antagonist) and repopulation on social behavior and PNNs after repeated sevoflurane exposure.
RESULTS: We found that repeated neonatal sevoflurane exposure led to social memory deficit in male mice. This deficit coincided with significant PNN loss in the prefrontal cortex, increased excitability of PV interneurons, and enhanced inhibitory input to pyramidal neurons. Microglia exhibited elevated phagocytic activity toward PNNs after repeated neonatal sevoflurane exposure. Notably, microglial depletion and repopulation rescued PNN integrity and social memory performance.
CONCLUSIONS: Our findings reveal microglia-dependent PNN degradation as a key mechanism underlying early-life sevoflurane exposure-induced social memory impairments in male mice. Targeting microglial activity or preserving PNNs may offer new strategies to prevent anesthesia-induced neurodevelopmental impairments.

Keywords:  Microglia; Neonatal; Parvalbumin; Perineuronal nets; Sevoflurane

DOI:  https://doi.org/10.1016/j.bbi.2025.106148
Adv Sci (Weinh). 2025 Oct 30. e15877

Microglial Rack1 Deficiency Alleviates Alzheimer's Disease Pathology through Enhancing IGF1-Mediated Astrocytic Phagocytosis.

Jingdan Zhang, Yanling He, Pin Yang, Hengchang Zhang, Yueyang Tong, Lingling Jiang, Zehan Li, Meichen Yan, Xiaoheng Li, Qinghu Yang, Jing Yang, Zengqiang Yuan, Jiyan Zhang, Jinbo Cheng.

  Alzheimer's disease (AD) is the most common neurodegenerative disorder. Microglia make significant contributions to neuroinflammation and the progression of AD. However, the regulatory role of microglial activation and the communication between microglia and astrocytes in AD are largely unknown. Here, it is found that Rack1 levels are elevated in microglia of patients with AD and AD model mice. The conditional knockout of Rack1 in microglia reduced Aβ aggregation, alleviated neuroinflammation, and rescued cognitive impairments in AD model mice. Mechanistically, the knockout of Rack1 in microglia decreased the number of microglia while increasing both the numbers and phagocytic activities of astrocytes by upregulating the levels of IGF1. The inhibition of IGF1R blocked microglial Rack1 deficiency-induced astrocyte proliferation and astrocyte-mediated phagocytosis both in vitro and in vivo. Collectively, the results demonstrated that microglial Rack1 contributes to AD pathology, at least partially through influencing IGF1-IGF1R signaling between microglia and astrocytes, thus providing a potential target for AD treatment.

Keywords:  IGF1; Rack1; alzheimer's disease; microglia; microglia‐astrocyte crosstalk

DOI:  https://doi.org/10.1002/advs.202515877
Mol Neurodegener. 2025 Oct 27. 20(1): 113

Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology.

Yongzhen Miao, Ting Zhang, Zhuoya Ma, Huanhuan Du, Qipei Gu, Mengni Jiang, Kangping Xiong, Chun-Feng Liu, Hongrui Meng.

   BACKGROUND: The accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.
METHODS: To this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.
RESULTS: We found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.
CONCLUSIONS: These findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.

Keywords:  Neuroinflammation; O-GlcNAcylation; Proteolysis; α-synuclein

DOI:  https://doi.org/10.1186/s13024-025-00904-2
Brain Behav Immun. 2025 Oct 23. pii: S0889-1591(25)00396-4. [Epub ahead of print] 106154

Anxiety induced by systemic inflammation involves microglial engulfing of nucleus accumbens inputs and diminished excitability of D1 receptor neurons.

Shingo Nakajima, Anita Kabahizi, Solal Aubailly, Samar Naili-Douaouda, Akari Tomita, Anthony Bosson, Thierry Alquier, Ciaran Murphy-Royal, Stephanie Fulton.

  The neuroimmune corollaries of systemic inflammation can generate anxiodepressive behaviors and psychomotor slowing. The nucleus accumbens (NAc) is a neural hub encoding motivation and emotion that contributes to the mood dampening effects of neuroinflammation. Dopamine receptor 1 mediums spiny neurons (D1-MSNs) of the NAc regulate locomotion, motivated behavior and emotional states and are modulated by reactive microglia. Here, we evaluated anxiety-like behaviors along with D1-MSN activity and microglial responses in the NAc to systemic lipopolysaccharide (LPS) administration. LPS stimulated anxiety, blunted locomotion and reduced c-Fos expression in D1-MSNs of the NAc core and shell of adult D1RCre male mice. These effects associated with reduced frequency of excitatory synaptic inputs (EPSCs) as measured by whole cell patch-clamp recording of YFP-labeled D1-MSNs. To determine if microglia contribute to changes in MSN activity, Ca2+ imaging of primary NAc neurons was carried out in conditions with or without primary microglia harvested from the NAc. The presence of reactive microglia decreased intracellular Ca2+ in NAc neurons in response to dopamine and glutamate application and increased phagocytosis of synaptic elements. Immunohistochemical analyses revealed that in vivo LPS treatment enhanced morphological indices of microglia reactivity and engulfment of presynaptic processes positive for vesicular glutamate transporter 1 (vGLUT1) in the NAc. Our results suggest that LPS stimulates anxiety-like behavior via increasing microglia reactivity and pruning in the NAc and accentuate microglia engulfment of excitatory inputs in the behavioral consequences of acute systemic infection.

Keywords:  D1 receptor; Endotoxemia; Medium spiny neurons; Microglia pruning; Neuroinflammation; Ventral striatum

DOI:  https://doi.org/10.1016/j.bbi.2025.106154
Acta Neuropathol Commun. 2025 Oct 30. 13(1): 220

The border-associated macrophage marker MRC1 contributes to an early neuroprotective inflammatory response to traumatic brain injury in mice.

Jenny Strehle, Pawit Somnuke, Shuailong Li, Sudena Wang, Tobias Hirnet, Yong Wang, Michael K E Schäfer.

  Macrophages are crucial for neuroinflammatory responses following traumatic brain injury (TBI), encompassing various subtypes, such as border-associated macrophages (BAMs) that contribute to both brain damage and repair. However, the pathophysiological relevance of subtype-specific molecular markers is poorly understood. This study investigated the role of the BAM marker mannose receptor C-type 1 (MRC1, also known as CD206) during the early phase of TBI using controlled cortical impact (CCI). MRC1 gene expression was up-regulated, peaking between 3 to 7 days post-injury (dpi), and MRC1 protein expression predominantly localized to BAMs. To assess pathophysiological relevance, MRC1-deficient (MRC1-KO) and wild-type littermates (MRC1-WT) were examined following CCI for early neurological deficits, brain structural damage, intracerebral hematoma, and neuroinflammatory marker expression. At 5 dpi, MRC1-KO mice showed increased brain lesion volume and hippocampal neuron loss, with minor differences in neurological deficits compared to MRC1-WT mice. Intracerebral hematoma size increased in male but remained unchanged in female MRC1-KO mice. Immunostaining revealed no genotype-specific effects on GFAP+ astrocytes, while the number of perilesional CD68+ macrophages/microglia were reduced in MRC1-KO mice. Analysis of neuroinflammatory gene markers revealed an overall reduction in MRC1-KO mice. Sex-specific regulation was observed for the M2-like macrophage/microglia marker Arg1, with decreased expression in male and increased expression in female MRC1-KO compared to MRC1-WT mice. In conclusion, lack of MRC1 exacerbated brain tissue damage following experimental TBI. Reduced CD68+ macrophages/microglia and neuroinflammatory marker expression suggests impaired neuroinflammatory response in MRC1-KO, indicating MRC1 expression on BAMs contributes to beneficial early neuroinflammatory response following TBI.

Keywords:  Astrocytes; Border-associated macrophages; CD206; CNS-associated macrophages; MRC1; Microglia; Neuroinflammation; Structural brain damage; Traumatic brain injury

DOI:  https://doi.org/10.1186/s40478-025-02156-z
Mol Psychiatry. 2025 Oct 26.

Genome-wide consensus transcriptional signatures identify synaptic pruning linking Alzheimer's disease and epilepsy.

Huihong Li, Zhiran Xie, Yuxuan Tian, Ruoyin Zhou, Yaxi Yang, Bingying Lin, Si Chen, Jie Wu, Zihan Deng, Jianwei Li, Mingjie Chen, Xueke Liu, Yushan Sun, Naili Wei, Bing Huang, Xiaoyu Ji.

Alzheimer's disease (AD) and epilepsy (EP) share a complex bidirectional relationship, yet the molecular mechanisms underlying their comorbidity remain insufficiently explored. To identify potential transcriptional programs across animal models and human patients with AD and EP, we conducted a comprehensive genome-wide transcriptomic analysis. Our investigation included mouse models of temporal lobe epilepsy (pilocarpine- and kainic acid-induced; n = 280), AD transgenic models (7 transgenic models expressing human tau or amyloid pathology; n = 257), and performed cross-species validation in human cohorts (EP: n = 182; AD: n = 301). We identified a highly conserved immune-related module across all models and patient cohorts. The hub consensus signatures of this module were centered around a microglial synaptic pruning pathway involving TYROBP, TREM2, and C1Q complement components. Gene regulatory network analysis identified TYROBP as the key regulatory signature. These signatures showed consistent up-regulation in both conditions and diagnostic potential. Differential expression analyses revealed their predominant expression in specific microglial subpopulations associated with complement-mediated synaptic pruning and immune activation. Neural circuit modeling further demonstrates the asymmetric sensitivity of synaptic pruning to network dynamics. Loss of inhibitory synapses has a disproportionately significant impact on neural network excitation/inhibition balance and synchronization. Our findings support microglial complement-mediated synaptic pruning as a conserved central pathway linking neurodegeneration to epileptogenesis, suggesting a promising therapeutic target for AD and EP comorbidity.

DOI: https://doi.org/10.1038/s41380-025-03318-0
J Neuroinflammation. 2025 Oct 31. 22(1): 255

Microglia from patients with multiple sclerosis display a cell-autonomous immune activation state.

Tanja Hyvärinen, Johanna Tilvis, Luca Giudice, Iisa Tujula, Marjo Nylund, Sohvi Ohtonen, Flavia Scoyni, Henna Jäntti, Lassi Virtanen, Sara Pihlava, Roosa Kattelus, Heli Skottman, Susanna Narkilahti, Laura Airas, Tarja Malm, Sanna Hagman.



Keywords:  Human induced pluripotent stem cells; Microglia; Multiple sclerosis; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-025-03575-4
J Neuroinflammation. 2025 Oct 27. 22(1): 243

STING activates ZBP1-mediated PANoptosis to defend against HSV-1 retinal infection.

Wei Liu, Haifeng Cui, Li Wang, Xiangyu Ge, Xingfei Zhu, Xingmiao Liang, Ziqing Chen, Yuwen Gan, Le Shi, Xuebin Hu, Xiaohu Ding, Zhengjie Xu, Xiaoling Liang, Lili Gong.

  Herpes simplex virus type 1 (HSV-1) is the most common cause of infectious blindness and is a major cause of acute retinal necrosis (ARN), a severe condition marked by rapid necrosis of the retina. Effective treatments for HSV-1 retinal infection are limited to general antiviral drugs, which do not specifically target the underlying pathophysiology. Here, we investigate the role of stimulator of interferon genes (STING), a key player in innate immunity, in HSV-1 retinal infections. STING knockout (KO) mice are highly susceptible to HSV-1 retinal infection, evidenced by impaired antiviral immune responses, increased ocular virus load and severe retinal necrosis. Mechanistically, STING is required for Z-DNA binding protein 1 (ZBP1)-mediated PANoptosis, an inflammatory programmed cell death pathway, in microglia and macrophages. STING forms a complex with ZBP1 and Z-form nuclei acid during HSV-1 infection. Further, activation of STING induced Z-form nuclei acid and subsequent activation of ZBP1. ZBP1 KO mice exhibited a similar defective antiviral phenotype as STING KO mice, whereas treatment with ZBP1 agonist Curaxin CBL0137 rescued the impaired antiviral response in STING-deficient microglia and macrophages and mitigates retinal necrosis in both WT and STING KO mice following HSV-1 infection. Together, our study revealed a STING-ZBP1-PANoptosis signal axis against HSV-1 infection in retina, which should provide new insights for the treatment of retinal virus infection such as ARN.

Keywords:  Acute retinal necrosis; Herpes simplex virus; Neuroinflammation; PANoptosis; STING; ZBP1

DOI:  https://doi.org/10.1186/s12974-025-03595-0
Cell Mol Biol Lett. 2025 Oct 28. 30(1): 127

FGF21 confers neuroprotection in Parkinson's disease by activating the FGFR1-sirt1 pathway.

Tingting Liu, Jianshe Wei.

   BACKGROUND: Parkinson's disease (PD) lacks disease-modifying therapies. Fibroblast growth factor 21 (FGF21) is implicated in PD, but its neuroprotective mechanisms via fibroblast growth factor receptor 1 (FGFR1)-sirtuin 1 (Sirt1) remain unclear.
METHODS: Using 1-methyl-4-phenyl-1,2,3,6-te-trahydropyridine (MPTP)-induced PD mice and lipopolysaccharides (LPS)-stimulated BV2 microglia, this study employed recombinant adeno-associated virus (rAAV)-mediated FGF21 overexpression (OE). Multi-dimensional analyses (behavior, immunofluorescence, molecular docking, Western blot, PCR, transmission electron microscopy (TEM)) assessed FGF21's effects and mechanisms.
RESULTS: FGF21OE significantly improved motor deficits (gait, rotarod) and non-motor symptoms (depression/anxiety) in PD mice. It repaired the blood-brain barrier (BBB) by upregulating tight junction proteins (claudin, zonula occludens (ZO-1), occludin) and reducing astrocyte activation (glail fibrillary acidicprotein, GFAP). Mechanistically, FGF21 binding to FGFR1 activated Sirt1, enhancing mitochondrial fusion (optic atrophy 1 (OPA1), mitofusin 1 (Mfn1)) and inhibiting fission (dynamin-related protein 1 (Drp1), Fission 1 (Fis1)), improving membrane potential and ultrastructure. FGF21 also activated the AMP-activated protein kinase (AMPK)/mammalian target of rapamycin (mTOR) pathway, boosting PINK1/Parkin-mediated mitophagy and inhibiting Casp3/Bax-dependent apoptosis. Furthermore, FGF21 reduced neuroinflammation by suppressing nuclear factor kappa-B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) and shifting microglia from pro-inflammatory M1 to anti-inflammatory M2. Molecular docking and co-IP confirmed FGF21 enhances direct FGFR1-Sirt1 interaction, synergistically regulating these pathways.
CONCLUSION: FGF21 exerts multi-faceted protection in PD via the FGFR1-Sirt1 axis, including BBB repair, mitochondrial homeostasis restoration, microglial polarization towards M2, balancing autophagy and apoptosis, and promoting neuronal survival.

Keywords:  Blood–brain barrier; FGF21; Microglia; Mitochondrial dysfunction; Parkinson’s disease; Sirt1

DOI:  https://doi.org/10.1186/s11658-025-00807-6
Exp Neurol. 2025 Oct 29. pii: S0014-4886(25)00402-9. [Epub ahead of print] 115537

Semaglutide attenuates Alzheimer's disease model progression by targeting microglial NLRP3 inflammasome-mediated neuroinflammation and ferroptosis.

Mingxiao Zheng, Qianye Zhang, Hans-Christian Siebert, Gabriele Loers, Min Wen, Qingpeng Wang, Ruiyan Zhang, Jun Han, Ning Zhang.

  Microglial activation driven by NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome signaling exacerbates Alzheimer's disease (AD) pathology through enhanced neuroinflammation and amyloid beta (Aβ) accumulation. Semaglutide (SEM) has attracted growing attention for its potential therapeutic effects in AD, while its underlying mechanisms remain unclear. In this study, we investigated the neuroprotective effects of SEM in both APP/PS1 transgenic mice and LPS + ATP-stimulated BV2 microglia. Our results demonstrate that SEM treatment rescued APP/PS1 mice from cognitive impairment and suppressed Aβ aggregation and tau hyper-phosphorylation in the hippocampus of APP/PS1 mice. Furthermore, we found that SEM inhibited microglial NLRP3 activation, promoted microglial M2 polarization and alleviated ferroptosis via NLRP3/nuclear factor kappa B (NF-κB) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/ cystine/glutamate antiporter SLC7A11 (xCT)/glutathione peroxidase 4 (GPX4) pathways in APP/PS1 mice and LPS + ATP-stimulated BV2 microglia. These findings were further corroborated by microglia-specific NLRP3 knockdown, which reduced Aβ deposition, promotied M2 polarization, attenuated neuroinflammation, and suppressed ferroptosis. Our findings provide further theoretical support for the clinical application of SEM in AD treatment, while also establishing a scientific foundation for AD therapeutic strategies targeting the microglial NLRP3 pathway.

Keywords:  Alzheimer's disease; Ferroptosis; Microglia; NLRP3; Semaglutide

DOI:  https://doi.org/10.1016/j.expneurol.2025.115537
Biomedicines. 2025 Oct 09. pii: 2456. [Epub ahead of print]13(10):

miR-21-5p Alleviates Retinal Ischemia-Reperfusion Injury by Inhibiting M1 Polarization of Microglia via Suppression of STAT3 Signaling.

Liangshi Qin, Junle Liao, Cheng Tan, Can Liu, Wenjia Shi, Dan Chen.

  Background/Objectives: Retinal ischemia-reperfusion (I/R) injury is a common mechanism in glaucoma, diabetic retinopathy, and retinal vein occlusion, leading to progressive loss of retinal ganglion cells (RGCs). This study investigates the regulatory role of miR-21-5p and its interaction with Signal Transducer and Activator of Transcription 3 (STAT3) in retinal I/R injury. Methods: An acute intraocular hypertension (AIH) rat model was used to induce retinal I/R. The interaction between miR-21-5p and STAT3 was examined by dual-luciferase reporter assays. miR-21-5p and STAT3 expression were quantified by qRT-PCR and Western blotting. Retinal morphology, microglial polarization, and RGC survival were assessed by H&E staining and immunofluorescence. In vitro, microglia and RGCs were subjected to oxygen-glucose deprivation/reperfusion (OGD/R), and microglial-conditioned media (MCM) were applied to RGCs. Results: (1) miR-21-5p ameliorated AIH-induced retinal damage in vivo. (2) Overexpression of miR-21-5p inhibits M1 polarization of RM cultured in vitro. (3) MCM from miR-21-5p-overexpressing microglia attenuated OGD/R-induced RGC death. (4) miR-21-5p downregulates STAT3 expression to inhibit RM M1 polarization. (5) miR-21-5p down-regulation of STAT3 levels inhibits M1 polarization and reduces apoptosis of RGCs in retinal microglia of AIH rats. Conclusions: miR-21-5p alleviates retinal I/R injury by restraining microglial M1 polarization through direct repression of STAT3, thereby promoting RGC survival. These findings identify the miR-21-5p/STAT3 axis as a potential therapeutic target for ischemic retinal diseases.

Keywords:  Retinal ischemia/reperfusion; STAT3; acute ocular hypertension; miR-21-5p; miRNA; microglia; nerve injury; oxygen–glucose deprivation; retina; retinal ganglion cells

DOI:  https://doi.org/10.3390/biomedicines13102456
Nat Commun. 2025 Oct 29. 16(1): 9538

epDevAtlas: mapping GABAergic cells and microglia in the early postnatal mouse brain.

Josephine K Liwang, Fae N Kronman, Hyun-Jae Pi, Yuan-Ting Wu, Daniel J Vanselow, Steffy B Manjila, Deniz Parmaksiz, Donghui Shin, Yoav Ben-Simon, Michael Taormina, Sharon W Way, Hongkui Zeng, Bosiljka Tasic, Lydia Ng, Yongsoo Kim.

During development, brain regions follow encoded growth trajectories. Compared to classical brain growth charts, high-definition growth charts could quantify regional volumetric growth and constituent cell types, improving our understanding of typical and pathological brain development. Here, we create high-resolution 3D atlases of the early postnatal mouse brain, using Allen CCFv3 anatomical labels, at postnatal days (P) 4, 6, 8, 10, 12, and 14, and determine the volumetric growth of different brain regions. We utilize 11 different cell type-specific transgenic animals to validate and refine anatomical labels. Moreover, we reveal region-specific density changes in γ-aminobutyric acid-producing (GABAergic) neurons, cortical layer-specific cell types, and microglia as key players in shaping early postnatal brain development. We find contrasting changes in GABAergic neuronal densities between cortical and striatal areas, stabilizing at P12. Moreover, somatostatin-expressing and vasoactive intestinal peptide-expressing cortical interneurons undergo regionally distinct density changes. Remarkably, microglia transition from high density in white matter tracks to gray matter at P10, and show selective density increases in sensory processing areas that correlate with the emergence of individual sensory modalities. Lastly, we create an open-access web-visualization ( https://kimlab.io/brain-map/epDevAtlas ) for cell-type growth charts and developmental atlases for all postnatal time points.

DOI: https://doi.org/10.1038/s41467-025-64549-x