bims-microg 2025-11-23 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–11–23
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Cathepsin B overexpression and lysosomal leakage in inflammatory microglia promote neuroinflammation in olfactory dysfunction by triggering mitochondrial dysfunction and pyroptosis.
C5aR1+ microglia exacerbate neuroinflammation and cerebral edema in acute brain injury.
Sex differences in microglia morphology and function across the lifespan are mediated by the early hormone environment.
Early microglia-mediated neuroinflammation after status epilepticus causes behavioral dysfunction and neurocognitive deficits but not epilepsy in mice.
The impact of repetitive neonatal procedural pain on cognitive behavioral development in male Mice: A microglial Perspective.
Induction of endogenous IL-10 promotes resolution and tolerance of nitric oxide in microglia.
Temporally-regulated genetic access to IL-1β-expressing cellular networks in homeostasis and following peripheral or central immune stimuli.
Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy.
NLRP3-mediated trained immunity of microglia is involved in the recurrence-like episode of depressive disorders.
Evodiamine attenuates neurological impairment by inducing PANoptosis in microglia after severe traumatic brain injury.
Age-related inflammatory changes and perineuronal net dynamics: implications for aging.
Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.
3,4-dihydroxybenzalacetone from Phellinus linteus reduces glial activation, mitigates oxidative stress and inflammation, and preserves retinal function in ischemia-reperfusion-like injury.
Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.
Cellf-deception: human microglia clone 3 (HMC3) cells exhibit more astrocyte-like than microglia-like gene expression.
Global human myeloid replacement with peripheral progenitors induces interferonopathy and neurodegeneration.
Microglial colonization of the developing mouse brain is controlled by both microglial and neural CSF-1.
miR155 triplicated in Down syndrome regulates hippocampal GABAergic neurogenesis in Alzheimer's disease.
Fluid-Niche and Microglial Signatures Prime Robust Intraventricular Macrophage Response to Blood During Brain Development.
Gestational psychedelic exposure disrupts brain development and offspring behavior in mice.

Brain Behav Immun. 2025 Nov 19. pii: S0889-1591(25)00430-1. [Epub ahead of print] 106188

Cathepsin B overexpression and lysosomal leakage in inflammatory microglia promote neuroinflammation in olfactory dysfunction by triggering mitochondrial dysfunction and pyroptosis.

Huiqin Zhou, Li Wang, Yuanyuan Yang, Fangzhou Ye, Xuanyu Zhao, Kesen Zhu, Huang Ziheng, Wei Lv, Hongmeng Yu.

  Olfactory dysfunction (OD) is a common sensory disorder with age-related prevalence and serves as an early clinical marker for neurodegenerative and inflammatory diseases. Microglia in the olfactory bulb (OB) rapidly respond to olfactory injury and initiate immune responses, but the cell state dynamics and pathways driving OD remain poorly understood. Here, we performed single-cell RNA sequencing of mouse OBs at 0, 7, and 30 days post olfactory injury, identifying 3 distinct microglial states including inflammatory, negative regulatory, and homeostatic.The inflammatory microglia exacerbated neuroinflammation by secreting cytokines and chemokines that recruited immune cells and amplify local immune responses. Cathepsin B was identified as a key regulator of this inflammatory microglial activity. In vitro studies using BV2 and primary microglia demonstrated that both pharmacological inhibition and genetic deletion of CTSB attenuated lipopolysaccharide (LPS)-induced mitochondrial dysfunction, NLRP3 activation, and pro-inflammatory cytokine release. In mice with OD, pharmacological inhibition of CTSB with CA074me promoted olfactory function recovery and modulated microglial pro-inflammatory responses. Our findings uncover inflammation-associated microglial subpopulations enriched in OD and suggest a deleterious role for CTSB-mediated neuroinflammatory signaling in OD pathogenesis. Targeting CTSB may represent a promising therapeutic strategy to mitigate microglia-mediated neuroinflammation and facilitate olfactory recovery in OD. Olfactory dysfunction (OD) is a common sensory disorder with age-related prevalence and serves as an early clinical marker for neurodegenerative and inflammatory diseases. Microglia in the olfactory bulb (OB) rapidly respond to olfactory injury and initiate immune responses, but the cell state dynamics and pathways driving OD remain poorly understood. Here, we performed single-cell RNA sequencing of mouse OBs at 0, 7, and 30 days post olfactory injury, identifying 3 distinct microglial states including inflammatory, negative regulatory, and homeostatic. The inflammatory microglia exacerbated neuroinflammation by secreting cytokines and chemokines that recruited immune cells and amplify local immune responses. Cathepsin B was identified as a key regulator of this inflammatory microglial activity. In vitro studies using BV2 microglia demonstrated that both pharmacological inhibition and genetic deletion of CTSB attenuated lipopolysaccharide (LPS)-induced mitochondrial dysfunction, NLRP3 activation, and pro-inflammatory cytokine release. In mice with OD, pharmacological inhibition of CTSB with CA074me promoted olfactory function recovery and modulated microglial pro-inflammatory responses. Our findings uncover inflammation-associated microglial subpopulations enriched in OD and suggest a deleterious role for CTSB-mediated neuroinflammatory signaling in OD pathogenesis. Targeting CTSB may represent a promising therapeutic strategy to mitigate microglia-mediated neuroinflammation and facilitate olfactory recovery in OD.

Keywords:  Cathepsin B; Inflammatory response; Microglia; Neuroinflammation; Olfactory bulb; Olfactory dysfunction; Pyroptosis

DOI:  https://doi.org/10.1016/j.bbi.2025.106188
Neuron. 2025 Nov 18. pii: S0896-6273(25)00803-7. [Epub ahead of print]

C5aR1+ microglia exacerbate neuroinflammation and cerebral edema in acute brain injury.

Jinpeng Zhou, Shuoyao Ma, Dayun Feng, Yang Tian, Leiyang Li, Hao Guo, Yingwu Shi, Wenxing Cui, Jingyu Dong, Sijia Hao, Chengxuan Guo, Meng Xu, Liying Han, Hao Bai, Dan He, Xiao Cui, Lian Chen, Xun Wu, Fei Gao, Qing Hu, Ziwen Zhang, Kai Wang, Gaoyang Zhou, Tian Feng, Dongzhi Xue, Qian Lin, Liang Wang, Li Gao, Lijun Heng, Tianzhi Zhao, Tao Luo, Bo Tian, Xingye Zhang, Wei Guo, Zhihong Li, Haixiao Liu, Shunnan Ge, Qiang Liu, Yan Qu.

  Microglia rapidly respond to acute brain injury and contribute to neuroinflammation that drives cerebral edema, a major cause of mortality and disability in stroke and traumatic brain injury (TBI). However, microglial heterogeneity complicates precise therapeutic targeting because specific disease-associated subtypes remain poorly characterized. Here, we define a previously unrecognized C5a receptor 1 (C5aR1)-expressing microglial subtype enriched in human cerebral edema tissue from decompressive surgery for TBI and intracerebral hemorrhage (ICH). In preclinical models, C5aR1+ microglia engage locally and peripherally derive C5a to amplify neuroinflammation, drive neurotoxic astrocyte polarization, and recruit neutrophils, leading to cerebral edema. Genetic ablation of microglial C5ar1 or its pharmacological inhibition with an Food and Drug Administration (FDA)-approved antagonist attenuates cerebral edema in both TBI and ICH. These findings delineate the role of C5aR1+ microglia in neuroinflammatory cascades and cerebral edema following acute brain injury, indicating C5aR1 as a potential therapeutic target.

Keywords:  C5aR1(+) microglia; cerebral edema; microglial heterogeneity; neurotoxic astrocytes; neutrophils recruitment

DOI:  https://doi.org/10.1016/j.neuron.2025.10.022
Brain Behav Immun. 2025 Nov 19. pii: S0889-1591(25)00429-5. [Epub ahead of print] 106187

Sex differences in microglia morphology and function across the lifespan are mediated by the early hormone environment.

Lourdes K Davis, Miranda M Anders, Steven P Guerin, Sophia E Khoury, Lindsay M Thompson, Jeffrey S Darling, Andrea C Gore, Laura K Fonken.

  Microglia, the resident immune cell of the central nervous system (CNS), contribute to a range of physiological processes across the lifespan. Microglia exhibit notable sex differences in morphology, reactivity, and transcriptomic profiles. Steroid hormones in early life are believed to elicit sex differences in many cells, including microglia, in the CNS. However, few studies have examined how neonatal hormone environment impacts microglial morphology and function across the lifespan. Therefore, here we used steroid hormones to manipulate the early hormone environment to assess the appearance and persistence of sex differences in a rat model of healthy aging. Rat pups were dosed with steroid hormones on postnatal day (P)0 and 1: females received testosterone to "masculinize" them and males received flutamide, an androgen antagonist, to "feminize" them. Brain tissue was then collected at three distinct developmental timepoints: adolescence (P30), adulthood (P150), and aging (P700) for immunohistochemistry and ex vivo microglial stimulation. Transcriptomic changes in hippocampal tissue of aged animals were also assessed using 3'UTR biased transcriptome sequencing (Tag-seq). We report that testosterone treatment in females leads to lifelong alterations in body size and vaginal morphology and results in microglia that display a more "masculinized" phenotype compared to controls. Flutamide had more moderate effects on microglia morphology in males, contributing to a more "feminized" phenotype in the hippocampus in adult and aged males. Testosterone treatment also resulted in greater transcriptomic changes in the aged hippocampus compared to flutamide treatment, especially in genes related to mitochondrial function and inflammation. These results indicate that (1) early hormone environment is critical for the induction of sex differences in microglial morphology and (2) sex differences in microglial morphology reverse during aging, and this reversal is also recapitulated with early hormone treatment.

Keywords:  Aging; Flutamide; Hormones; Microglia; Neuroimmunology; Sex differences; Testosterone

DOI:  https://doi.org/10.1016/j.bbi.2025.106187
Brain Behav Immun. 2025 Nov 13. pii: S0889-1591(25)00425-8. [Epub ahead of print]131 106183

Early microglia-mediated neuroinflammation after status epilepticus causes behavioral dysfunction and neurocognitive deficits but not epilepsy in mice.

Peravina Thergarajan, Gadeer Al-Hobaish, Grace Sutherland, Evelyn Tsantikos, Bianca Jupp, Mohammad B Haskali, Pablo M Casillas-Espinosa, Margaret L Hibbs, Terence J O'Brien, Idrish Ali, Nigel C Jones.

   BACKGROUND: Neuroinflammation is implicated in epilepsy pathogenesis, and microglia are key immune cells of the brain that participate in neuroinflammatory responses associated with epilepsy. This study investigated the role of early microglial activation following an epileptogenic brain injury on the incidence and severity of epilepsy and associated neurobehavioral impairments in a model of acquired epilepsy.
METHODS: Status epilepticus (SE) was induced in male C57BL/6 mice via electrical stimulation of the ventral hippocampus, while additional mice were enrolled as sham controls (n = 125 total). Following termination of SE, mice received injections of the colony stimulating factor 1 (CSF1) receptor inhibitor PLX5622 (PLX; 50 mg/kg ip twice daily) to suppress microglial activation caused by SE, or vehicle, for seven days. At the end of treatment, the effect of microglial suppression on the neuroinflammatory response to SE was characterised using gene expression, immunohistochemistry, and flow cytometry. Additional mice were followed for four months and underwent a series of neurobehavioral tests and epilepsy assessment.
RESULTS: PLX treatment significantly reduced Iba1 + cell counts, reduced GFAP + immunoreactivity, and downregulated the expression of proinflammatory cytokines in the hippocampus compared to vehicle following SE, intimating that the neuroinflammatory response of SE was suppressed by PLX. Flow cytometry revealed that SE significantly reduced microglial expression of CX3CR1 and CD206, but increased expression of CD16/32, shifting microglia towards a pro-inflammatory state. However, PLX treatment did not influence the relative expression of these genes. In the chronic stage, SE mice treated with PLX exhibited improved spatial memory (Y-maze test: p = 0.0016) and reduced depressive-like behavior (tail suspension test: p = 0.04; sucrose preference: p = 0.14) compared to vehicle-treated SE mice. However, PLX treatment did not alter the incidence of epilepsy after SE (58 % in vehicle treated mice vs 50 % PLX treated mice; p = 0.65) or seizure frequency in epileptic animals.
CONCLUSION: Suppression of microgliosis with PLX eliminates the neuroinflammatory response after SE, and this is associated with prevention of long-term behavioral impairment. However, this intervention does not influence the development of epilepsy. These results demonstrate that acquired epilepsy and its behavioral comorbidities have different pathogenic mechanisms after SE, with early microglial driven neuroinflammation most relevant to the latter.

Keywords:  Animal behavior; CSF1 receptor; Epileptogenesis; Flow cytometry; Microglia; Mouse model; Neuroinflammation

DOI:  https://doi.org/10.1016/j.bbi.2025.106183
Brain Behav Immun. 2025 Nov 13. pii: S0889-1591(25)00424-6. [Epub ahead of print] 106182

The impact of repetitive neonatal procedural pain on cognitive behavioral development in male Mice: A microglial Perspective.

Yueshu Wang, Ru Ling, Wen Zheng, Dongqing Xia, Cuiting Min, Mengying Chen, Wei Zhou, Xiaonan Li.

  Early life experiences, such as repetitive neonatal procedural pain (RNP), may result in alterations in the function of the nervous and immune systems. In this study, we investigated the effect of RNP (postnatal day 0-7, 4 times/day) in male juvenile mice. Specifically, we evaluated (1) the spatial learning and memory, (2) the hippocampal microglia change, and (3) the regulatory role of microglial SIRP in hippocampal neuroinflammatory response. Our results show that RNP led to cognitive-behavioral changes. In addition, RNP activated hippocampal microglia in mice, promoting a proinflammatory phenotype and increasing the expression of relevant markers. Both in vivo and in vitro experiments revealed abnormal hippocampal microglia-mediated synaptic pruning in the pain model. Hippocampus-specific knockout model of microglial SIRPα, as well as microglial SIRPα overexpression/knockdown in vitro, was performed to demonstrate the regulatory role of SIRPα in microglia-mediated synaptic pruning and its contribution to RNP-induced brain function abnormalities and behavioral development abnormalities. Taken together, our results suggest that RNP causes spatial learning and memory impairment in juveniles. SIRPα as a "don't eat me" signaling molecule regulates engulfment of spines by activated microglia, potentially contributing to pain-related cognitive-behavioral development deficits, as well as impairment of microglia-mediated synaptic pruning.

Keywords:  Hippocampus; Microglia; Neonatal repeated procedural pain; Pruning; SIRPα; Synaptic

DOI:  https://doi.org/10.1016/j.bbi.2025.106182
Brain Behav Immun Health. 2025 Nov;49 101094

Induction of endogenous IL-10 promotes resolution and tolerance of nitric oxide in microglia.

Hsing-Chun Kuo, Jia-Shing Chen, Chun-Nun Chao, Kam-Fai Lee, Yi-Te Huang, Pin-Cheng Mao, Tzu-Chia Lin, Shu-Chen Chiu, Ya-Ling Huang, Chun-Hsien Chu.

  Endogenous interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is induced in a timely and coordinated manner to dampen microglia-mediated brain inflammation. However, it remains unclear how it alters the inflammatory process to shape the immune polarization of microglia. This study aimed to investigate the anti-inflammatory mechanisms of endogenous IL-10 in activated and tolerized microglia using in vitro multiple-reconstituted primary brain cell cultures and an in vivo IL-10 knockout (IL-10KO) animal model. Upon a single or repeated lipopolysaccharide (LPS) treatment regimen, the expression levels of the inflammatory factors during the neuroinflammatory/tolerance process were measured by quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA), and Griess reagent assay. ELISA data showed that cell-autonomous induction of endogenous IL-10 occurs in LPS-activated and LPS-tolerized microglia. Furthermore, comparing the LPS-elicited pro-inflammatory factor expressions at different neuroinflammatory stages between the wild-type and IL-10KO groups, our data revealed the failure of negative-feedback suppression of inducible nitric oxide synthesis (iNOS) during immune resolution in the IL-10KO brains. Moreover, LPS-treated IL-10KO microglia increase the supernatant level of nitrite and become overactive during late-stage inflammation, despite no changes in cell number; in contrast, LPS-tolerized IL-10KO microglia fail to program endotoxin tolerance of nitric oxide/inducible nitric oxide synthesis (iNOS). In summary, our data demonstrate that the cell-autonomous induction of endogenous IL-10 in microglia is crucial for mitigating brain immune responses, particularly in the resolution and tolerance of nitric oxide.

Keywords:  Endotoxin tolerance; IL-10; Immune resolution; Microglia; Neuroinflammation; Nitric oxide

DOI:  https://doi.org/10.1016/j.bbih.2025.101094
Brain Behav Immun. 2025 Nov 19. pii: S0889-1591(25)00419-2. [Epub ahead of print] 106177

Temporally-regulated genetic access to IL-1β-expressing cellular networks in homeostasis and following peripheral or central immune stimuli.

Daniel P Nemeth, Xiaoyu Liu, Loretta Chen, Margaret R Hawkins, Haroon S Ali, Madison G Lapid, Vesal Farsian, Ashley Kim, Julianna Saez, Gabriella Maxey, Numana Luqman, Samantha McGovern, Matt Schrier, Chris Vargas, Josh St Juste-Ellis, Jasmine Yip, Joris Romain, Adam D Bachstetter, Ning Quan.

   BACKGROUND: The proinflammatory cytokine Interleukin-1 beta (IL-1β) regulates nearly all aspects of immune function. In the brain, IL-1β is implicated in neural and immune functions under both basal and inflammatory conditions. Under basal conditions, IL-1β is known to alter sleep, memory, and affect. Under inflammatory conditions, IL-1β can induce sickness behaviors, HPA activation, and exacerbate neurological and psychological disorders. Sensitive detection and specific manipulation of IL-1β-expressing cells in the brain is currently not achievable; therefore, we generated the first mouse line to allow both robust visualization and genetic manipulation of the IL-1β-expressing cells.
METHODS: The IL-1β-TRAP mouse was generated through Crispr9-mediated recombination. IRES-CreERT2 was inserted following exon 7 after the stop codon of the Il1b gene which yielded an IL-1β-IRES-Cre-ERT2 mouse (IL-1β-TRAP). To visualize IL-1β-expressing cells, IL-1β-IRES-Cre-ERT2 line was crossed with ROSA26-lox-stop-lox-tdTomato mouse to generate the IL-1β-IRES-Cre-ERT2:ROSA26-lox-stop-lox-tdTomato (IL-1β-TRAP-reporter). The IL-1β-TRAP-reporter mice were given intraperitoneal (i.p.) Tamoxifen before peripheral LPS or central IL-1β administration. PBS was used as control. The IL-1β-TRAP-reporter mice were also exposed to repetitive closed head injury (CHI) or i.p. kainic acid. tdTomato was allowed to express for 7d and distribution of IL-1β-expressing cells were observed via immunohistochemistry and/or lightsheet microscopy.
RESULTS: Under basal conditions, IL-1β was found primarily to be expressed in MHCII+ and CD206+ meningeal and ventricular macrophages with sparse IL-1β-expressing microglia and neurons in brain parenchyma. Following i.p. LPS and i.c.v. IL-1β injections, IL-1β expression was found in meningeal macrophages and parenchymal P2YR12+ microglia. Following CHI, IL-1β-expressing macrophages increased in the meninges and IL-1β-expressing microglia were induced in the parenchyma at the injury site and along white matter tracts.
CONCLUSIONS: This is the first time active populations of cytokine-expressing cells are visualized, characterized, and genetically accessed using a mouse line with a knockin CreER. With this tool, we identified the choroid plexus as the predominant IL-1β-expressing region in homeostasis. Further, this mouse can be used to identify newly activated IL-1β-expressing cells; they can be targeted for manipulation in physiological and pathological contexts.

Keywords:  Brain; Choroid plexus; Inflammation; Mouse model; Neuroinflammation; Ventricle

DOI:  https://doi.org/10.1016/j.bbi.2025.106177
Acta Neuropathol. 2025 Nov 20. 150(1): 54

Genetic variation in TMEM106B alters microglial activation and cytokine responses in chronic traumatic encephalopathy.

Shahar Hartman, Nurgul Aytan, Raymond Nicks, Samantha Hawkins, Jonathan Cherry, Victor E Alvarez, Gaoyuan Meng, Yorghos Tripodis, Brett Martin, Joseph Palmisano, Lee E Goldstein, Douglas I Katz, Brigid Dwyer, Daniel H Daneshvar, John F Crary, Michael Alosco, Weiming Xia, Ann C McKee, Jesse Mez, Thor D Stein.

  Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease caused by repetitive head impacts (RHI). However, individuals with similar RHI exposure can show differing pathology, suggesting a role for genetic variation. A common Transmembrane Protein 106B (TMEM106B) risk variant is associated with greater CTE severity, though its mechanism remains unclear. To determine whether TMEM106B alters the inflammatory response to pathology in CTE, we examined associations between microglia, via immunohistochemistry, and inflammatory cytokines, via immunoassay, in brain donors with CTE with and without the risk genotype (rs3173615). We analyzed 323 RHI-exposed brain donors: 55 without pathology (controls) and 268 with CTE. Regression models tested associations between TMEM106B risk and CTE presence, CTE stage, TDP-43, and dementia in those < = 65 and > 65 years of age. Within a subset of 122 brain donors, we examined associations between microglia, cytokines, and pathology stratified by TMEM106B genotype. Among donors > 65 years old, the TMEM106B risk genotype was associated with increased CTE stage (OR = 2.748 [95% CI 1.183-6.383], p = 0.019), comparable to the effect of playing > 8 years of contact sports, and with greater odds of having TDP-43 inclusions (OR = 3.649 [95% CI 1.278-10.422], p = 0.016). In donors < = 65, TMEM106B risk was associated with higher odds of dementia (OR = 6.912 [95% CI 2.015-23.705], p = 0.002). TMEM106B gene variation had a significant effect on associations between inflammatory markers and CTE-related pathology. In the protective genotype, IL-8 and IL-6 demonstrated positive associations with CD68, TREM2, and tau pathology within the dorsolateral prefrontal cortex. In the risk genotype, IFN-γ, IL-4, TNF-α, TNF-β, and IL-10 demonstrated negative associations with TREM2 (p's < 0.05), and TNF-α was negatively associated with cortical tau (p = 0.003). These results suggest that the microglial production of TREM2-associated cytokines and their association with pathology is aberrant in the TMEM106B risk genotype in CTE. Overall, TMEM106B rs3173615 is associated with an increased risk of developing higher stage CTE and TDP-43 pathology, potentially via impaired microglial activation and aberrant cytokine production.

Keywords:  CTE; Cytokines; Microglia; Neuropathology; RHI; TMEM106B

DOI:  https://doi.org/10.1007/s00401-025-02955-7
Mol Psychiatry. 2025 Nov 18.

NLRP3-mediated trained immunity of microglia is involved in the recurrence-like episode of depressive disorders.

Gaojie Xu, Minlan Yuan, Hui He, Jin Yi, Xinyu Li, Hao Yan, Gangcai Liu, Ziqiang Wu, Xiaomei Zhang, Yuxiang Chen, Shanyu Lin, Qian Yang, Jinqiang Zhang, Michael Maes, Wei Zhang, Huafu Chen, Zili You.

Recurrent major depression is associated with increased morbidity, suicidal behaviors and increasing neurocognitive deficits. Microglia-mediated neuroinflammatory processes deeply participate in the physiopathology of depression. In response to stress, microglia can develop trained immunity mediated by epigenetic reprogramming, which can enhance the neuro-inflammatory response to subsequent insults. Here, we investigate whether, in animal models, previous depressive-like behaviors are associated with microglial trained immunity, which increases the susceptibility of mice to stress, resulting in the reocurrence of depressive-like behaviors. In the hippocampus and after recovery of initial chronic mild stress (CMS)-induced depressive behaviors, this study discovered increased and persistent chromatin accessibility and H3K4me3 marks in genes related to proinflammatory response, but without sustaining microglial activation and neuroinflammation. Furthermore, the initial CMS induced increased H3K4me3 deposition on the promotor region of NLRP3, inducing impairments in the adult hippocampal neurogenesis and stress sensitization when mice are re-exposed to subthreshold stress (reCMS) for 2 weeks, resulting in the reocurrence of depressive-like behaviors, which could be reversed through specific knockdown of NLRP3 in hippocampal microglia. Blockade of H3K4me3-mediated NLRP3 activation via the H3K4me3 inhibitor rescued neurogenesis impairment induced by initial CMS, and ameliorated the enhanced susceptibility of mice to stress re-exposure. Collectively, initial CMS induced a NLRP3-dependent trained immunity of microglia, which was mediated by epigenetic reprogramming, facilitating the susceptibility of mice to subsequent stress, thereby contributing to the reocurrence of depressive-like behaviors. Our findings might provide a perspective strategy for the prevention and treatment of depression recurrence.

DOI: https://doi.org/10.1038/s41380-025-03344-y
Pharmacol Res. 2025 Nov 14. pii: S1043-6618(25)00459-1. [Epub ahead of print] 108034

Evodiamine attenuates neurological impairment by inducing PANoptosis in microglia after severe traumatic brain injury.

Huiqin Zheng, Xuejun Tian, Yadong Wang, Xiaodi Ye, Xiaoxu Ren, Yangyang Gu, Juehan Wang, Gaoli Zheng, Xiaofeng Yang.

  Severe traumatic brain injury (sTBI) lacks effective therapies despite its high morbidity and mortality in young adults. Here, we demonstrate that evodiamine (EVO), a natural alkaloid from Evodia rutaecarpa, significantly improves neurological outcomes in a murine sTBI model (controlled cortical impact). EVO administration (0.3-3.0mg/kg, intraperitoneal) attenuated cerebral edema, preserved neuronal ultrastructure, and reduced neuroinflammation by suppressing microglial activation and cytokine release. Mechanistically, while EVO showed no direct neuroprotection against H2O2, CoCl2, or oxygen-glucose deprivation-injury in vitro, it significantly enhanced neuronal survival in BV2 microglia-OxyHb co-cultures. Crucially, EVO selectively induced PANoptosis - a coordinated activation of pyroptosis, apoptosis, and necroptosis with PANoptosome formation- in microglia, thereby disrupting their pro-inflammatory activity. This study identifies microglial PANoptosis as the primary therapeutic target of EVO to alleviate post-sTBI neuroinflammation. Our findings position EVO as a promising early-phase intervention for sTBI, offering the first evidence of microglial PANoptosis modulation in neurological therapeutics.

Keywords:  PANoptosis; evodiamine; inflammation; microglia; severe traumatic brain injury

DOI:  https://doi.org/10.1016/j.phrs.2025.108034
J Neuroinflammation. 2025 Nov 18. 22(1): 274

Age-related inflammatory changes and perineuronal net dynamics: implications for aging.

Zachary A Colon, Shannon C Chan, Kathleen A Maguire-Zeiss.

   BACKGROUND: Healthy aging alone can lead to cognitive decline, decreased brain size, protein aggregation, accumulation of senescent cells and neuroinflammation. Furthermore, age is the primary risk factor for several neurodegenerative disorders such as Parkinson's and Alzheimer's disease. Age-related neuroinflammation, as known as inflammaging, is thought to restrict brain plasticity. Perineuronal nets (PNNs), specialized extracellular matrix structures surrounding fast-spiking parvalbumin (PV) interneurons, regulate plasticity and protect neurons from oxidative stress. Given the known impact of inflammaging on neural circuits, this study examines age-associated changes in PNN homeostasis, glial activation, and neuroinflammation in two brain regions relevant to age-related neurodegenerative diseases.
METHODS: We analyzed young (4-month-old) and aged (22-month-old) C57BL/6J male mice for several behavioral phenotypes [hippocampal-dependent spatial learning using the Barnes maze; locomotion and anxiety-related behaviors using Open field and T-maze]. Using immunostaining, PNNs (Wisteria floribunda agglutinin and aggrecan), PV interneurons, and microglial activation (Iba1) were quantified in both the hippocampus and dorsal striatum. Glial morphology was examined using a battery of cell body, branching, and endpoint analyses. Quantitative RT-PCR was used to analyze changes in the gene expression of inflammatory and extracellular matrix markers.
RESULTS: Aged mice exhibited hippocampal-dependent memory deficits without alterations in locomotion or anxiety-related behavior. PNN counts increased in the aged hippocampus, particularly in CA2, with a higher proportion of WFA+ and aggrecan+ PNNs. In contrast, PNN homeostasis was maintained in the dorsal striatum. In general, Aged mice showed increases in microglial activation and a subset of inflammatory markers. We report brain region- and age- specific gene expression changes in complement, matrix metalloproteinases, and other inflammatory markers. Aged striatal microglia displayed an activated morphology with larger cell bodies and reduced branching, as well as increased expression of markers for microgliosis (Iba1, TREM2, CD68).
CONCLUSIONS: These findings suggest that aging differentially affects neuroinflammation and PNN integrity across brain regions. The hippocampus exhibits PNN accumulation, neuroinflammation, and behavioral changes, whereas the striatum maintains PNN homeostasis concurrent with increased microglial activation. This work suggests that neuroinflammation contributes to age-related changes in PNNs and behavior underscoring the importance of region-specific therapeutic strategies targeting PNN regulation.

Keywords:  Hippocampus; Inflammaging; Neuroinflammation; Parvalbumin; Striatum

DOI:  https://doi.org/10.1186/s12974-025-03568-3
Alzheimers Res Ther. 2025 Nov 20. 17(1): 248

Selective agonism of GPR34 stimulates microglial uptake and clearance of amyloid β fibrils.

Hayato Etani, Sho Takatori, Wenbo Wang, Jumpei Omi, Yusuke Amiya, Aika Akahori, Hirotaka Watanabe, Iki Sonn, Hideyuki Okano, Norikazu Hara, Mai Hasegawa, Akinori Miyashita, Masataka Kikuchi, Takeshi Ikeuchi, Maho Morishima, Yuko Saito, Shigeo Murayama, Takashi Saito, Takaomi C Saido, Toshiyuki Takai, Tomohiko Ohwada, Junken Aoki, Taisuke Tomita.

   BACKGROUND: Microglia play a crucial role in brain homeostasis through phagocytosis of amyloid-β (Aβ) fibrils, a hallmark of Alzheimer disease (AD) pathology. The balance between Aβ production and clearance is critical for AD pathogenesis, with impaired clearance mechanisms potentially contributing to disease progression. G-protein coupled receptor 34 (GPR34), a microglia-enriched Gi/o-coupled receptor, is highly expressed in homeostatic microglia and may regulate phagocytic functions, yet its role in Aβ clearance remains poorly understood.
METHODS: Using flow cytometry-based assays, we investigated the effect of a selective GPR34 agonist (M1) on Aβ uptake in mouse primary microglia and human induced pluripotent stem cell-derived microglia. We evaluated uptake specificity across different Aβ species and phagocytic substrates, and measured intracellular cyclic adenosine monophosphate (cAMP) levels to determine the signaling mechanism. We performed in vivo studies using human amyloid precursor protein knock-in mice with intrahippocampal M1 injections. Additionally, we analyzed GPR34 expression in Japanese AD patient brain samples using single-nucleus RNA sequencing and examined age-dependent expression changes across multiple datasets.
RESULTS: M1 specifically enhanced uptake of Aβ fibrils through reduction of intracellular cAMP levels, without affecting monomeric or oligomeric Aβ internalization. Gpr34 knockdown experiments confirmed GPR34 as the molecular target of M1. An intrahippocampal injection of M1 significantly increased microglial Aβ uptake in vivo, an effect that required functional TREM2 signaling. GPR34 expression was significantly reduced in microglia from AD patients and showed age-dependent decline in both humans and mice.
CONCLUSIONS: Our findings identify GPR34 as a promising therapeutic target for enhancing microglial Aβ clearance and highlight the potential of GPR34 agonists for AD treatment. The age-dependent decline in GPR34 expression may contribute to reduced Aβ clearance efficiency in aging brains, exacerbating amyloid accumulation. Pharmacological activation of GPR34 represents a novel strategy to counteract impaired Aβ clearance in both aging and AD brains, potentially modifying disease progression through enhancement of microglial phagocytic function.

Keywords:  Alzheimer disease; Amyloid-β; GPCR; GPR34; Microglia; Phagocytosis; Single-nucleus RNA sequencing; Therapeutic target

DOI:  https://doi.org/10.1186/s13195-025-01891-8
Exp Eye Res. 2025 Nov 20. pii: S0014-4835(25)00535-4. [Epub ahead of print]262 110762

3,4-dihydroxybenzalacetone from Phellinus linteus reduces glial activation, mitigates oxidative stress and inflammation, and preserves retinal function in ischemia-reperfusion-like injury.

Liang-Huan Wu, Yueh-Hsiung Kuo, Fan-Li Lin, Ida Fitriana, Chih-Hao Yang, Yan-Cheng Shen, Yi-Chien Liu, Cheng-Yan Jiang, Jing-Lun Yen, Yen-Mei Lee, Yu-Wen Cheng, George Hsiao.

  Retinal ischemia-reperfusion (I/R) injury is a key pathological feature of acute glaucoma that induces oxidative stress, inflammation, and retinal glial activation, ultimately leading to retinal degeneration and neuronal dysfunction. This study evaluated the therapeutic potential of 3,4-dihydroxybenzalacetone (DBA) in protecting against I/R-induced retinal damage. DBA was tested in LPS-stimulated BV-2 microglia, in TNFα- or tBHP-treated rMC-1 Müller glial cells, and in a rat model of retinal I/R injury. In vitro assays demonstrated that DBA suppressed oxidative and inflammatory responses in microglia by reducing ROS, NO, IL-6, iNOS, and COX-2 levels. In Müller cells, DBA activated the NRF2/HO-1 pathway under oxidative stress and attenuated TNFα-induced upregulation of MMP-9 and MCP-1. Signaling analysis revealed that DBA inhibited the phosphorylation of p65 and STAT3 in both glial cell types, with additional ERK inhibition observed specifically in Müller cells. In vivo, DBA preserved retinal electrophysiological activity, as evidenced by maintained a- and b-wave responses, and reduced the expression of MMP-9, GFAP, and CD68 in the retina. These findings indicate that DBA confers partial retinal protection by modulating multiple glial-related signaling pathways and suggest its potential as a multi-target therapeutic agent for retinal neurodegenerative diseases.

Keywords:  Electroretinography; Glaucoma; Microglia; Müller glia; Neuroinflammation; Retinal ischemia

DOI:  https://doi.org/10.1016/j.exer.2025.110762
Alzheimers Dement. 2025 Nov;21(11): e70930

Human microglia differentially respond to β-amyloid, tau, and combined Alzheimer's disease pathologies in vivo.

Morgan A Coburn, Ghazaleh Eskandari-Sedighi, Jonathan Hasselmann, Whitney England, Sepideh Kiani Shabestari, Kimiya Mansour, Amanda McQuade, Michael Armen Mgerian, Jean Paul Chadarevian, Christina Tu, Jorge Silva, Jaclyn Beck, Zahara Keulen, Robert C Spitale, Hayk Davtyan, Mathew Blurton-Jones.

   INTRODUCTION: Recent studies have identified important species-dependent differences in the response of microglia to β-amyloid (Aβ) pathology. Yet, whether human microglia also interact differently with the pathognomonic combination of amyloid and tau pathologies that occur in Alzheimer's disease (AD) remains unclear.
METHODS: We generated a xenotolerant mouse model of AD that develops both plaque and tangle pathologies, transplanted stem cell-derived microglial progenitors and examined the interactions between human microglia and AD pathologies with scRNA sequencing, immunohistochemistry, and in vitro modeling.
RESULTS: The combined amyloid and tau pathologies induced robust type-I interferon and proinflammatory cytokine responses, as well as an increased adoption of a distinct "rod" morphology in human microglia. The rod morphology could be induced with type-I interferon treatment in vitro.
DISCUSSION: We provide new insights into human microglial responses to combined AD pathologies and a novel platform to investigate and manipulate human microglia in vivo.
HIGHLIGHTS: Amyloid pathology promotes the rapid development of neurofibrillary tangles and neuronal loss in a novel chimeric model of AD. Combined Alzheimer's disease pathologies lead to an expansion of disease-associated microglia (DAM) and exacerbate Interferon-responsive and cytokine/chemokine-enriched states in xenotransplanted human microglia. The combination of amyloid and tau promotes the development of a distinctive rod microglial phenotype that closely correlates with tau pathology and neurodegeneration. Rod morphology and transcriptional changes can be modeled in vitro by treatment of induced pluripotent stem cells (iPSC) -microglia with type-I interferons.

Keywords:  Alzheimer's disease; amyloid beta; human microglia; iPSC; rod microglia; tau; type I interferon

DOI:  https://doi.org/10.1002/alz.70930
Front Bioinform. 2025 ;5 1681811

Cellf-deception: human microglia clone 3 (HMC3) cells exhibit more astrocyte-like than microglia-like gene expression.

Kylee K Rahm, Branden S Kinghorn, Myanna J Moody, Ben C Stone, Kenton C Strong, Brian S Kim, Yen Jou Chang, Samantha N Sleight, Alyssa A Nitz, David V Hansen, Matthew H Bailey.

   Introduction: Recent advances in Alzheimer's research suggest that the brain's immune system plays a critical role in the development and progression of this devastating disease. Microglial cells are vital as immune cells in the brain's defense system. Human Microglia Clone 3 (HMC3) is a cell line developed as a promising experimental model to understand the role of microglial cells in human diseases including Alzheimer's and other neurodegenerative diseases. The frequency of HMC3 cell usage has increased in recent years, with the idea that this cell line could serve as a convenient model for human microglial cell functions.
Methods: We utilized gene-pair ratios from bulk and single-cell RNA sequencing (scRNA-seq) expression data to create predictive models of cell-type origins.
Results: Our model reveals that the HMC3 cell line represents various cell types, with the highest cell similarity score relating to astrocytes, not microglia.
Discussion: These findings suggest that the HMC3 cell line is not a reliable human microglia model and that extreme caution should be taken when interpreting the results of studies using the HMC3 cell line.

Keywords:  Alzheimer’s disease; HMC3 cells; astrocytes; cell-type classification; iPSC-derived microglia (iMG); microglia

DOI:  https://doi.org/10.3389/fbinf.2025.1681811
Res Sq. 2025 Oct 03. pii: rs.3.rs-7762822. [Epub ahead of print]

Global human myeloid replacement with peripheral progenitors induces interferonopathy and neurodegeneration.

Jing Wang, Anna Warden, Bing Xia, Katie E Mostoller, Benjamin Brandon, Michelle Du, Nathanael Spann, Rick Z Li, Mana M Parast, Karen Mestan, Fatir Qureshi, Olivia Corradin, Christopher Glass, Nicole G Coufal.

Microglia, the brain's resident macrophages, arise from yolk sac hematopoietic progenitor cells (HPCs) that migrate into the brain during early embryonic development and differentiate in response to microenvironment-specific signals. The resulting spatial and stage-specific programs of gene expression enable microglia to function as key modulators of diverse homeostatic processes that include synaptic pruning, myelination, and neurogenesis throughout the lifespan. Dysregulation of these core microglia functions has been linked to numerous neurodevelopmental and neurodegenerative diseases. Although normally a closed niche, studies in mice indicate that peripheral monocytes, originating from hematopoietic stem cells (HSCs), can infiltrate the brain in circumstances in which the blood brain barrier is disrupted, with context-dependent protective or detrimental consequences. A major unanswered question with significant implications for therapy of CNS diseases driven by microglia dysfunction is the extent to which human HSC-derived cells can adopt microglia-like phenotypes that would allow them to restore brain homeostasis by replacement of pathologic HPC-derived microglia. To address this question, we directly compared the differentiation potential of primary human microglia, human iPSC-derived HPCs and human HSCs in the brain utilizing a murine xenotransplantation model. HSCs and monocytes were capable of differentiating into microglia like cells in this model, they also acquired a strong interferon, phagocytic, and antigen presenting phenotype distinct from engrafted primary human microglia and HPC-derived cells. Analyses of the epigenetic landscapes of the engrafted HPC and HSC-derived cells enabled identification of the transcription factors networks underlying ontogeny-specific brain myeloid fates. Ultimately, human peripheral myeloid cells in the CNS led to astrogliosis, myelin fragmentation and synaptic loss. These findings reveal transcriptional network differences influenced by ontogeny, and together with the accompanying study by Davtvan and colleagues provide critical insights for developing human microglial or bone marrow transplant-based therapies for CNS disorders.

DOI: https://doi.org/10.21203/rs.3.rs-7762822/v1
EMBO J. 2025 Nov 17.

Microglial colonization of the developing mouse brain is controlled by both microglial and neural CSF-1.

Cécile Bridlance, Sarah Viguier, Nicolas Olivié, Edmond Dupont, Dorine Thobois, Benjamin Mathieu, Jean X Jiang, Guillermina López-Bendito, Melanie Greter, Burkhard Becher, Florent Ginhoux, Aymeric Silvin, Esther Klinger, Sonia Garel, Morgane Sonia Thion.

  Microglia are brain-resident macrophages critical for cerebral development, function, and homeostasis. During development, yolk sac-derived microglial progenitor cells colonize and populate the brain following a well-defined spatiotemporal pattern. However, the mechanisms controlling microglial colonization and proliferation remain largely unknown. Here, we describe two broad waves of microglial proliferation in the developing mouse forebrain. Microglia accumulate in transient hotspots, in a proliferative axon tract-associated microglia (ATM)-like state. Prenatal and early postnatal patterns of microglial colonization do not rely on neuronal activity. Instead, using conditional inactivation of the microglial regulator colony-stimulating factor 1 (Csf1) gene, we reveal that the distribution and proliferation of embryonic cortical microglia critically rely on neural CSF-1, mainly produced by cortical progenitor cells but also by post-mitotic neurons, with the action of CSF-1 being local, dose-dependent, and transient. In addition, intrinsic CSF-1 expressed by ATM microglia contributes to their sustained proliferation in developmental hotspots. Our study reveals that microglia rely on distinct, local, and cell-type-specific sources of CSF-1 for their developmental distribution, which has major implications for understanding how microglia colonize the brain in health and disease.

Keywords:  Colonization; Cytokine; Development; Microglia; Proliferation

DOI:  https://doi.org/10.1038/s44318-025-00625-8
bioRxiv. 2025 Sep 30. pii: 2025.09.28.679053. [Epub ahead of print]

miR155 triplicated in Down syndrome regulates hippocampal GABAergic neurogenesis in Alzheimer's disease.

Xiaodong Zhu, Jean-Vianney Haure-Mirande, Mesude Bicak, Pengfei Dong, Ilya Kruglikov, Aisha Al-Subaie, Valentina Fossati, Scott Noggle, Sam Gandy, Michelle E Ehrlich.

MicroRNA dysregulation is implicated in neurodegenerative disorders, including Alzheimer's disease (AD). The role of neuronal microRNA155 (miR155), elevated in both AD and Down syndrome (DS), remains unknown. We found that MIR155HG (miR155 host gene) colocalizes with APP (amyloid-beta precursor protein) in a neuron-specific, topologically-associated domain (TAD) within a regulatory network, in the obligate portion of chromosome 21 triplicated in DS which causes AD neuropathology and in most cases, dementia. We investigated miR155 role during neuron development and then validated these findings in an amyloidopathy model. In human induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs), cortical neurons and cortical organoids, MIR155 deletion enhanced NSC proliferation, ventral patterning and GABAergic interneuron generation. However, MIR155 overexpression inhibited NSC marker expression and GABAergic interneuron generation. MIR155 upregulates its mRNA targets, NR2F1 / 2 , key modulators of hippocampal GABAergic interneuron development. In an amyloidopathy mouse model, miR155 deletion induced the expansion of hippocampal NSCs and increased hippocampal GABAergic interneurons. These findings reveal previously unrecognized miR155 roles in NSC dynamics and GABAergic interneuron development which directionally diverge from extensively studied microglial miR155 in their beneficial vs negative impact on AD mouse models, suggesting that approaching miR155 therapeutically may require balancing the effects in neurons and microglia.

DOI: https://doi.org/10.1101/2025.09.28.679053
bioRxiv. 2025 Oct 02. pii: 2025.10.02.679906. [Epub ahead of print]

Fluid-Niche and Microglial Signatures Prime Robust Intraventricular Macrophage Response to Blood During Brain Development.

Miriam E Zawadzki, Christine Hehnly, Jordan C Benson, Dario X Figueroa Velez, Sivan Gelb, Ceva Stanley, Lillian I J Byer, Huixin Xu, Cameron Sadegh, Aja Pragana, Maria K Lehtinen.

Intraventricular macrophages (IVMs) reside in cerebrospinal fluid (CSF) and are considered a border-associated macrophage (BAM) population in the brain. Although they represent the first line of defense against intraventricular challenges, their developmental roles and responses to injury are poorly understood. This knowledge is relevant for conditions including neonatal intraventricular hemorrhage (IVH), where blood extravasates into brain ventricles, leading to life-long negative sequelae including cerebral palsy and hydrocephalus. Here, we show that IVMs are first responders to blood in developing brain ventricles, phagocytosing red blood cells and upregulating iron-processing machinery. Live imaging of developing mouse ventricles and choroid plexus revealed that IVMs are dynamic and morphologically distinct from non-IVM macrophages. Their transcriptional profiles distinguish them from other BAMs as they also exhibit signatures of "youth-associated microglia" and characteristics of cavity macrophages found in fluid niches such as the peritoneum. Our findings provide insights into IVM development and function, highlighting their therapeutic potential.

DOI: https://doi.org/10.1101/2025.10.02.679906
bioRxiv. 2025 Sep 30. pii: 2025.09.30.677638. [Epub ahead of print]

Gestational psychedelic exposure disrupts brain development and offspring behavior in mice.

Ya'el Courtney, Josephine M Anderson, Christian Lagares-Linares, Cody J Wenthur, Maria K Lehtinen.

Despite increasing non-medical use and clinical investigation of psychedelics, the consequences of prenatal exposure remain unknown. In mice, maternal lysergic acid diethylamide (LSD; 0.3 mg kg -1 ) crossed the placenta, appearing in embryonic cerebrospinal fluid (CSF) within minutes at E12.5 and E16.5. Within 30 minutes, LSD and other serotonergic psychedelics induced a 5-HT 2 C agonist-like response in the choroid plexus, triggering apical remodeling and increasing CSF protein. A single E12.5 exposure altered cerebral cortical laminar organization and composition at postnatal day 8, and repeated dosing (E12.5-E16.5) amplified male-biased shifts from SATB2 + to CTIP2 + neuronal identities and increased microglia. Adult offspring showed reduced prepulse inhibition (male-predominant) and rotational stereotypy. These data identify an embryo-facing interface that detects maternal psychedelics and link CSF access to enduring neurodevelopmental and behavioral consequences.

DOI: https://doi.org/10.1101/2025.09.30.677638