bims-microg 2026-08-30 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–08–30
nineteen papers selected by
Marcus Karlstetter, Universität zu Köln

Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology.
Spatial multi-omics unveils sphingolipid metabolic reprogramming within the retinal pathological niche.
Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity.
Neuron-derived SPP1 instructs microglia to limit degeneration.
Multi-omics identification of haptoglobin as a novel target for increased Alzheimer's disease risk associated with obesity through inhibiting the phagocytosis of Aβ by disease-associated microglia.
Bisphenol mixture impairs offspring social memory via an H4K8 Lactylation-Fyn-Microglial synaptic pruning axis.
CCL5 and CD11b-fibrin interactions regulate microglia migration and morphology in hyperinflammatory experimental cerebral malaria.
CGRP receptor antagonism impairs microglial anti-inflammatory function: IL-4 supplementation as a compensatory strategy for migraine.
Core activation program and selective regional responsiveness of microglia during aging and parabiosis.
Microglial TLR7 contributes to traumatic brain injury-induced neuroinflammation in mice.
Reduced microvascular coverage links a hypoxia-associated niche to microglial autophagic dysfunction in Parkinson's disease.
CCL7-CCR3 signaling mediates olfactory dysfunction in a mouse model of allergic rhinitis.
NF-κB-dependent and independent inflammatory responses during acute HIV-1 infection in a model of human microglia.
Reduction of Lipid Droplets Modulates the Injury Response and Enhances CNTF-Induced Axon Regeneration Following Optic Nerve Crush.
VSIG4 Inhibits Microglia-Mediated Neuroinflammation and Neuronal Injury by Modulating the JAK2-STAT3/NF-κB Signaling Pathway in Parkinson's Disease.
Platelet-Rich Plasma Modulates Neuroinflammation in an iPSC Model of Sensory Neurons and Microglia.
Microglial RIOK3 promotes post-ischemic neuroinflammation by facilitating YBX1 phosphorylation and nuclear accumulation.
Cellular Prion Protein as a Novel Regulator of Vascular Plexus Stability During Retinal Angiogenesis.
Downregulation of miR-33a-5p regulates TNF-α/NF-κB signaling and is associated with reduced diabetic neuropathic pain through targeting SIRT6.

Nature. 2026 Aug 26.

Aberrant excitatory neuronal ERBB4 promotes Alzheimer's disease pathology.

Se Young Lee, Eunseok Park, Ha-Eun Lee, Seongbin Kim, Yeji Yeo, Juwon Park, Young-Jin Choi, Kiheon Lee, Ki-Jun Yoon, Sanghoon Park, Eunjoon Kim, Jae-Ick Kim, Won-Suk Chung.

Neuroinflammation and synapse loss are associated with cognitive decline in Alzheimer's disease (AD). Although microglial hyperphagocytic activity has been implicated in synapse loss1-4, the mechanisms underlying these pathologies remain obscure. Here we demonstrate that, during AD progression in mice, astrocytes and microglia increase phagocytic elimination of excitatory synapses while reducing elimination of inhibitory synapses, suggesting that neuroinflammation alone may be dispensable for early AD synapse loss. Instead, single-nucleus RNA-sequencing analysis identified the emergence of early-responsive excitatory neurons (EREN), characterized by expression of ectopic Erb-B2 receptor tyrosine kinase 4 (Erbb4), as one of the earliest major alterations in AD mouse models. Selective Erbb4 deletion in AD excitatory neurons abrogated abnormal neuronal network activities and synapse loss, as well as reactive gliosis, amyloid plaque deposition and cognitive deficits. Conversely, Erbb4 overexpression in wild-type excitatory neurons recapitulated these core AD-like phenotypes without amyloid plaques. Mechanistically, these effects required mammalian target of rapamycin (mTOR) signalling downstream of ERBB4. Subsequent transcriptomic analyses showed that excitatory neuronal Erbb4 is both necessary and sufficient to induce EREN and reactive gliosis. Directed mediation analysis of human AD transcriptomic data further support a model in which excitatory neuronal ERBB4 contributes to a pathogenic cascade that links amyloid pathology to tau propagation and cognitive decline. These findings identify aberrant Erbb4 expression in excitatory neurons as an early driver of AD pathophysiology and a potential therapeutic target across neurodegenerative diseases.

DOI: https://doi.org/10.1038/s41586-026-10964-z
Imeta. 2026 Aug;5(4): e70163

Spatial multi-omics unveils sphingolipid metabolic reprogramming within the retinal pathological niche.

Yunhong Shi, Jinpei Lin, Yi Wu, Shengsong Xu, Naiyuan Zhang, Yiji Pan, Anli Ren, Ying Fang, Yu Huang, Xiayin Zhang, Zhuoting Zhu, Yehong Zhuo, Honghua Yu.

  Retinal ischemia-reperfusion (RIR) injury is a central mechanism underlying irreversible vision loss in glaucoma and other retinal diseases, yet the spatial organization of the pathogenic microenvironment remains poorly understood. Here, we constructed a high-resolution, whole-eye spatial multi-omics atlas integrating Stereo-seq transcriptomics and MALDI-MSI-based metabolomics to capture the early molecular events in the RIR mouse model. Spatially, retinal ganglion cell (RGC) interactions with surrounding cells were markedly reduced after injury, whereas immune-glial interactions were enhanced, revealing a shift from a neuron-centered to an immunometabolic state. Within the ganglion cell layer (GCL), the primary pathological locus, we identified Trem2 + microglia that expand in situ, establish close proximity to degenerating RGCs, and exhibit strong spatial association with dysregulated sphingolipid metabolism. Mechanistically, using Trem2 knockout mice and microglia-specific Trem2 siRNA knockdown, we demonstrate that TREM2 directly binds to SPTLC2, the rate-limiting enzyme of de novo sphingolipid biosynthesis, driving ceramide-centric metabolic reprogramming that modulates the AKT-mTOR signaling axis and amplifies inflammatory activation. Pharmacological inhibition of serine palmitoyl transferase (SPT) with myriocin reverses this cascade, protecting RGCs. Multi-omics integration of human glaucoma aqueous humor datasets further reveals conserved upregulation of sphingolipid biosynthetic enzymes, sphingolipid metabolites, and lipid-sensing immune effectors, offering preliminary translational clues. Collectively, our findings reveal that spatially defined immunometabolic remodeling-in which Trem2 + microglia are central-converges on sphingolipid metabolism as a druggable regulatory axis, with the TREM2-SPTLC2 interface thus emerging as a new therapeutic opportunity for retinal neurodegenerative diseases.

Keywords:  Trem2+ microglia; immunometabolic remodeling; retinal ischemia‐reperfusion; spatial metabolomics; spatial transcriptomics

DOI:  https://doi.org/10.1002/imt2.70163
Adv Sci (Weinh). 2026 Aug 29. e00020

Early Retinal UCHL1 Dysregulation Coupled With Synaptic Loss Reflects Alzheimer's Disease Severity.

Altan Rentsendorj, Jean-Philippe Vit, Alexandre Hutton, Yosef Koronyo, Saba Shahin, Edward Robinson, Ernesto Barron, Anthony Rodriguez, Ousman Jallow, Julia Sheyn, Bhakta Prasad Gaire, Lalita Subedi, Miyah R Davis, Barathan Gnanabharathi, Alexander V Ljubimov, Stuart L Graham, Vivek K Gupta, Mehdi Mirzaei, Debra Hawes, Katlin Silm, Keith L Black, Lon S Schneider, Alfredo A Sadun, Jesse G Meyer, Dieu-Trang Fuchs, Maya Koronyo-Hamaoui.

  Synaptic dysfunction is a major driver of cognitive decline in Alzheimer's disease (AD), yet its extent and molecular basis in the retina remain poorly defined. We integrated postmortem retinal and matched brain histopathology with ultrastructural, proteomic, biochemical, and machine-learning analyses across cognitively normal, mild cognitive impairment, and AD cohorts. Retinal glutamatergic synapses exhibited early, progressive degeneration, marked by loss of presynaptic vesicular glutamate transporter 1 (VGLUT1) and synaptophysin and postsynaptic density protein 95 (PSD95) and N-methyl-D-aspartate receptor subunit 2A (NMDAR2A), along with ribbon synapse ultrastructural disruption. Synaptic deficits correlated with amyloid-β42 (Aβ42), pathogenic tau, oxidative stress, the Aβ-binding p75 neurotrophin receptor, and glial activation that paralleled disease progression. Proteomics revealed widespread synaptic remodeling accompanied by disease-associated microglia, astrocyte-mediated excitotoxicity, and pyroptotic pathways. The synapse-enriched deubiquitinase ubiquitin C-terminal hydrolase L1 (UCHL1) was dysregulated early, particularly in horizontal and bipolar interneurons, and strongly associated with synaptic loss and neuroinflammation. Mechanistically, fibrillar Aβ42 induced rapid UCHL1 and synaptic depletion in human and murine neurons before overt neurodegeneration. Machine-learning models identified retinal UCHL1 as the strongest predictor of Braak stage and cognitive impairment. These findings establish the retina as an early site of AD synaptopathy and position UCHL1 as a candidate biomarker and mechanistic mediator linking amyloid pathology, neuroinflammation, and synaptic vulnerability.

Keywords:  MCI; N‐methyl‐D‐aspartate receptor subunit 2A; dementia; excitatory synapse; p75NTR; postsynaptic density protein 95; ubiquitin–proteasome system; vesicular glutamate transporter 1

DOI:  https://doi.org/10.1002/advs.202600020
Sci Adv. 2026 Aug 28. 12(35): eaee4940

Neuron-derived SPP1 instructs microglia to limit degeneration.

Song Li, Tatjana C Jakobs.

Neurons actively shape immune responses that maintain central nervous system integrity. We identify SPP1 (secreted phosphoprotein 1) as a neuron-derived signal that reprograms microglia into a neuroprotective, homeostatic state after injury and during neurodegeneration. In mouse models of glaucoma and optic nerve damage, neuronal SPP1 enhances microglial autophagy, debris clearance, and anti-inflammatory activity, preserving neuronal survival and visual function. SPP1 is elevated in neurons of human and primate glaucomatous retinas, where SPP1+ cells show increased resilience. In Alzheimer's disease brain, neuronal SPP1 correlates with neuronal survival, while microglia around Aβ plaques display defective autophagy. In human iPSC co-cultures, SPP1 enhances microglial Aβ clearance and prevents neurodegeneration. Thus, SPP1 defines a protective neuron-microglia axis in glaucoma and possibly other neurodegenerative diseases.

DOI: https://doi.org/10.1126/sciadv.aee4940
Alzheimers Dement. 2026 Aug;22(8): e71759

Multi-omics identification of haptoglobin as a novel target for increased Alzheimer's disease risk associated with obesity through inhibiting the phagocytosis of Aβ by disease-associated microglia.

Xiaohang Qian, Zhongxuan Wang, Peijing Cui, Siyue Chen, Yang Xue, Yawen Yang, Jianhua Xu, Xiaoli Liu, Gangyu Ding, Huidong Tang.

   INTRODUCTION: Obesity may increase Alzheimer's disease (AD) risk, yet the underlying mechanisms remain unclear.
METHODS: We investigated this link through global epidemiology, Mendelian randomization (MR), transcriptomics, clinical cohort validation, and mechanistic exploration.
RESULTS: High body mass index (BMI)-attributable AD disability-adjusted life years and deaths increased 4-fold from 1990-2021, with projections indicating a tripling by 2050. MR analyses found that elevated BMI was genetically related to increased AD risk. Haptoglobin (HP) was identified as a core mediator between them. HP expression was correlated with plasma AD biomarkers and cognitive scores. Mechanistically, HP localized to plaque-associated microglia and suppressed microglial amyloid beta (Aβ) phagocytosis and DNAX activating protein of 12 kDa (Dap12)/Spleen tyrosine kinase (Syk) pathway with modulating disease-associated microglial transcriptional programs.
CONCLUSION: This study identified HP as a strong candidate mediator linking obesity to AD pathogenesis through inhibiting the phagocytosis of Aβ by microglia.

Keywords:  Alzheimer's disease; Aβ pathology; haptoglobin; microglia; obesity

DOI:  https://doi.org/10.1002/alz.71759
Environ Int. 2026 Aug 25. pii: S0160-4120(26)00440-X. [Epub ahead of print]215 110482

Bisphenol mixture impairs offspring social memory via an H4K8 Lactylation-Fyn-Microglial synaptic pruning axis.

Ke Zhang, Yaopeng Zheng, Xinyuan Liu, Jiangyan Pan, Han Qi, Anqian Wang, Xinzhu Li, Feng Wu, Xiaojun Shen, Haixin Liu, Yangna Wu, Yi Lin, Xiaoyan Zhang, Mingkuan Sun.

  Bisphenol A (BPA) and its structural analogs, i.e., bisphenol S (BPS) and bisphenol F (BPF), are commonly incorporated into consumer products, resulting in simultaneous human exposure to multiple bisphenols. Prospective cohort studies have linked prenatal exposure to individual bisphenols to disrupted neurodevelopment and cognitive dysfunction; however, the mechanisms by which bisphenol mixtures affect neural health remain underexplored. Here, we show that maternal exposure to an environmentally relevant bisphenol mixture during pregnancy and lactation elicits aberrant microglial activation in male offspring, mediated by estrogen receptor β-dependent metabolic reprogramming. This exposure enhances microglial glycolytic activity and histone H4K8 lactylation, thereby directly boosting Fyn transcription. Elevated Fyn expression accelerates microglia-mediated synaptic pruning, leading to decreased hippocampal synaptic density and subsequent deficits in social memory. Notably, genetic and pharmacological suppression of microglial activity, including microglial ablation and selective Fyn inhibition during the exposure period, substantially alleviates these synaptic deficits and behavioral impairments. Similar microglia-dependent synaptic abnormalities are further validated in cell-based and human brain organoid co-culture models. Together, these results reveal a previously unrecognized metabolic-epigenetic pathway by which chemical mixtures disrupt neurodevelopment, emphasizing the critical importance of examining the neurodevelopmental consequences of exposure to real-world chemical mixture during early development.

Keywords:  Bisphenol mixture; Fyn; Histone lactylation; Memory; Microglia; Synapse density

DOI:  https://doi.org/10.1016/j.envint.2026.110482
J Neuroinflammation. 2026 Jul 24. pii: 288. [Epub ahead of print]23(1):

CCL5 and CD11b-fibrin interactions regulate microglia migration and morphology in hyperinflammatory experimental cerebral malaria.

Nadia D Domingo, Olivia D Solomon, Paula Villarreal, Florentin Aussenac, Difernando Vanegas, Mark Joseph Endrino, Andrew S Mendiola, Lucinda Puebla-Clark, Komi Gbedande, Astrid E Cardona, Katerina Akassoglou, Matthew J Flick, Gracie Vargas, Robin Stephens.

   BACKGROUND: Microgliosis and severe coagulation, including fibrinogen deposition, are features of both experimental and human cerebral malaria (CM), a lethal disease. Vascular-associated microglia migrate to coagulated cerebral vessels containing inflammatory monocytes and T cells in experimental CM. We previously showed that microglial depletion exacerbates coagulation and disease severity, including hypothermia, while anticoagulant treatment reduces microgliosis and prevents mortality. These data suggest an overall protective effect of microglia on eCM, and indicate a link between microgliosis, hypothermia, and coagulation. Therefore, mechanisms of migration and activation of microglia, T cells, and monocytes were studied in relation to the role of fibrin(ogen) in eCM.
METHODS: Using both Plasmodium berghei ANKA infection or experimental CM, and P. chabaudi infection of IL-10-deficient mice (IL-10 KO), which causes a hyperinflammatory response including neuropathology, intravital two-photon microscopy and flow cytometry, were used to test patterns and mechanisms of migration. In vivo methods included intranasal administration of CCL5 receptor antagonist Met-CCL5; systemic integrin-blocking antibodies and mutant animals (IL-10 KO, ICAM1 KO), and anticoagulant treatment. Clotting-deficient mice (Fga KO, FibAEK) were tested for the absence of fibrinogen in clotting, while fibrinogen γ-chain mutation (Fibγ390-396 A) mice and intranasal administration of a fibrinogen γ-derived inhibitory peptide (Fibrin γ377-395), which disrupts CD11b-fibrin interactions, assessed the role of CD11b-fibrin interactions in microglial activation in eCM.
RESULTS: Intraluminal adhesion and crawling of CCR2RFP+ cells, including T cells and inflammatory monocytes, was observed in cerebral vessels; however, there was no evidence that brain adherence of T cells or monocytes depends on classical adhesion molecules or coagulation. Intranasal administration of met-CCL5 reduced both microglial recruitment to vessels and CD8 T cell adherence and fibrin(ogen) deposition. Despite the previously published protective effects of the anticoagulant drug in IL-10 KO, clotting-deficient mice showed no change in P. berghei ANKA mortality. However, disruption of fibrin-CD11b interactions by both genetic and peptide inhibition led to exacerbated hypothermia in both experimental CM models. Reduced microglial hypertrophy also occurred in Fibrin γ377-395 peptide-treated IL-10 KO mice infected with P. chabaudi.
CONCLUSIONS: These data support our previous study suggesting that microglia are involved in the regulation of hypothermia in eCM and reveal CCL5 and fibrin-CD11b signaling in microglia as key molecular pathways modulating neuroinflammation in malaria.

Keywords:  Cerebral malaria; Chemokines; Fibrinogen; Mice; Microglia; Neuroinflammation

DOI:  https://doi.org/10.1186/s12974-026-03969-y
Brain Behav Immun. 2026 Aug 25. pii: S0889-1591(26)00721-X. [Epub ahead of print] 106973

CGRP receptor antagonism impairs microglial anti-inflammatory function: IL-4 supplementation as a compensatory strategy for migraine.

Zichao Li, Dan-Li, Zhen-Zhen Fan, Hong-Bin Cai, Zhao-Ming Ge.

  Calcitonin gene-related peptide (CGRP) is a key therapeutic target for migraine, yet its dual role in central neuroimmune regulation remains incompletely understood. This study reveals a critical paradox: while CGRP directly promotes anti-inflammatory activation of microglia in vitro, treatment with the CGRP receptor antagonist BIBN4096BS in a chronic migraine mouse model rapidly alleviated pain but was not accompanied by an increase in microglial anti-inflammatory markers, including CD206 and p-STAT6. This finding suggests that complete CGRP blockade may inadvertently attenuate a masked endogenous pro-repair tone. To supplement this signaling, we introduced IL-4 intervention. IL-4 not only restored microglial anti-inflammatory function via STAT6 pathway activation but also produced synergistic analgesic effects when combined with the CGRP antagonist, superior to either monotherapy. STAT6 overexpression further enhanced the anti-inflammatory effect of the CGRP and IL-4 combination, while STAT6 knockdown completely reversed this protective effect. These findings demonstrate that CGRP antagonism, while providing rapid analgesia, may come at the cost of suppressing neuroimmune repair. Combining CGRP antagonism with STAT6 pathway activation may offer a strategy to simultaneously block vasogenic pain and support immune homeostasis, providing a new conceptual framework for migraine therapy.

Keywords:  CGRP; Chronic migraine; Microglial phenotype; Neuroinflammation; STAT6

DOI:  https://doi.org/10.1016/j.bbi.2026.106973
Cell Rep. 2026 Aug 28. pii: S2211-1247(26)00997-6. [Epub ahead of print]45(9): 117919

Core activation program and selective regional responsiveness of microglia during aging and parabiosis.

Huma Naz, Nannan Lu, Caroline C Escoubas, Leah Sager, Jinglin Xiong, Robert Pálovics, Shinnosuke Yamada, Anna V Molofsky, Tony Wyss-Coray, Qingyun Li, Guoyan Zhao.

  Aging is associated with immune dysregulation in the brain and is the greatest risk factor for many neurodegenerative diseases. Rejuvenation interventions can mediate beneficial effects. Microglia are major contributors to neurodegenerative disease progression; however, the molecular changes underlying brain aging and rejuvenation remain poorly understood at the single-cell level. We identified and benchmarked several reproducible microglial states and a core set of genes that drive microglial activation in the mouse brain. We investigated microglial heterogeneity and examined the impact of aging and parabiosis-mediated exposure to young and old blood on microglial subpopulations across four brain regions: the cerebellum, cortex, hippocampus, and striatum. We revealed region-specific differences in microglial composition and age-related changes. The cerebellum consistently emerged as the most responsive region, whereas the striatum showed minimal responsiveness to parabiosis interventions. These findings highlight regional vulnerability and inform microglia-targeted strategies to modulate brain aging.

Keywords:  CP: neuroscience; aging; core activation signatures; microglia; regional vulnerability; rejuvenation; single-cell transcriptomics

DOI:  https://doi.org/10.1016/j.celrep.2026.117919
Acta Pharmacol Sin. 2026 Aug 24.

Microglial TLR7 contributes to traumatic brain injury-induced neuroinflammation in mice.

Yi-Teng Du, Xiao-Li Ma, Shu-Hui Gao, Yan-Xia Wang, Yan Liu, Xue-Mei Feng, Chen Fan, Hong-Zhuan Chen, Ming-Ke Song.

  Neuroinflammation driven by activated microglia is an important component of secondary injury after traumatic brain injury (TBI), but the underlying molecular mechanisms remain incompletely understood. Here, we investigated the role of microglial Toll-like receptor 7 (TLR7) in TBI-induced neuroinflammation and evaluated the therapeutic effect of the TLR7-targeting compound Enpatoran (M5049). Analysis of public single-cell transcriptomic datasets showed that TLR7 is preferentially expressed in microglia among resident brain cells. In the controlled cortical impact (CCI) mouse TBI model, TBI increased TLR7 expression in microglia and elevated the abundance of cleaved-TLR7 in the peri-contusional cortex. Knockdown of the asparaginyl endopeptidase (AEP) attenuated TLR7 cleavage and downstream signaling in cultured microglia. Deletion of AEP decreased cleaved-TLR7 and inflammatory marker expression in TBI mice, indicating an AEP-mediated proteolytic processing of TLR7 and suggesting TLR7's involvement in TBI inflammation. Global TLR7 deletion in mice failed to reduce TBI-induced inflammation and was accompanied by marked TLR8 upregulation. In contrast, inducible microglia-specific TLR7 deletion in mice attenuated CD86, TNF-α, and IL-1β expression without a pronounced TLR8 upregulation. The TLR7 inhibitor M5049 suppressed TLR7 agonist-induced inflammation in cultured microglia without inhibiting mouse TLR8. In TBI mice, treatment with M5049 at 0.1, 0.3, and 3 mg/kg all significantly reduced TBI-induced IL-1β and IL-6 mRNA expression. Pharmacological tests further showed that M5049 is effective in suppressing TBI-induced microglial activation and inflammatory cytokine secretion in wild-type mice but lost this efficacy in TLR7 knockout mice. Therefore, M5049's anti-inflammatory action relies on the presence of TLR7. Additionally, M5049 was not able to rescue glutamate- and H2O2-induced cell death in HT22 mouse hippocampus neuronal cells, or broadly suppress the examined peripheral immune transcriptional program. These findings identify microglial TLR7 as an important player in TBI-induced neuroinflammation and support a predominantly TLR7-dependent anti-inflammatory effect of M5049.

Keywords:  M5049; TLR7; asparaginyl endopeptidase; inflammation; microglia; traumatic brain injury

DOI:  https://doi.org/10.1038/s41401-026-01915-5
Acta Neuropathol Commun. 2026 Aug 19. pii: 178. [Epub ahead of print]14(1):

Reduced microvascular coverage links a hypoxia-associated niche to microglial autophagic dysfunction in Parkinson's disease.

Hualin Wang, Zhuang Zhu, Zefu Yin, Yao Geng, Yihang Xu, Yi Fan, Kezhong Zhang.

  Microglial hyperactivation contributes to Parkinson's disease (PD) progression, yet the upstream microenvironmental cues that sustain this state remain incompletely understood. While α-synuclein (α-Syn) aggregation is a primary trigger, aging and PD are also associated with microvascular and perfusion abnormalities. However, how vascular-associated hypoxic stress interacts with protein toxicity in microglial fate determination remains unclear. We integrated human single-nucleus RNA sequencing (snRNA-seq) data, a chronic progressive transgenic mouse model (9-month-old A53T), and an in vitro "double-hit" model. Neuropathological and immunofluorescence analyses were employed to assess the neurovascular unit and microglial phenotypes. The snRNA-seq analysis of human PD brains revealed a Disease-Associated Microglia (DAM) subset characterized by enrichment of hypoxia and glycolysis pathways, with HIF1A acting as a central node. In vivo, 9-month-old A53T mice exhibited motor deficits and dopaminergic degeneration, accompanied by reduced CD31+ microvascular coverage in the substantia nigra. This reduction in CD31+ vascular coverage was associated with microglial HIF1A accumulation and increased IBA1-defined soma area. In vitro, physical hypoxia amplified α-Syn preformed fibril (PFF)-induced microglial reactivity, intracellular accumulation of phosphorylated α-Syn (p-αSyn). Our study supports a "double-hit" model in which hypoxia-associated stress may amplify α-Syn-induced microglial dysfunction through HIF1A-linked metabolic remodeling and impaired autophagy-related protein handling. Targeting neurovascular-immune interactions may offer therapeutic opportunities for advanced PD.

Keywords:  Autophagic dysfunction; Disease-associated microglia; Hypoxia; Neurovascular unit; Parkinson's disease; single-nucleus RNA sequencing

DOI:  https://doi.org/10.1186/s40478-026-02412-w
Front Immunol. 2026 ;17 1893377

CCL7-CCR3 signaling mediates olfactory dysfunction in a mouse model of allergic rhinitis.

Ting Yang, Hui Shen, Tingting Zhao, Yakui Mou, Yue Hu, Xiaoyu Song, Yao Wang, Yujiao Chen, Hanrui Wang, Chao Ren, Xicheng Song.

   Background: Allergic rhinitis (AR) is a prevalent chronic upper airway inflammatory disorder. Olfactory dysfunction (OD) in AR patients represents a frequent and burdensome complication that significantly compromises quality of life. While the pathogenesis of AR-associated OD remains incompletely characterized, emerging evidence points to olfactory bulb (OB) microglial neuroinflammation as a crucial contributor. C-C motif chemokine ligand 7 (CCL7) is consistently upregulated in AR nasal mucosa and has been documented to drive microglial inflammation. However, its expression and function in OB microglia remain undefined. This study aimed to investigate the specific role of CCL7 in OB microglia and its potential contribution to AR-associated OD, with the goal of providing new mechanistic insights and potential intervention targets.
Methods: An ovalbumin (OVA)-induced murine AR-associated OD model was established and validated through behavioral, serological, and histopathological analyses. CCL7 and C-C chemokine receptor type 3 (CCR3) expression profiles in OB and nasal mucosa were evaluated by qPCR, ELISA, and immunofluorescence colocalization with microglial markers. The therapeutic efficacy of intranasal CCL7 inhibition was assessed using Bindarit over a sustained intervention period. The specificity of the CCL7-CCR3 axis was further validated by intranasal exogenous CCL7 administration in naive mice and stereotaxic injection of the CCR3-specific antagonist SB-328437 into the OB of AR mice with established OD. In vitro studies employed co-culture with allergen-stimulated nasal epithelial and microglial cells, with or without CCR3 antagonist-pretreatment.
Results: CCL7 expression was significantly elevated in OB of AR-associated OD mice, correlating positively with behavioral indices of OD. CCR3 was the only significantly upregulated CCL7 receptor in OB in this model, selectively localized to activated microglia. Intranasal Bindarit progressively improved olfactory function in AR mice, with marked improvement first observed at week 8 of treatment, with concomitant reduced CCL7 and neuroinflammatory mediators in OB. In contrast, intranasal exogenous CCL7 administration in naive mice recapitulated OD and upregulated these neuroinflammatory markers. Conversely, CCR3-specific antagonism with SB-328437 in the OB partially restored olfactory function in AR mice with established OD. In vitro, allergen-stimulated nasal epithelial cells secreted CCL7 that activated microglial cells through CCR3, an effect partially reversed by CCR3 antagonist.
Conclusion: The CCL7-CCR3 signaling axis links nasal allergic inflammation to OB microglial neuroinflammation and consequent OD in AR, identifying a promising therapeutic target for AR-associated OD.

Keywords:  C-C motif chemokine ligand 7 (CCL7); allergic rhinitis; microglia; olfactory bulb; olfactory dysfunction

DOI:  https://doi.org/10.3389/fimmu.2026.1893377
Front Immunol. 2026 ;17 1912292

NF-κB-dependent and independent inflammatory responses during acute HIV-1 infection in a model of human microglia.

Aracelly Gaete-Argel, Catarina Ananías-Sáez, Cecilia Rojas-Fuentes, Sebastian Giraldo-Ocampo, Daniela Jara, Tomás Hernández-Díaz, Camila Ortega-Orellana, Delia López-Palma, Hisashi Akiyama, Suryaram Gummuluru, Pablo A González, Fernando Valiente-Echeverría, Ricardo Soto-Rifo.

   Introduction: Microglia are the main targets of HIV-1 infection in the central nervous system (CNS) and are considered important contributors to chronic neuroinflammation in people living with HIV (PLWH). In this study, we investigated the mechanisms leading to inflammatory responses during acute HIV-1 infection in an adult human microglia model.
Methods: We used an adult human microglia model to characterize inflammatory responses induced by acute HIV-1 infection and analyzed publicly available datasets to assess the relationship between viral loads and cytokine levels in the cerebrospinal fluid of PLWH.
Results: HIV-1 infection induced a subset of pro-inflammatory mediators, including the neurotoxic cytokines IL-6, IL-8, and IL-11, through distinct mechanisms. IL-6 and IL-8 induction depended on activation of the NF-κB signaling pathway mediated by the viral accessory protein Nef, whereas IL-11 expression relied on cellular sensing of Rev-dependent transcripts and subsequent activation of MAVS signaling. Analysis of public datasets revealed a significant correlation between viral loads and IL-6/IL-8 levels in the cerebrospinal fluid of PLWH, suggesting that active HIV-1 replication in microglia contributes to increased CNS pro-inflammatory cytokine levels even under suppressed systemic viral loads.
Discussion/Conclusion: These findings highlight the complexity of inflammatory responses during active HIV-1 replication and provide a mechanistic framework for understanding the contribution of microglia to neuroinflammation in the CNS of PLWH.

Keywords:  HIV-1; MAVS; NF-κB; Nef; microglia; neuroinflammation

DOI:  https://doi.org/10.3389/fimmu.2026.1912292
Mol Neurobiol. 2026 Aug 22. pii: 851. [Epub ahead of print]63(1):

Reduction of Lipid Droplets Modulates the Injury Response and Enhances CNTF-Induced Axon Regeneration Following Optic Nerve Crush.

Xiaowei Fan, Ruyue Li, Shen Wu, Xuejing Yan, Yue Wan, Jingxue Zhang, Ningli Wang.

  Disruption of lipid metabolism occurs in both the retina and optic nerve following optic nerve crush (ONC); however, whether the regulation of lipid droplets (LDs) influences the survival and function of retinal ganglion cells (RGCs) remains largely elusive. Here, we identified the distribution of LDs in the retina and optic nerve of ONC mice, and A922500, a selective inhibitor of diacylglycerol acyltransferase 1 (DGAT1), was applied to investigate the effect of suppressing LD biogenesis on RGC survival and visual function. The results showed that LDs were localized in Tuj1-positive cells within the retina and in IBA1-positive cells within GFAP-negative region of optic nerve following injury. A922500 significantly reduced LD accumulation and attenuated microglial density in both retina and optic nerve, but did not affect RGC survival following injury. No regenerating CTB-labeled axons were observed with A922500 monotherapy. However, combined treatment with A922500 and AAV2-CNTF enhanced axon regeneration compared to CNTF-treated alone. A922500 also significantly improved flash visual evoked potential recordings in both ONC control mice and CNTF-treated mice after injury. This study demonstrates that optic nerve crush induces LD accumulation in retinal RGC somas and in microglia at the optic nerve injury site, and reducing LDs does not preserve RGC survival but attenuates injury response, enhances CNTF-induced axon regeneration, and improves visual function.

Keywords:  Axon regeneration; Lipid droplets; Microglia; Optic nerve crush; Retinal ganglion cell

DOI:  https://doi.org/10.1007/s12035-026-06159-2
Mol Neurobiol. 2026 Aug 27. pii: 860. [Epub ahead of print]63(1):

VSIG4 Inhibits Microglia-Mediated Neuroinflammation and Neuronal Injury by Modulating the JAK2-STAT3/NF-κB Signaling Pathway in Parkinson's Disease.

Jingcong Zhuang, Pingping Cai, Zhongjie Chen, Quanlong Hong, Rong Wang, Feng Wang, Yaxin Zhang, Danjie Wu, Fengzhu Chen.

  V-set and immunoglobulin domain-containing 4 (VSIG4) was found to regulate microglial inflammation and oxidative stress in our previous study. This study aimed to further explore the effect and mechanism of VSIG4 on neuroinflammation and neuronal injury in Parkinson's disease (PD). Mouse microglia were infected with VSIG4-overexpressing adeno-associated virus (AAV) or shRNA AAV or VSIG4-overexpressing AAV with or without AZD1480 (a JAK inhibitor). Furthermore, a coculture system was established, where mouse dopamine neurons were cocultured with the infected microglia or their culture medium under the presence of α-synuclein. PD mice were treated with VSIG4-overexpressing AAV, with or without AZD1480. In microglia, VSIG4 overexpression inhibited the release of tumor necrosis factor-α, interleukin-6, and interleukin-1β and modulated the JAK2-STAT3/NF-κB pathway, but its knockdown had the opposite effect. In the coculture system, VSIG4-overexpressing microglia promoted dopamine neuron viability but suppressed p-α-synuclein and neuron apoptosis, whereas VSIG4-knockdown microglia presented the opposite effect. The culture medium of VSIG4-modified microglia had a similar effect on dopamine neuron functions to that of VSIG4-modified microglia. In PD mice, VSIG4 was insufficiently expressed in microglia, while VSIG4 overexpression improved the performances in open field and pole tests, promoted dopamine neuron viability and dopamine transport, and suppressed p-α-synuclein and neuroinflammation. Moreover, the addition of AZD1480 attenuated the effects of VSIG4 overexpression both in vitro and in vivo. VSIG4 ameliorates microglia-mediated neuroinflammation and neuronal injury via the JAK2-STAT3/NF-κB pathway in PD, shedding light on its supplementation as a potential treatment option for PD.

Keywords:  Dopamine neurons; JAK2-STAT3/NF-κB pathway; Microglia; Parkinson’s disease; V-set and immunoglobulin domain-containing 4

DOI:  https://doi.org/10.1007/s12035-026-06135-w
Int J Mol Sci. 2026 Aug 08. pii: 7127. [Epub ahead of print]27(16):

Platelet-Rich Plasma Modulates Neuroinflammation in an iPSC Model of Sensory Neurons and Microglia.

Jon Mercader-Ruiz, Daniel Marijuan-Pinel, Diego Delgado, Deiene Lasuen Aguirre, Xabier Sansinanea, Jorge Guadilla, Mikel Sánchez.

  Neuropathic pain (NP) is driven by neuroimmune interactions where in activated microglia release pro-inflammatory mediators that sustain central sensitization. Platelet-rich plasma (PRP) is a promising therapy, but its efficacy depends on its biochemical composition. This study aimed to evaluate how modifying the molecular profile of PRP influences its capacity to modulate neuroinflammation in a human-derived co-culture model. We compared standard PRP (sPRP) and balanced protein-concentrate plasma (BPCP), enriched in extraplatelet molecules, using an iPSC direct co-culture of sensory neurons (hSNs) and microglia (hMG). Neuroinflammation was induced for 24 h with serum-free (SF) or 10% sPRP or BPCP supplementation. Neuroinflammation, microglial activation, apoptosis, and neuronal plasticity were analyzed via RT-qPCR and Luminex. Both formulations attenuated pro-inflammatory mediators. However, BPCP demonstrated superior suppressive efficacy, reducing the levels of major cytokines (IL-1β, TNF-α, IL-6, IL-8) by half as compared to sPRP. BPCP significantly decreased IL-6, IL-8, and MCP-1 protein levels; kept microglial activation markers (CD86, CTSS) downregulated; and downregulated the apoptotic cascade (BAX, CASP9, CASP3). Conversely, sPRP displayed a distinct pro-resolving and neuroprotective trend, upregulating IL-10 and TGF-β1 and rescuing the expression of SLC12A5 (KCC2), which regulates neuronal excitability. sPRP and BPCP modulated neuroinflammation via complementary mechanisms. BPCP acted as an immunomodulatory shield suppressing macro-inflammation, while sPRP drove inflammation resolution and neuroplastic rescue.

Keywords:  iPSC model; microglia; neuroinflammation; neuropathic pain; platelet-rich plasma; sensory neurons

DOI:  https://doi.org/10.3390/ijms27167127
Exp Neurol. 2026 Aug 28. pii: S0014-4886(26)00363-8. [Epub ahead of print] 115997

Microglial RIOK3 promotes post-ischemic neuroinflammation by facilitating YBX1 phosphorylation and nuclear accumulation.

Yang Geng, Ningning Zong, Chao Zhou, Jian Chen, Huaiping Tang, Liang Sun, Shengnan Xia, Xinyu Bao, Yun Xu.

  Excessive activation of microglia exacerbates secondary brain injury after ischemic stroke, yet the upstream mechanisms governing this response remain incompletely understood. This study aimed to investigate the role of RIO kinase 3 (RIOK3) in microglia-mediated neuroinflammation after ischemic stroke and to explore the underlying molecular mechanisms. RIOK3 expression was examined in mice subjected to transient middle cerebral artery occlusion and in primary microglia exposed to lipopolysaccharide or oxygen-glucose deprivation/reoxygenation. Microglia-targeted RIOK3 knockdown was achieved using a Cre-dependent adeno-associated virus-shRNA strategy in Tmem119-CreERT2 mice. RIOK3 was markedly upregulated in microglia after cerebral ischemia and in primary microglia following LPS or OGD/R stimulation. Microglia-targeted RIOK3 knockdown reduced infarct volume, improved early neurological and sensorimotor outcomes, preserved microglial process complexity, and reduced post-ischemic inflammation. In vitro, RIOK3 knockdown reduced microglial inflammatory responses and microglia-mediated neurotoxicity. Transcriptomic and biochemical analyses further showed that RIOK3 knockdown suppressed NF-κB-related transcriptional programs and decreased the phosphorylation of IκBα and p65. Mechanistically, immunoprecipitation assays identified Y-box-binding protein 1 (YBX1) as a RIOK3-interacting protein and mapped this interaction to the C-terminal kinase domain-containing region of RIOK3. RIOK3 enhanced YBX1 Ser102 phosphorylation and nuclear accumulation, whereas YBX1 knockdown attenuated NF-κB activation and the pro-inflammatory effects of RIOK3 overexpression. These findings identify microglial RIOK3 as an important driver of post-ischemic neuroinflammation and highlight the RIOK3-YBX1 axis as a potential therapeutic target for ischemic stroke.

Keywords:  Ischemic stroke; Microglia; NF-κB; Neuroinflammation; RIOK3; YBX1

DOI:  https://doi.org/10.1016/j.expneurol.2026.115997
Neurochem Res. 2026 Aug 26. pii: 248. [Epub ahead of print]51(5):

Cellular Prion Protein as a Novel Regulator of Vascular Plexus Stability During Retinal Angiogenesis.

Bárbara Gomes da Rosa, Felipe Leser, Marco Aurélio Alves, Eliel de Souza Leite, Celina Garcia, Luiz Henrique Medeiros Geraldo, Rackele Ferreira do Amaral, Catarina Freitas, Flavia Regina Souza Lima.

  Angiogenesis is essential not only during embryogenesis but also in adult physiology and disease, relying on vascular endothelial growth factor (VEGF) gradients to guide tip cell sprouting. Cellular prion protein (PrPC), expressed in several neurovascular unit (NVU) cell types, regulates neuronal and astrocytic differentiation through laminin binding, yet its role in angiogenesis remains understudied. Here, we investigated its function in retinal vascular development. In PrPC knockout mice, the superficial retinal plexus exhibited increased tip cell density and branching, accompanied by microglial morphofunctional alterations and reduced Vegf-c expression, features consistent with impaired vascular stability. Conditioned media from PrPC knockout microglia was sufficient to increase endothelial instability in vitro, indicating that altered microglial signalling can modulate vascular phenotype. Moreover, Laminin 411 / 511 isoforms and Collagen IV showed decreased expression in the retinal vascular basement membrane, supporting altered basement membrane composition. At later developmental stages, absence of PrPC led to increased vertical sprouting into deeper retinal layers, resulting in transient hypervascularization of the deep plexus and defective laminin deposition across all vascular layers. These changes were accompanied by altered ZO-1 distribution and disrupted retinal layer organization, as indicated by reduced inter-plexus distance. Collectively, our findings identify PrPC as regulator of sprouting angiogenesis and vascular stabilization in the developing retina. The data support a model in which PrPC modulates neurovascular interactions, through both microglia-dependent and endothelial-intrinsic mechanisms, although the relative contribution of these components remains to be determined.

Keywords:  Angiogenesis; Cellular prion protein; Laminin; Microglia; Neurovascular unit; Retina

DOI:  https://doi.org/10.1007/s11064-026-04867-8
Eur Neurol. 2026 Aug 28. 1-16

Downregulation of miR-33a-5p regulates TNF-α/NF-κB signaling and is associated with reduced diabetic neuropathic pain through targeting SIRT6.

Wenju Li, Yimei Li, Yongxin Wang.

BACKGROUND: The pathogenesis of diabetic neuropathic pain (DNP) remains unclear, with neuroinflammation mediated by abnormal TNF-α/NF-κB pathway activation being a key factor. This study aims to elucidate how this pathway contributes to DNP.
METHODS: miR-33a-5p levels were measured via qPCR in the serum of diabetic patients and in cell models. Its diagnostic value for DNP was assessed using ROC and logistic regression. A high-glucose HMC3 microglia model was established. TNF-α and NF-κB levels were quantified by ELISA. Cell proliferation and oxidative stress were evaluated. The targeting relationship between miR-33a-5p and SIRT6 was confirmed by dual-luciferase assay, and their regulatory effects on TNF-α and NF-κB expression were examined.
RESULTS: miR-33a-5p was significantly elevated in DNP patients (p < 0.001) and correlated positively with HbA1c (p < 0.001), demonstrating strong diagnostic value (AUC = 0.906, p < 0.001). DNP was associated with higher miR-33a-5p expression, in addition to its association with HbA1c levels. In vitro, high glucose upregulated miR-33a-5p (p < 0.01), NF-κB (p < 0.001), and TNF-α (p < 0.001) in microglia. Mechanistically, miR-33a-5p targets SIRT6, activating the NF-κB/TNF-α/p38MAPK pathway and worsening oxidative stress (p < 0.001). Inhibiting miR-33a-5p or overexpressing SIRT6 alleviated microglial activation and inflammation (p < 0.01).
CONCLUSION: miR-33a-5p aggravates DNP by regulating SIRT6 and enhancing TNF-α/NF-κB signaling; its inhibition may reduce neuroinflammation and pain.

DOI: https://doi.org/10.1159/000552973