bims-microg 2025-10-12 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2025–10–12
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Astrocytes make room for microglia.
Brain-infiltrating CD4 T cells drive inflammatory microglia proliferation during cryptococcal meningitis in mice.
Alternate day fasting alleviates neuroinflammation in diabetic mice by regulating δ-valerobetaine-carnitine-microglia axis via enrichment of Akkermansia muciniphila.
Role for NF-κB in herpes encephalitis pathology in mice genocopying an inborn error of IRF3-IFN immunity.
Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.
Microglial Nr4a1 deficiency and neuronal C3 deposition mediate TMJ inflammation-induced hippocampal excessive synaptic pruning and depression-like behaviors in mice.
Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells.
Decoding amyloid beta clearance systems at inner blood-retina barrier using three-dimensional ex vivo retinal imaging in Alzheimer's disease.
Generation of vascularized retinal organoids containing microglia based on a PDMS microwell platform.
Transpupillary in vivo two-photon imaging reveals enhanced surveillance of retinal microglia in diabetic mice.
Tailored brain metastatic tumor cells-derived apoptotic bodies ameliorate Alzheimer's disease by promoting microglia efferocytosis and neuroinflammation mitigation.
A neuroimmune cerebral assembloid model to study the pathophysiology of familial Alzheimer's disease.
Early antiviral treatment following gammaherpesvirus-68 infection of the central nervous system prevents subsequent multiple sclerosis-like disease.
Lung cancer cells upregulate stearoyl-CoA desaturase 1 in microglia by activating the STAT3 pathway to change microglial inflammatory response in lung-to-brain metastases.
Time-restricted feeding provides limited microglial immunometabolic improvements in diet-induced obese rats.
LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.
Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in Monocyte-Derived Macrophages and Induced Pluripotent Stem Cell-Derived Microglia.
Gut microbiota dysbiosis exacerbates post-stroke depression via microglial NLRP3 inflammasome activation.
Characterization of SPTLC2 as a key driver promoting microglial activation and energy metabolism reprogramming after ischemic stroke through bulk and single-cell analyses combined with experimental validation.
Glioma‑associated microglia and macrophages as a potential target for mTOR inhibition in glioblastoma.

Nat Neurosci. 2025 Oct;28(10): 2008

Astrocytes make room for microglia.

Rebecca Wright.

DOI: https://doi.org/10.1038/s41593-025-02082-2
Nat Commun. 2025 Oct 09. 16(1): 8995

Brain-infiltrating CD4 T cells drive inflammatory microglia proliferation during cryptococcal meningitis in mice.

Sofia Hain, Man Shun Fu, Lucy Wigg, Lorna George, David Lecky, Alexander J Whitehead, Erin Clipston, Ko Sato, Masahiro Ono, Marcel Wuthrich, Bruce Klein, Kazuyoshi Kawakami, Julie Rayes, David Bending, Rebecca A Drummond.

Cryptococcal meningitis is a fungal infection in patients with compromised CD4 T cell function. CD4 T cells provide killing signals to macrophages, principally IFNγ, to limit intracellular fungal replication. However, CD4 T cells may also drive inflammatory tissue damage. Yet, it is not fully understood how fungal-specific CD4 T cells infiltrate the brain and how they influence functional phenotypes of CNS-resident myeloid cells. In the current work, we develop a mouse model to track fungal-specific CD4 T cells and determine their influence on microglia. We found IFNγ+ fungal-specific CD4 T cells have limited TCR signalling and characterise a population of inflammatory microglia that upregulate MHCII and IFNγ-regulated genes during infection. Inflammatory microglia have poor fungicidal capacity and significantly expand during infection, a process that depends on CD4 T cell infiltration. Taken together, these data identify the early inflammatory consequences of fungal-specific CD4 T cell infiltration and identify proliferating microglia as important drivers of brain inflammation during infection.

DOI: https://doi.org/10.1038/s41467-025-64034-5
Microbiome. 2025 Oct 09. 13(1): 202

Alternate day fasting alleviates neuroinflammation in diabetic mice by regulating δ-valerobetaine-carnitine-microglia axis via enrichment of Akkermansia muciniphila.

Kaiyan Gong, Shuhui Zhang, Yangjie Pan, Qingpeng Cai, Mengjun Wu, Xiaoli Yin, Jiahui Ma, Hao Ji, Zhen Wang, Wenjun Wu, Hong Zheng.

   BACKGROUND: Alternate day fasting (ADF) as a healthy dietary pattern has been reported to improve brain functions and behaviors, but the effect of ADF on diabetes-related brain disorders and the potential mechanisms remain unclear. In this study, we investigated the impact of ADF on neuroinflammation and exploratory behavior in type 1 diabetic (T1D) mice and explored the specific molecular mechanisms from the perspective of the gut microbiota and host metabolism.
RESULTS: ADF can effectively relieve neuroinflammation and exploratory behavioral disorders in T1D mice. According to fecal microbiota transplant and bacterial supplementation, we demonstrated that ADF-driven enrichment of Akkermansia muciniphila (AKK) was necessary for boosting exploratory behavior in T1D mice. The gut microbiota-derived metabolite δ-valerobetaine (VB) reduced hepatic carnitine synthesis by inhibiting BBOX, and caused exploratory behavioral disorders in mice. In vitro and in vivo studies revealed that AKK bacteria had the ability to consume VB, and thereby increased systemic carnitine level. In addition, carnitine was found to deplete lipid droplet accumulation in microglia by enhancing fatty acid oxidation and lipolysis, reduce neuroinflammation and neuron injury, and then increase exploratory behavior in T1D mice.
CONCLUSIONS: Our study sheds light on the gut-liver-brain metabolic axis mechanism on the protective role of ADF in T1D-associated neuroinflammation and exploratory behavioral disorders and AKK bacteria exert as a key mediator. Video Abstract.

Keywords:  Behavior; Diabetes; Fasting; Gut-brain axis; Neuroinflammation

DOI:  https://doi.org/10.1186/s40168-025-02196-6
J Exp Med. 2026 Jan 05. pii: e20250064. [Epub ahead of print]223(1):

Role for NF-κB in herpes encephalitis pathology in mice genocopying an inborn error of IRF3-IFN immunity.

Manja Idorn, Xiangning Ding, Stefanie Fruhwürth, Søren Holste, Line S Reinert, Christian S Skoven, Katarina Türner-Stenström, Alexander Schmitz, Mikkel H Vendelbo, Benedicte P Ulhøi, Dzeneta Vizlin-Hodzic, Mona Wefelmeyer, Ryo Narita, Lona J Kroese, Ivo J Huijbers, Michelle Møhlenberg, Anne Kruse Hollensen, Xin Lai, Marie B Iversen, Brian Hansen, Trine H Mogensen, Søren R Paludan.

Herpes simplex encephalitis (HSE) is a devastating disease with high mortality and serious sequelae. Genetic defects in the IFN-I pathway predispose individuals to HSE, but underlying mechanisms remain unclear. Using transgenic mice with the IRF3 R278Q mutation, ortholog to HSE-associated IRF3 R285Q, and iPSC-derived CNS cells from a pediatric patient carrying the variant, we investigated mechanisms in HSE. IRF3 R278Q transgenic mice exhibited aggravated HSV-1 brain disease and elevated CNS viral loads. Accordingly, microglia from the IRF3 R278Q mice showed reduced HSV-1-induced IFN-I expression. Surprisingly, unaltered Ifnb levels along with elevated levels of inflammatory cytokines were detected in infected transgenic mouse brains, correlating with higher viral load. This was successfully modeled in patient microglia. Multiomics-based immune profiling revealed an inflammatory monocyte population in the infected IRF3 R278Q mouse brain, which was enriched for NF-κB activation. NF-κB inhibition improved disease outcomes, surpassing the effect of acyclovir. These findings suggest that IFN-I defects lead to elevated levels of HSV-1 replication in the brain, which subsequently enables NF-κB-driven immunopathology, offering insights with therapeutic potential.

DOI: https://doi.org/10.1084/jem.20250064
Adv Sci (Weinh). 2025 Oct 06. e10270

Uric Acid Functions as an Endogenous Modulator of Microglial Function and Amyloid Clearance in Alzheimer's Disease.

De Xie, Qiuyang Zheng, Jiaming Lv, Qian Zhang, Zhiwei Cui, Shuai Huang, Wei Yu, Binyang Chen, Wanling Que, Shanpan Fu, Yuemei Xi, Jiayu Chen, Xueling Ye, Shuyi Chen, Hairong Zhao, Tetsuya Yamamoto, Hidenori Koyama, Xin Wang, Jidong Cheng.

  Epidemiological studies have linked uric acid (UA), the end product of purine metabolism in humans, with reduced Alzheimer's disease (AD) risk. Decreased serum UA levels are observed in AD patients versus age-matched controls, while upstream purine metabolites remained unchanged. In 5×FAD mice, two months of UA supplementation improved cognitive function and reduced amyloid plaque burden. Mechanistically, UA enhances microglial amyloid-β (Aβ) phagocytosis and induces transcriptional reprogramming in AD mouse microglia, characterized by upregulated phagocytic pathways and attenuated inflammatory responses. UA treatment restored the recycling of Aβ receptors CD36 and TREM2 in microglia, enhanced lysosomal biogenesis, and facilitated Aβ degradation. These findings identify UA as a critical endogenous modulator of microglial Aβ processing and suggest exploring UA supplementation as a therapeutic strategy for AD.

Keywords:  Alzheimer's disease; amyloid‐β; microglia; uric acid

DOI:  https://doi.org/10.1002/advs.202510270
Brain Behav Immun. 2025 Oct 07. pii: S0889-1591(25)00370-8. [Epub ahead of print] 106128

Microglial Nr4a1 deficiency and neuronal C3 deposition mediate TMJ inflammation-induced hippocampal excessive synaptic pruning and depression-like behaviors in mice.

Dexin Zhu, Muyun Wang, Fei Liu, Suying Zhan, Yuheng Feng, Chen Li, Yating Yi, Chunjie Li, Cheng Zhou, Yanyan Zhang, Jiefei Shen.

  Temporomandibular joint (TMJ) inflammation-induced depression-like behaviors represent a common clinical complication in oral medicine. Microglia-mediated aberrant synaptic pruning in the hippocampus (HPC) plays a pivotal role in the pathogenesis of emotional disorders. However, the underlying mechanisms of TMJ inflammation-induced depression-like behaviors remain elusive, causing a severe lack of therapeutic targets for this condition. Here, we demonstrated that complete Freund's adjuvant (CFA)-induced TMJ inflammation model induced depression-like behaviors in mice, concomitant with hippocampal microglial activation and abnormal synaptic pruning. Minocycline-mediated suppression of microglial activity ameliorated TMJ inflammation-induced pathological synaptic remodeling. In addition, nuclear receptor subfamily 4 group A member 1 (Nr4a1) expression was significantly downregulated in microglia of HPC following CFA treatment. Nr4a1 silencing promoted the expression of lysosomal protein Cluster of Differentiation 68 (CD68) on microglial surfaces by activating nuclear factor kappa-light-chain-enhancer of activated B Cells (NF-κB) signaling pathway, whereas Nr4a1 overexpression suppressed microglial phagocytic activity. Meanwhile, following TMJ inflammation, complement 3 (C3) expression was upregulated in the HPC, with immunofluorescence (IF) revealing C3 localization in neurons and colocalization between synaptic terminals and microglia accompanied by synaptic loss. Notably, the overexpression of C3 also promoted excessive synaptic pruning in the HPC and induced depression-like behaviors. Collectively, Nr4a1 deficiency in the HPC activated microglia to mediate neuronal synaptic loss through a C3-dependent mechanism, ultimately contributing to emotional disorders in TMJ inflammation. This study elucidated the pivotal role of microglial Nr4a1 and neuronal C3 in synaptic pruning processes, suggesting that targeting these molecules may offer a potential therapeutic strategy for post-TMJ inflammation emotional complications.

Keywords:  Complement 3; Synaptic pruning; Temporomandibular joint inflammation, depression; nuclear receptor subfamily 4 group A member 1

DOI:  https://doi.org/10.1016/j.bbi.2025.106128
Alzheimers Dement. 2025 Oct;21(10): e70772

Alzheimer's disease-associated PLCG2 variants alter microglial state and function in human induced pluripotent stem cell-derived microglia-like cells.

Logan M Bedford, Kaylee D Tutrow, Karly Hooper, Evan J Messenger, Melody Hernandez, Bruce T Lamb, Jason S Meyer, Timothy I Richardson, Stephanie J Bissel.

   INTRODUCTION: Variants of phospholipase C gamma 2 (PLCG2), a key microglial immune signaling protein, are genetically linked to Alzheimer's disease (AD) risk. Understanding how PLCG2 variants alter microglial function is critical for identifying mechanisms that drive neurodegeneration or resiliency in AD.
METHODS: Induced pluripotent stem cell (iPSC) -derived microglia carrying the protective PLCG2P522R or risk-conferring PLCG2M28L variants, or loss of PLCG2, were generated to ascertain the impact on microglial transcriptome and function.
RESULTS: Protective PLCG2P522R microglia showed significant transcriptomic similarity to isogenic controls. In contrast, risk-conferring PLCG2M28L microglia shared similarities with PLCG2KO microglia, with functionally reduced TREM2 expression, blunted inflammatory responses, and increased proliferation and cell death. Uniquely, PLCG2P522R microglia showed elevated cytokine secretion after lipopolysaccharide (LPS) stimulation and were protected from apoptosis.
DISCUSSION: These findings demonstrate that PLCG2 variants drive distinct microglia transcriptomes that influence microglial functional responses that could contribute to AD risk and protection. Targeting PLCG2-mediated signaling may represent a powerful therapeutic strategy to modulate neuroinflammation.
HIGHLIGHTS: The impact of Alzheimer's disease protective- and risk-associated variants of phospholipase C gamma 2 (PLCG2) on the transcriptome and function of induced pluripotent stem cell (iPSC) -derived microglia was investigated. PLCG2 risk variant microglia exhibited a basal transcriptional profile similar to PLCG2-deficient microglia but significantly different from isotype control and the transcriptionally similar PLCG2 protective variant microglia. PLCG2 risk variant and PLCG2-deficient microglia show decreased levels of triggering receptor expressed on myeloid cells 2 (TREM2). The differential transcriptional pathways of protective and risk-associated PLCG2 variant microglia functionally affect proliferation, apoptosis, and immune response. Protective PLCG2 microglia show resilience to apoptosis and increased cytokine/chemokine secretion upon exposure to lipopolysaccharide (LPS).

Keywords:  Alzheimer's disease; PLCG2; RNA: sequence analysis, RNA; apoptosis; cell death; cell proliferation; genetic predisposition to disease; genetic variants; induced pluripotent stem cells; microglia; phenotype

DOI:  https://doi.org/10.1002/alz.70772
Alzheimers Dement. 2025 Sep;21(9): e70592

Decoding amyloid beta clearance systems at inner blood-retina barrier using three-dimensional ex vivo retinal imaging in Alzheimer's disease.

Printha Wijesinghe, Amir Hosseini, Matthew Campbell, Shivani Tejpal, Justin Haynes, Jeanne Xi, Ian R Mackenzie, Veronica Hirsch-Reinshagen, Ging-Yuek Robin Hsiung, Benjamin W Spiller, Brian E Wadzinski, Wellington Pham, Joanne A Matsubara.

   INTRODUCTION: Impaired amyloid beta (Aβ) clearance contributes to sporadic Alzheimer's disease (AD). This study investigated retinal Aβ clearance involving neuronal, glial, and vascular interactions at the inner blood-retina barrier (iBRB), a functional analog of the blood-brain barrier (BBB).
METHODS: Retinal wholemounts from AD donors and controls were analyzed alongside transgenic amyloid precursor protein/presenilin 1 (APP-PS1) and non-carrier control mouse retinal cross-sections using three- and two-dimensional ex vivo imaging.
RESULTS: AD neuroretinas displayed increased larger Aβ42 deposits, microglial elongation, and substantial reductions in macroglial support and water channel expression. The uptake of soluble Aβ oligomers (SAβOs) by peripheral macrophage-like, Aβ-binding myeloid lineage cells was also diminished. In APP-PS1 mice, elevated glia levels, alongside increased APP/Aβ expression, suggest gliosis and failures in clearance processes with disease progression.
DISCUSSION: Ex vivo three-dimensional retinal imaging at the iBRB provides novel insights into Aβ clearance in AD, which is difficult to replicate in ex vivo brain studies at the BBB.
HIGHLIGHTS: Impaired clearance mechanisms play a key role in sporadic AD. The iBRB serves as a functional analog to the BBB. At the iBRB, the glymphatic system and microglial phagocytosis help mitigate Aβ burden. Peripheral macrophage-like myeloid lineage cells may aid SAβO clearance. The imaging plane (surface vs cross-section) may affect AD pathogenesis findings.

Keywords:  Alzheimer's retina; glymphatic structures; inner blood–retina barrier; microglia; soluble Aβ oligomer

DOI:  https://doi.org/10.1002/alz.70592
Sci Adv. 2025 Oct 10. 11(41): eady6410

Generation of vascularized retinal organoids containing microglia based on a PDMS microwell platform.

Hang Chen, Yuqin Liang, Xihao Sun, Wei Xiong, Tingting Yang, Yuan Liang, Xiuhong Ye, Xiaoxue Li, Wenxuan Wang, Jianing Gu, Jun Zhang, Liqun Chen, Hon Fai Chan, Jiansu Chen.

Retinal organoids (ROs) offer a biomimetic in vitro model for investigating human retinal development and disease. However, current ROs face several limitations, such as the absence of vascular networks and microglial cells (MGs). Here, we developed a vascularized retinal organoids (vROs) model by coculturing vascular organoids (VOs) with ROs in a V-bottom polydimethylsiloxane (PDMS) microwell platform. Through coculturing for 30 to 120 days, we observed the presence of tubular blood vessels at the center of vROs. Transcriptomic analysis revealed that the vascularization in ROs was associated with angiogenesis and immune response. Furthermore, we observed that MGs in VOs migrated and integrated into the vROs as VOs and ROs fused, with the vROs exhibiting responsiveness to inflammatory stimuli. The vROs expressed tight junction protein claudin-5 and displayed similar characteristics to the inner blood-retinal barrier (iBRB). These vRO models, which incorporate vascular structures and MGs, provide an alternate avenue for retinal vascular disease research and hold promise for future clinical applications.

DOI: https://doi.org/10.1126/sciadv.ady6410
Proc Natl Acad Sci U S A. 2025 Oct 14. 122(41): e2426241122

Transpupillary in vivo two-photon imaging reveals enhanced surveillance of retinal microglia in diabetic mice.

Noriyuki Sotani, Sentaro Kusuhara, Ryuto Nishisho, Hiroto Kuno, Hidenori Shima, Koichiro Haruwaka, Yuka Mori, Maya Kishi, Tomoyuki Furuyashiki, Kenta Kobayashi, Hiroaki Wake, Toru Takumi, Makoto Nakamura, Yoshihisa Tachibana.

  The retina, located outside the cranium, serves as an ideal structure for investigating information processing within the central nervous system due to its well-organized neurovascular unit comprising diverse cell types, including neurons, glial cells (such as microglia, Müller glia, and astrocytes), pericytes, and vascular endothelial cells. Disrupted retinal homeostasis contributes to various ocular diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa. However, noninvasive in vivo imaging methods to study the pathogenesis of these disorders remain limited. Here, we developed a two-photon microscopy technique for real-time, transpupillary in vivo visualization of the retinal neurovascular unit in mice. Our approach integrates systematic head fixation, a custom-made polymethyl methacrylate contact lens, and a glycerin immersion objective lens with an extended working distance and a higher numerical aperture, specifically designed for two-photon microscopy. This method enabled us to visualize dynamic microglial process activity around retinal blood vessels. Our results revealed that retinal microglia exhibit enhanced surveillance under diabetic conditions, which is undetectable by static confocal microscopy. Furthermore, we demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist commonly used for the treatment of diabetes and obesity, reversed the enhanced microglial behaviors in the diabetic retina. Our simple yet effective approach mitigates the need for advanced optical systems like adaptive optics, providing an effective tool for real-time imaging of the retina. This method offers a valuable resource for visual neuroscience research and holds great potential for clinical applications, particularly in the early diagnosis, intervention, and monitoring of retinal diseases.

Keywords:  diabetes mellitus; liraglutide; microglia; retina; two-photon microscopy

DOI:  https://doi.org/10.1073/pnas.2426241122
J Nanobiotechnology. 2025 Oct 09. 23(1): 633

Tailored brain metastatic tumor cells-derived apoptotic bodies ameliorate Alzheimer's disease by promoting microglia efferocytosis and neuroinflammation mitigation.

Zhenlong Mu, Yang Chen, Yunfeng Hu, Hui Wang, Jin Li.

  Neuroinflammation, characterized by microglial overactivation and oxidative stress, plays a critical role in the initiation and progression of Alzheimer's disease (AD). In this study, we focus on simulating the natural efferocytosis process to reprogram microglial and mitigate chronic neuroinflammation for combinational AD therapy. To achieve this goal, engineered apoptotic bodies derived from brain metastatic tumor cells (LAbs) are successfully developed. Specifically, LAbs-based nanocomposites were fabricated by hybridizing LAbs with liposomes co-loaded with manganese dioxide nanoenzyme (BMn) and autophagy-activating rapamycin (Rapa), referred to as LAbs@Lip@BMn/Rapa. LAbs@Lip@BMn/Rapa exhibits efficient BBB penetration via LAbs-associated brain metastasis propensity of apoptotic bodies. Within the AD microenvironment, oxygen produced through BMn catalyzation in response to H2O2 triggers the structural disintegration of LAbs-camouflaged liposomes and their reassembly into ultra-small vesicles, thereby significantly enhancing intracranial delivery efficiency. In vitro and in vivo experiments confirm that this multi-target strategy effectively normalizes microglia toward anti-inflammatory M2 phenotype, scavenges reactive oxide species (ROS) accumulation, promotes β-amyloid and phosphorylated tau clearance through synergistic intervention, restores the pathological microenvironment in the brain, and enhances cognitive functions in AD model mice. This study demonstrates a novel LAbs-based biomimetic construction strategy that effectively penetrates the BBB and regulates microglia functions, offering a promising approach for AD treatment.

Keywords:  Alzheimer's disease; Apoptotic bodies; Brain-targeting; Efferocytosis; Microglia transformation; Synergistic treatment

DOI:  https://doi.org/10.1186/s12951-025-03750-y
J Neuroinflammation. 2025 Oct 08. 22(1): 227

A neuroimmune cerebral assembloid model to study the pathophysiology of familial Alzheimer's disease.

Andrea Becerra-Calixto, Anik Banerjee, Huihui Fan, Chunfeng Tan, Eunyoung Lee, Louise D McCullough, Juneyoung Lee.

  Alzheimer's disease (AD) is the leading cause of dementia globally. The accumulation of amyloid and tau proteins, neuronal cell death and neuroinflammation are seen with AD progression, resulting in memory and cognitive impairment. Microglia are crucial for AD progression as they engage with neural cells and protein aggregates to regulate amyloid pathology and neuroinflammation. Recent studies indicate that microglia contribute to the propagation of amyloid beta (Aβ) via their immunomodulatory functions including Aβ phagocytosis and inflammatory cytokine production. Three-dimensional cell culture techniques provide the opportunity to study pathophysiological changes in AD in human-derived samples that are difficult to recapitulate in animal models (e.g., transgenic mice). However, these models often lack immune cells such as microglia, which play a critical role in AD pathophysiology. In this study, we developed a neuroimmune assembloid model by integrating cerebral organoids (COs) with induced microglia-like cells (iMGs) derived from human induced pluripotent stem cells from familial AD patient with PSEN2 mutation. After 120 days in culture, we found that iMGs were successfully integrated within the COs. Interestingly, our assembloids displayed histological, functional and transcriptional features of the pro-inflammatory environment seen in AD, including amyloid plaque-like and neurofibrillary tangle-like structures, reduced microglial phagocytic capability, and enhanced neuroinflammatory and apoptotic gene expression. In conclusion, our neuroimmune assembloid model effectively replicates the inflammatory phenotype and amyloid pathology seen in AD.

Keywords:  Alzheimer’s disease; Amyloid beta; Assembloids; Cerebral organoids; Microglia; Neuroinflammation; Stem cells

DOI:  https://doi.org/10.1186/s12974-025-03544-x
J Neuroinflammation. 2025 Oct 08. 22(1): 228

Early antiviral treatment following gammaherpesvirus-68 infection of the central nervous system prevents subsequent multiple sclerosis-like disease.

Alexander Muselman, Sameera Kongara, Nathan Hsu, Asha Aggarwal, Joanna Yu, Jayakumar Rajadas, Edgar G Engleman.

   BACKGROUND: Growing evidence indicates that Epstein-Barr virus (EBV), a gammaherpesvirus, plays a central role in the pathogenesis of multiple sclerosis (MS). The presence of EBV-infected cells in the central nervous system (CNS) of MS patients, but not in neurologically healthy individuals, suggests that viral persistence in the CNS may drive MS. However, why there is such a long interval between initial infection and the development of disease is unknown.
METHODS: To model the effects of EBV infection on the brain, we intracerebrally infected mice with murine gammaherpesvirus-68 (MHV68), a virus genetically related to EBV that causes transient pathology strikingly similar to that seen in humans after acute EBV infection. One month following MHV68 infection, we administered myelin oligodendrocyte glycoprotein (MOG) peptide to evaluate the effects of prior MHV68 infection on the response to an additional inflammatory stimulus of the CNS. Virus persistence, microglial activation and immune cell infiltration were evaluated over time using flow cytometry.
RESULTS: Intracerebral MHV68 infection induced mild brain demyelination and ataxia, a common symptom of MS, that both quickly resolved. However, administration of MOG peptide one month later led to more severe brain demyelination and more sustained ataxia, suggesting that prior MHV68 infection sensitized the mice to a newly introduced immune stimulus. Further investigation revealed that following CNS infection, MHV68 persisted in microglia, where it induced a primed phenotype marked by elevated MHC-II expression and heightened immune reactivity for at least six months. Primed microglia displayed increases in the labile iron pool, and iron chelation reduced microglial priming. Early antiviral treatment during MHV68 infection completely prevented subsequent MOG-induced demyelinating disease.
CONCLUSIONS: These findings support a two-step mechanism by which CNS infection with a gammaherpesvirus closely related to EBV sensitizes the host to a second unrelated immune stimulus that triggers MS-like disease manifestations. Chronic priming of microglia resulting from the initial infection contributes to this process, and prevention of such priming with early antiviral treatment also prevents neuropathology following the second stimulus. EBV infection may similarly sensitize humans to a second stimulus and, if so, treatment of acute EBV infection may avert subsequent MS development.

Keywords:  Epstein-Barr virus; Immune priming; Iron; Metabolism; Microglia; Multiple sclerosis; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-025-03547-8
Cell Death Dis. 2025 Oct 06. 16(1): 702

Lung cancer cells upregulate stearoyl-CoA desaturase 1 in microglia by activating the STAT3 pathway to change microglial inflammatory response in lung-to-brain metastases.

Peng Chen, Yufeng Zuo, Minghuan Wang, Rui Liu, Ying Li, Ziyue Wang, Hao Huang, Xiang Luo, Wei Wang, Yingying Wu, Zhiyuan Yu.

Lung cancer brain metastases have been considered a terminal disease stage with limited treatment options. Many studies have shown that microglia as the resident macrophages in the brain form a major component of the brain immune system, and the lipid metabolism of macrophages in the tumor microenvironment could directly influence tumor progression. However, limited studies have explored the regulatory role of lipid metabolism on microglia in brain metastases. In this study, we found that lung cancer cells could promote microglia to express stearoyl-CoA desaturase 1 (SCD1) and accumulate lipid droplets. Increased activity of SCD1 in microglia reduced its response to inflammatory stimuli and promoted the proliferation of cancer cells. Notably, the treatment of tumor-bearing mice with an SCD1 inhibitor combined with an inhibitor of colony-stimulating factor 1 receptor (CSF1R) significantly reduced brain metastases. Mechanistically, we demonstrated that lung cancer cells activated the STAT3 signaling pathway in microglia leading to increased SCD1 expression. In conclusion, our findings indicate that lung cancer cells activate the microglial STAT3-SCD1-lipid metabolism-inflammatory response pathway in the brain tumor microenvironment and present a potential new strategy for treating brain metastases of lung cancer.

DOI: https://doi.org/10.1038/s41419-025-08003-2
Cell Rep. 2025 Oct 08. pii: S2211-1247(25)01151-9. [Epub ahead of print]44(10): 116380

Time-restricted feeding provides limited microglial immunometabolic improvements in diet-induced obese rats.

Han Jiao, Jarne Jermei, Xian Liang, Hendrik J P van der Zande, Frank Vrieling, Valentina Sophia Rumanova, Milan Dorscheidt, Anhui Wang, Ewout Foppen, Bob Ignacio, Dirk Jan Stenvers, Tiemin Liu, Kimberly Bonger, Rinke Stienstra, Zhi Zhang, Andries Kalsbeek, Chun-Xia Yi.

  Time-restricted eating has shown great promise for improving metabolic health in humans with obesity, but its mechanism is still not completely resolved. In this study, we investigated how time-restricted feeding (TRF) affects microglial immunometabolism using Wistar rats. High-fat diet (HFD)-fed animals became obese, but restricting food intake to the active phase reduced fat mass, reinforced the rhythmicity of the microglial transcriptome, and prevented an increase in hypothalamic microglial cell numbers. However, TRF failed to reverse HFD-induced microglial immune dysfunction and metabolic disturbances, including suppressed electron transport chain activity, increased lipid metabolism gene expression, and impaired metabolic flexibility. These findings suggest that obesity-driven microglial immunometabolic reprogramming persists despite TRF-induced weight loss and may contribute to obesogenic memory and weight regain after weight loss induced by dietary interventions.

Keywords:  CP: Immunology; CP: Metabolism; circadian rhythm; immunometabolism; microglia; obesity; time-restricted feeding

DOI:  https://doi.org/10.1016/j.celrep.2025.116380
Transl Psychiatry. 2025 Oct 06. 15(1): 375

LRRK2 deficiency mitigates amyloid β deposition-mediated pathology in a murine Alzheimer's disease model by reprogramming microglia.

Qiuyang Zhang, Hsuan Lo, Yue Song, Linjuan Feng, Hanlin You, Xiaochun Chen, Yanping Wang, Xiaodong Pan.

Leucine-rich repeat kinase 2 (LRRK2), primarily expressed in microglia, is responsible for the modulation of innate immune responses and associated with various immunological disorders. Available evidence documents that though as the predominant etiological factor for familial Parkinson's disease, LRRK2 mutations rarely occur in Alzheimer's disease (AD) and that LRRK2 polymorphism is potentially associated with late-onset AD. However, the role of LRRK2 in AD immunopathogenesis remains unknown. In this study, we investigated the impact of LRRK2 deficiency on cognitive function, Aβ plaque accumulation, and plaque-associated neuropathology in AD mice. The results revealed that compared with the 5xFAD mice, the 8-month-old 5xFAD;LRRK2-/- mice reported improved learning and memory, reduced cerebral and hippocampal Aβ plaque burden, and decreased microglia and astrocytes within the central region of hippocampal Aβ plaques. The 5xFAD;LRRK2-/- mice also showed a decrease in several complement and proinflammatory cytokines in the brain, indicating an altered microglial phenotype. Furthermore, the absence of LRRK2 prevented synaptic loss and restored the disrupted equilibrium between excitatory and inhibitory synapses in the 5xFAD mice. These findings suggest that LRRK2 may play an essential role in Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brain of the 5xFAD mice and that a genomic transgene-blockade of LRRK2 may reprogram the microglial responsivity, thus mitigating the neuropathological and behavioral deficits in AD mice. The 5xFAD;LRRK2-/- mice reduced cognitive impairment in the Morris water maze test compared with the 5xFAD mice. The protective effect of LRRK2 inhibition is not dependent on the APP production process or Aβ degradation. Conversely, 5xFAD;LRRK2-/- mice enhanced microglial phagocytosis, reducing Aβ aggregation and glial activation. Additionally, compared with the 5xFAD, the 5xFAD;LRRK2-/- mice exhibited preserved synaptic structure, characterized by higher PSD95 expression, lower C1qa/C3 expression in both excitatory and inhibitory synapses, upregulated VGLUT1 expression, and downregulated VGAT expression.

DOI: https://doi.org/10.1038/s41398-025-03598-8
J Neuroimmune Pharmacol. 2025 Oct 11. 20(1): 87

Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in Monocyte-Derived Macrophages and Induced Pluripotent Stem Cell-Derived Microglia.

Alexander Starr, Sara Rathore, Marzieh Daniali, Peter J Gaskill, Cagla Akay-Espinoza, Kelly L Jordan-Sciutto.

  Emerging evidence suggests brain-resident myeloid cells, including perivascular macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS), and their inflammatory activation is a proposed pathogenic mechanism in HIV-associated neurocognitive disorders (HAND). We investigated whether cannabinoid receptor 2 (CB2), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB2-specific agonist JWH-133, we found that CB2 activation reduced HIV replication in primary human monocyte-derived macrophages (MDMs) and human induced pluripotent stem cell-derived microglia (iMg) at differing doses, corresponding to the basal expression of CNR2, which encodes CB2, and related endocannabinoid transcripts in each cell type. JWH-133 broadly reduced release of cytokines from HIV-infected MDMs but not iMg. RNA-seq revealed that CB2 agonism primarily altered interferon and integrated stress response pathways in MDMs while altering homeostatic pathways, including synapse maintenance and phagocytosis, in iMg. Further analyses in iMg revealed that NLRP3 inflammasome activation, but not priming, was reduced by CB2 activation, which did not inhibit HIV-induced nuclear factor kB activation. This study identifies key differences in CB2 response between myeloid lineage cell types and implicates CB2-specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation.

Keywords:  Cannabinoid receptor 2; Human immunodeficiency virus; Inflammation; JWH-133; Microglia; Myeloid lineage

DOI:  https://doi.org/10.1007/s11481-025-10254-x
Exp Neurol. 2025 Oct 04. pii: S0014-4886(25)00353-X. [Epub ahead of print]395 115488

Gut microbiota dysbiosis exacerbates post-stroke depression via microglial NLRP3 inflammasome activation.

Yuxiao Chen, Liqiang Yu, Lulu Zhang, Cuiping Liu, Yi You, Hui Guo, Zhen Li, Xulong Yin, Ting Hong, Lidong Ding, Qi Fang.

   BACKGROUND: Post-stroke depression (PSD) is a neuropsychiatric complication prevalent among stroke survivors. Emerging evidence suggests that dysregulation of the microbiota-gut-brain axis is implicated in the pathogenesis of PSD. However, the exact mechanism is not clear and further research is necessary.
METHODS: Initially, Sprague-Dawley (SD) rats were randomly allocated into three experimental groups: Sham, Middle Cerebral Artery Occlusion (MCAO), and PSD. Behavioral tests were conducted to evaluate depressive-like behavior. Fecal samples from all groups underwent 16S rRNA sequencing for comprehensive gut microbiota analysis. Colonic tissues were collected from rats and subjected to immunohistochemical analysis for quantification of tight junction proteins (ZO-1, Occludin, and Claudin). Peripheral blood plasma was obtained for the determination of IL-1β, IL-6, TNF-α, and IL-18 levels using enzyme-linked immunosorbent assay (ELISA). Lastly, hippocampus tissues were harvested for molecular characterization of Nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation and inflammatory cytokines expression through tripartite methodology: Reverse Transcription quantitative PCR (RT-qPCR), Western blot, and immunofluorescence. Concurrently, hippocampal concentrations of 5-HT, BDNF, and PSD-95 were also measured by ELISA. Subsequently, Fecal Microbiota Transplantation (FMT) was performed by administering fecal suspensions from PSD and Sham donor rats to healthy SD recipients via oral gavage. Then, use the above methods to test the same indicator.
RESULT: Comparative analyses showed that microbial species richness and diversity indices were significantly reduced in PSD model rats, along with a compositional imbalance of the gut microbiota. Concurrently, reduced expression of the colonic tight junction proteins ZO-1, Occludin, and Claudin was observed, accompanied by elevated levels of peripheral inflammatory cytokines. In PSD rats, NLRP3 inflammasome activation was detected in the ischemic hippocampus, along with increased expression of the inflammatory cytokines IL-18 and IL-1β, and decreased levels of 5-HT, BDNF, and PSD-95. Subsequently, using FMT technology, PSD rat feces were innovatively prepared into a fecal suspension and administered to healthy SD rats. Analysis revealed that FMT-PSD rats exhibited a disrupted gut microbiota structure, impaired colonic barrier integrity, activation of the hippocampal NLRP3 inflammasome, elevated inflammatory cytokine levels, and reduced neurotransmitter expression.
CONCLUSION: In summary, these data demonstrate that dysbiosis of the intestinal microbiota compromises gut barrier integrity and elicits systemic inflammation, which may subsequently activate the NLRP3 inflammasome in hippocampal microglia. This activation promotes the release of pro-inflammatory cytokines IL-18 and IL-1β, and coincides with dysregulation of emotion-related neurotransmitters, collectively contributing to the pathogenesis of PSD.

Keywords:  Gut microbiota; Interleukin-18; Microglia; NLRP3 inflammasome; Post-stroke depression

DOI:  https://doi.org/10.1016/j.expneurol.2025.115488
Cell Biol Toxicol. 2025 Oct 07. 41(1): 137

Characterization of SPTLC2 as a key driver promoting microglial activation and energy metabolism reprogramming after ischemic stroke through bulk and single-cell analyses combined with experimental validation.

Yongxing Lai, Peiqiang Lin, Zhiyun Wu, Tin Chen, Wenyao Hong, Mouwei Zheng, Jianhao Chen, Nan Liu, Hongbin Chen.

   BACKGROUND: Ischemic stroke (IS) stands as a principal contributor to high rates of sickness and death. The condition's pathological development is complicated, featuring mechanisms like mitochondrial impairment and the activation of microglial cells. A thorough grasp of these intricate processes is vital for creating successful treatment strategies.
METHODS: We applied Weighted Gene Co-expression Network Analysis (WGCNA) to find gene sets with a strong correlation to IS. Integrated machine learning approachs were used to identify key mitochondrial-related genes (MRGs). From this analysis, SPTLC2 was identified as a pivotal MRG and was subsequently analyzed in detail using single-cell RNA sequencing (scRNA-seq) datasets. We performed functional confirmation using experimental stroke simulations, which included transient middle cerebral artery occlusion (tMCAO) in mice and in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) on primary microglia.
RESULTS: WGCNA revealed two critical modules (yellow and blue) comprising 5348 genes, which were predominantly enriched in immune response, nerve regeneration, and lipid metabolism. We exhibited the robust and superior performance of MRGs in stroke prediction, which contributed to an optimal combination of ridge regression and random forest fitted on 18 MRGs. Subsequently, elevated expression of the SPTLC2 gene was observed in microglia following stroke. Functional studies and experimental validation demonstrated that SPTLC2 promoted microglial pro-inflammatory phenotype, metabolic reprogramming towards glycolysis, and exacerbated cell-cell communication alterations. SPTLC2-specific knockdown in myeloid cells using an adeno-associated virus (AAV) in our tMCAO model alleviated neurobehavioral deficits, reduced infarct volume, and improved mitochondrial function by elevating oxidative stress and mitigating mitochondrial membrane potential depolarization. Additionally, SPTLC2 was regulated by the transcription factor FLI1, and molecular docking identified potential drugs targeting SPTLC2, including Nystatin A3, Moxidectin, and Lumacaftor.
CONCLUSION: Our study highlights SPTLC2 as a critical mediator of microglial activation and metabolic reprogramming in ischemic stroke, providing a foundation for developing novel therapeutic strategies targeting SPTLC2 to improve stroke outcomes.

Keywords:  Machine learning; Microglia; Mitochondria; SPTLC2; Single-cell RNA sequencing; Stroke

DOI:  https://doi.org/10.1007/s10565-025-10085-9
Mol Med Rep. 2025 Dec;pii: 343. [Epub ahead of print]32(6):

Glioma‑associated microglia and macrophages as a potential target for mTOR inhibition in glioblastoma.

Pia S Zeiner, Michael Schulz, Jana Schomber, Jan-Béla Weinem, Nadja I Lorenz, Benedikt Sauer, Bastian Roller, Katharina J Weber, Anna-Luisa Luger, Annemarie Berger, Karl H Plate, Lisa Sevenich, Joachim P Steinbach, Mohammed H Mosa, Patrick N Harter, Michael W Ronellenfitsch.

  Glioma‑associated microglia/macrophages (GAM) constitute the predominant immune cell population in glioblastoma (GB). Both GB cells and GAM exhibit upregulated mTOR signaling. The present study aimed to investigate the effects of pharmacological mTOR inhibition (mTORi) specifically on GAM. The effects of mTORi on signal transduction, cell growth and viability were analyzed in immortalized microglia cell lines. Additionally, a comprehensive analysis of the GAM phenotype was conducted, including whole transcriptome analyses and cytokine profiling. Effects were investigated in a tumor cell/GAM co‑culture model under mTORi with rapamycin or torin2 or treatment with temozolomide, the standard chemotherapy agent for patients with GB. In the in vitro model, mTORi had significant effects on central biological functions of GAM, resulting in reduced proliferation and oxygen consumption. Additionally, treatment with mTORi induced a pro‑inflammatory phenotype in microglia cell lines. These findings demonstrate the relevance of mTOR signaling on GAM biology. Moreover, they provide rationales for therapeutic interventions targeting mTOR signaling specifically in GAM as a potential novel treatment strategy.

Keywords:  glioma; mTOR; microglia; rapamycin; tumor microenvironment

DOI:  https://doi.org/10.3892/mmr.2025.13708