bims-microg 2026-06-07 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–06–07
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience.
Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.
Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.
Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.
Bifunctional ferritin nanoparticle blocks PD-1/PD-L1 pathway and alleviates oxidative stress for multi-target therapy of multiple sclerosis.
AETA peptide contributes to Alzheimer's disease signature of synapse dysfunction.
M2 microglia-derived migrasome-enriched extracellular vesicles restore mitochondrial homeostasis to orchestrate neurovascular unit recovery after ischemic stroke.
A human telomerase reverse transcriptase-derived peptide GV1001 rescues neurodegeneration in a mouse model of Alzheimer disease.
Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation.
Microglial galectin-3 disrupts parvalbumin interneurons and hippocampal synchrony, driving cognitive deficits.
GPNMB modulates neutrophil extracellular trap formation: therapeutic implications for ischemic stroke.
Microglial OTUD6A promotes neuroinflammation and Alzheimer's disease pathogenesis by deubiquitinating C/EBPβ.
Antiviral and anti-inflammatory effects of Cannabidiol in HIV/SIV infection.
Mammary tumors-derived exosomes induce striatal NF-κB signaling, microglial reactivity, and anxiety/depression-like behaviors.
Aerobic Exercise-Induced TGF-β Receptor Reprogramming Disrupts Neutrophil-Microglia Crosstalk to Attenuate Early Brain Injury after Subarachnoid Hemorrhage.
The prognostic significance of TSPO-PET imaging in IDH-mutant glioma: a single-center, retrospective study.
Microglia in diffuse midline glioma contribute to extracellular matrix remodelling and cancer cell invasion.
Astrocyte-microglia crosstalk via CSF1 and IFN-β promotes central nervous system repair.
Enhancing the specificity of microglia genetic targeting using a CSF1R inhibitor.
A temporal single-cell atlas of the retina uncovers the dynamic transcriptomic landscape of sodium iodate-induced retinopathy in mice.

Nat Med. 2026 Jun 04.

Human microglial transitions at the Aβ-tau inflection point associate with divergent pathways to dementia and resilience.

Ashley Lu, Wei-Ting Chen, Maria Dalby, Diego Sainz Garcia, Marisa Vanheusden, Luuk E de Vries, Veerle van Lieshout, Araks Martirosyan, Katleen Craessaerts, Sebastiaan Moonen, Magdalena Zielonka, Iordana Chrysidou, Anke Misbaer, Leen Wolfs, Benjamin Pavie, Dick Swaab, Dietmar Rudolf Thal, Inge Huitinga, Annemieke Rozemuller, Susan Karijn Rohde, Marc Hulsman, Henne Holstege, Rita Balice-Gordon, Niels Plath, Mark Fiers, Bart De Strooper.

Alzheimer's disease (AD) is not an inevitable outcome of pathology but a dynamic process shaped by how brain cells respond to amyloid-β (Aβ) and tau. To disentangle these responses, we combined spatial transcriptomics and single-nucleus RNA sequencing of the superior frontal cortex from octogenarians living with or without dementia and from cognitively intact centenarians with comparable Aβ accumulation. We identified six distinct tissue domains representing a spatial pathological continuum of AD, with a key inflection point marked by a shift from Aβ-associated inflammatory changes to tau-associated cellular programs. This transition was accompanied by a change in microglial states, from early inflammatory to late antigen-presenting phenotypes, termed early and late plaque-induced gene (PIG) programs. Resilient individuals showed distinct pathological patterns: octogenarians without dementia lacked late PIGs, whereas centenarians showed late PIG activation that was uncoupled from tau accumulation. Together, these findings highlight divergent resilience-associated mechanisms in human aging and position microglial state transitions at the Aβ-tau interface as candidate points of resilience with potential therapeutic relevance.

DOI: https://doi.org/10.1038/s41591-026-04393-8
Cell Metab. 2026 Jun 04. pii: S1550-4131(26)00191-9. [Epub ahead of print]

Activity-dependent protein synthesis in neurons requires microglial-metabolic coupling.

Drew Adler, Alejandro Martín-Ávila, Evan Cheng, Mauricio M Oliveira, Muxian Zhang, Harrison T Evans, Deliang Yuan, Richard Sam, Nicole D Zhang, Maria Clara Selles, Olivia Mosto, Wendy J Liu, Victor T Wu, Amy X Guo, Shane A Liddelow, Robert C Froemke, Moses V Chao, Wen-Biao Gan, Eric Klann.

  De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here, we demonstrate that microglia, the resident macrophages of the brain, are required for metabolic coupling between endothelial cells, astrocytes, and neurons, which fuels protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, which increases glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit that is required for on-demand protein synthesis in mouse motor cortex.

Keywords:  astrocyte-neuron-lactate-shuttle; brain immunometabolism; brain metabolism; immunometabolism; mRNA translation; microglia; microglia-endothelial interaction; microglia-neuron interaction; microglial-metabolic coupling; neuroimmunology; protein synthesis

DOI:  https://doi.org/10.1016/j.cmet.2026.05.006
Mol Neurodegener. 2026 Jun 03.

Insulin resistance alters cortical inhibitory neurons and microglia to exacerbate Alzheimer's knock-in mouse phenotypes.

LaShae Nicholson, Si Jie Tang, Tejaswini Karra, Habiba Abouelatta, Stephen M Strittmatter.

   BACKGROUND: Metabolic dysfunction contributes to the risk and progression of Alzheimer's disease (AD), yet the cellular mechanisms linking impaired insulin signaling and systemic metabolic stress to brain dysfunction remain incompletely defined.
METHODS: We examined the impact of chronic high-fat, high-sugar (HFHS)-induced insulin resistance on metabolic parameters, spatial learning and memory, and in vivo glial activation and neuropathology in Alzheimer's disease knock-in mice expressing human mutant APP and wild-type (WT) tau. Single-nucleus RNA sequencing was performed to resolve cell-type-specific transcriptional responses.
RESULTS: HFHS-diet induced weight gain, hyperglycemia, and glucose intolerance in WT and AD knock-in mice as compared to control diet-fed mice. However, impaired spatial learning was observed only in AD knock-in mice on the HFHS diet, even though there was no greater amyloid-β deposition or tau phosphorylation than in control diet AD knock-in mice. Transcriptomic profiling revealed that HFHS-fed AD mice engaged a distinct glial program, which we termed the metabolic impairment in neurodegeneration (MinD) state, characterized by upregulation of genes involved in synaptic targeting and trans-synaptic signaling shared across microglia, astrocytes, and oligodendrocytes. In parallel, we identified selective induction of the transcription factor Meis2 in cortical Layer 2 inhibitory neurons, which exhibited HFHS-diet transcriptional remodeling enriched for pathways regulating vesicle release, synaptic organization, and membrane excitability. These coordinated glial and neuronal transcriptional changes were associated with reduced inhibitory synapse density in HFHS-fed AD mice.
CONCLUSION: Diet-induced insulin resistance in AD knock-in mice is associated with coordinated glial and inhibitory neuron transcriptional remodeling and cognitive impairment, without alteration of the classical amyloid and tau pathology present in the AD mice fed a lean diet. These findings define cellular programs linking systemic insulin metabolic dysfunction to cortical circuity vulnerability in AD.

Keywords:  Alzheimer’s; Diabetes; Glucose; Inhibitory neurons; Insulin resistance; Microglia; Obesity; snRNA-seq

DOI:  https://doi.org/10.1186/s13024-026-00946-0
Nat Commun. 2026 Jun 05.

Microglial CD31 suppresses Aβ clearance and promotes Alzheimer pathology in 5×FAD mice.

Qiuzhi Zhou, Fei Sun, Yao Zhang, Xiaojian Cao, Mengzhu Li, Haitao Yu, Tao Jiang, Shihong Li, Weixia Wang, Jiazhao Xie, Ting He, Yanchao Liu, Dan Ke, Xiao-Chuan Wang, Peng Xu, Enjie Liu, Hong Chen, Jian-Zhi Wang.

Microglia play crucial roles in Alzheimer's disease (AD), yet the molecular mechanisms are unclear. Here, we show that CD31, a recognized endothelial marker, is predominantly expressed in microglia but not in neurons or astrocytes, and it is significantly elevated in the brains of AD patients and mouse models. Microglia-specific CD31 knockdown in 5xFAD mice substantially attenuated the dysregulated transcription networks, suppressed microglia hyperactivation and the disease-associated microglia (DAM), mitigated Aβ deposition and inflammation, and eventually improved cognitive functions in mice. Mechanistically, CD31 knockdown damaged the simultaneous recruitment of Src homology phosphatase 2 (SHP2) and STAT3, leading to a reduced dephosphorylation and enhanced activation of STAT3, a transcription factor. STAT3 activation increased transcription of membrane metalloendopeptidase (MME) and promoted Aβ clearance. Collectively, this study identifies microglial CD31, by regulating SHP2-STAT3-MME axis, plays a role in AD pathogenesis and targeting CD31 is promising in AD drug development.

DOI: https://doi.org/10.1038/s41467-026-74037-5
Biomaterials. 2026 May 21. pii: S0142-9612(26)00353-4. [Epub ahead of print]335 124329

Bifunctional ferritin nanoparticle blocks PD-1/PD-L1 pathway and alleviates oxidative stress for multi-target therapy of multiple sclerosis.

Shengnan Yang, Ke Sun, Ruya He, Ning Wang, Mengyao Li, Weimin Yang, Yanjie Jia, Ranran Duan.

  To address the limited immunotargeting specificity of PD-L1 antibodies and the exacerbated oxidative stress microenvironment in multiple sclerosis (MS), a bifunctional nanoplatform, Ru@Fn-PD-L1(IgV), was developed using an engineered ferritin nanocage. This system was constructed via site-specific conjugation of the PD-L1 extracellular domain(IgV) to ferritin using SpyTag-SpyCatcher bioconjugation, combined with the in-situ encapsulation of ruthenium-based nanozymes exhibiting superoxide dismutase/catalase (SOD/CAT) cascade activity within the nanocage. Ru@Fn-PD-L1 (IgV) efficiently traverses the blood-brain barrier (BBB) through transferrin receptor (TfR1)-mediated transcytosis, enabling targeted delivery to the central nervous system (CNS). Mechanistic studies demonstrated that Ru@Fn-PD-L1(IgV) selectively inhibits the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) signaling axis in activated T cells, thereby promoting apoptosis and suppressing pro-inflammatory cytokine secretion. Concurrently, the nanozymes effectively scavenge reactive oxygen species (ROS), including superoxide anions (O2·-), and hydrogen peroxide (H2O2), and induce polarization of microglia toward the M2 anti-inflammatory phenotype, substantially alleviating oxidative stress and neuroinflammatory injury. In vivo studies using a mouse model of MS demonstrated significant neuroprotection and enhanced cognitive performance, supporting the potential of Ru@Fn-PD-L1(IgV) as a novel immunotherapeutic strategy for treating MS.

Keywords:  Blood-brain barrier; Cascade catalytic nanozyme; Ferritin; Multiple sclerosis; PD-L1 extracellular domain

DOI:  https://doi.org/10.1016/j.biomaterials.2026.124329
Acta Neuropathol. 2026 06 03. pii: 65. [Epub ahead of print]151(1):

AETA peptide contributes to Alzheimer's disease signature of synapse dysfunction.

Jade Dunot, Carine Gandin, Marin Truchi, Giulia Pirro, Sébastien Moreno, Agathe Launay, Benjamin Azoulay, Hugo Landra, Sandy Ma Yishan, Luc Buée, Kevin Lebrigand, Paula A Pousinha, David Blum, Bernard Mari, Ingrid Bethus, Michael Willem, Hélène Marie.

  Alzheimer's disease (AD), the leading cause of dementia, is characterized by early synaptic dysfunction that precedes overt cognitive decline. While amyloid-β and Tau remain central to AD pathogenesis, molecular triggers of synapse weakening remain unclear. Here, we investigated AETA, a novel brain-secreted peptide derived from amyloid precursor protein (APP), as a potential mediator of synapse dysfunction in AD. We previously identified AETA as a unique modulator of NMDA receptor activity in the healthy brain; however, its role in AD etiology was yet to be explored. Post-mortem analyses of human hippocampal and prefrontal cortex tissues revealed significantly elevated AETA levels in AD patients, particularly in females. To further explore the contribution of AETA to AD synaptic pathology, we analyzed a new mouse model, the AETA-m mouse, exhibiting chronically increased brain AETA expression. Hippocampi of female AETA-m mice displayed an increase in the number of astrocyte and microglia, but no overt neuroinflammation. RNA sequencing of female AETA-m hippocampi revealed alterations in synaptic gene expression that closely paralleled those observed in vulnerable human AD brain regions, most notably in the hippocampus. These two phenotypes were absent in males. Functionally, hippocampal neurons from AETA-m mice displayed impaired NMDA receptor signaling, dendritic spine loss, and memory deficits especially in females, mirroring early AD-associated synaptic dysfunction. Together, these findings identify AETA as a novel key contributor of synaptic vulnerability in AD and associated memory processing, especially in females. Targeting AETA signaling may therefore offer new therapeutic avenues for preventing or mitigating synaptic and cognitive decline in AD.

Keywords:  Alzheimer’s disease; Amyloid precursor protein; Hippocampus; Memory; Synapse

DOI:  https://doi.org/10.1007/s00401-026-03033-2
J Nanobiotechnology. 2026 Jun 04.

M2 microglia-derived migrasome-enriched extracellular vesicles restore mitochondrial homeostasis to orchestrate neurovascular unit recovery after ischemic stroke.

Yuanjia Zhang, Jie Wu, Leyi Liu, Yiqian Zhu, Jierui Zhang, Jinghong Xu, Xuefeng Shi, Yu Yu, Chao Wang, Jiajing Xiao, Xuanchenye Zhang, Zhaorong Li, Wenqi Huang, Wenzhi Li, Zhongxing Wang, Tingting Li.

  Ischemic stroke is a major cause of disability with few treatment options available. Microglia-driven neuroinflammation contributes significantly to stroke pathology, and promoting anti-inflammatory microglial phenotypes represents a promising strategy. Migrasomes are newly discovered organelles mediating intercellular communication, yet their role in ischemic stroke remains unexplored. This study demonstrates that M2 microglia-derived migrasome-enriched extracellular vesicles (EVs) exert potent neuroprotection in both OGD/R cell models and MCAO mice. These migrasome-enriched EVs were efficiently internalized by microglia, astrocytes, neurons, and microvascular endothelial cells, promoting microglial M2 polarization, suppressing astrocytic aberrant activation, reducing neuronal apoptosis, and enhancing angiogenesis. Intracerebral administration of M2 microglia-derived migrasome-enriched EVs significantly reduced infarct volume, ameliorated cerebral edema, improved cerebral blood flow, and accelerated neurological and cognitive recovery without detectable toxicity. Mechanistically, migrasome-enriched EVs activated the cAMP/EPAC1/Rap1 signaling pathway in microglia, leading to restored mitochondrial homeostasis. Collectively, these findings identify M2 microglia-derived migrasome-enriched EVs as novel intercellular messengers that orchestrate neurovascular unit recovery after ischemic stroke, positioning migrasome-enriched EVs as promising candidates for stroke therapy.

Keywords:  Ischemic stroke; Microglia polarization; Migrasome-enriched extracellular vesicles; Mitochondrial homeostasis; Neurovascular unit recovery

DOI:  https://doi.org/10.1186/s12951-026-04643-4
Exp Mol Med. 2026 Jun 03.

A human telomerase reverse transcriptase-derived peptide GV1001 rescues neurodegeneration in a mouse model of Alzheimer disease.

Younghwan Lee, Hyeri Nam, Ji-Won Lee, Yeo Jin Ko, Eum Ji Kim, Sehee Ha, Nan Kim, Ja Wook Koo, Taekwon Son, Sangjae Kim, Seong-Woon Yu.

GV1001 is a peptide consisting of 16 amino acids derived from the catalytic subunit of human telomerase reverse transcriptase. A recent phase II clinical trial in patients with Alzheimer disease (AD) showed that GV1001 effectively improved memory impairment with proven safety, leading to larger clinical trials. However, the mechanisms underlying therapeutic effects of GV1001 on AD remain elusive. Here, we report that GV1001 reduces amyloid plaque burden and rescues synaptic loss and memory deficits in 5xFAD mice by increasing microglial migration toward large amyloid plaques and amyloid β degradation. Single-cell RNA-sequencing revealed that GV1001 promoted the migratory and phagocytic phenotypes by modulating disease-associated microglial profiles. At the molecular level, through virtual target screening and docking simulation combined with peptide pulldown, we identified that bradykinin receptor 1 is the binding target of GV1001. Furthermore, we revealed that GV1001 facilitated microglial migration and amyloid β phagocytosis in an mTORC2-dependent manner. Collectively, our work demonstrates the amyloidolytic effects and the relevant in-depth signaling mechanism of GV1001 in microglia, suggesting GV1001 as a promising disease-modifying therapeutic agent for AD.

DOI: https://doi.org/10.1038/s12276-026-01729-9
J Neuroinflammation. 2026 Jun 02.

Placental and juvenile immune responses to maternal immune activation are differentially regulated by sex chromosomes and gonads across gestation.

Stephanie Salia, Nadine T Burry, Meagan E Hinks, Kerri M Sparkes, Alison M Randell, Alexandre S Maekawa, Nicole Reid, Lucas F Fowler, Rachel Q Kelly, Jai-Lynn Francis, Madison C Youden, Stephanie H G Pelley, Susan G Walling, Ashlyn Swift-Gallant.

  Sex differences are a defining feature of neurodevelopmental disorders (NDDs), with males diagnosed up to four times more frequently than females. Gestational maternal immune activation (MIA) is an environmental risk factor for NDDs that produces stronger behavioral alterations among male offspring. To identify the contributions of sex chromosomes (XX vs. XY) and gonadal development (ovaries vs. testes) in this sex bias, we used the Four Core Genotypes (FCG) mouse model. We assessed placental, fetal, and juvenile brain immune responses, along with juvenile behavioral outcomes, following early (E12.5) or late (E17.5) gestational exposure to Poly(I: C), eliciting a robust systemic maternal immune response. Placental immune profiling revealed distinct sex-specific strategies: XX gonadal females mounted coordinated pro- and anti-inflammatory responses, whereas XY offspring and gonadal males exhibited relative immune suppression, particularly in late gestation, coinciding with the testicular androgen surge. Conversely, fetal brain chemo-cytokine responses 24 h post-MIA were similar across XX females and XY males. However, XY offspring juvenile neuroimmune alterations were associated with increased social avoidance. Early MIA eliminated the typical social advantage of gonadal females, shifting behavior toward male-typical patterns. Together, we identify the placenta as a key site of sex-specific immune responses to MIA and demonstrate that gestational timing, sex chromosome complement, and gonadal signals interact to shape long-term neuroimmune and behavioral outcomes relevant to sex-bias in NDDs.

Keywords:  Cytokines; Fetal brain; Four-core genotypes; Maternal immune activation; Microglia; Neurodevelopmental disorders; Placenta; Sex differences

DOI:  https://doi.org/10.1186/s12974-026-03881-5
J Neuroinflammation. 2026 Jun 05.

Microglial galectin-3 disrupts parvalbumin interneurons and hippocampal synchrony, driving cognitive deficits.

Min Jia, Hua Shao, Si-Qi Ma, Wen-Xue Liu, Meng Cai, Tong Zhu, Shan Xu, Gui-Zhou Li, Shuai-Fei Lu, Jin-Chun Shen, Jiang Chen, Yun Stone Shi, Kenji Hashimoto, Guang-Fen Zhang, Mu-Huo Ji, Jian-Jun Yang.

  Sepsis-associated encephalopathy (SAE), a devastating neurological complication of systemic inflammation, affects approximately 70% of patients with sepsis. It not only increases mortality but also leaves survivors with persistent cognitive deficits. However, the mechanisms underlying SAE progression remain incompletely understood. Here, using a lipopolysaccharide (LPS)-induced mouse model of SAE, we identify microglial galectin-3 (Gal-3) as a central pathogenic mediator driving systemic inflammation-induced cognitive impairment. Mechanistically, systemic LPS challenge robustly upregulates microglial Gal-3, which in turn activates Toll-like receptor 2 (TLR2) signaling and promotes NLRP3/AIM2 inflammasome assembly. This microglia-driven inflammatory cascade substantially exacerbates local oxidative stress, leading to selective structural and functional impairment of hippocampal parvalbumin (PV) interneurons. Dysfunction of these critical interneurons disrupts theta/gamma oscillations, impairs excitatory/inhibitory (E/I) balance and synaptic plasticity, and ultimately results in severe cognitive decline. Supporting this pathogenic cascade, pharmacological inhibition of Gal-3 with TD139 effectively suppresses TLR2/inflammasome activation, attenuates oxidative stress, and prevents memory deficits. Conversely, targeted rAAV-mediated overexpression of Gal-3 in microglia is sufficient to recapitulate neuroinflammation, PV-interneuron injury, oscillatory abnormalities, and cognitive impairment. Finally, chemogenetic reactivation of hippocampal PV interneurons using DREADDs restores theta/gamma oscillations and ameliorates LPS-induced cognitive deficits. Together, our findings define a coherent pathogenic axis linking microglial Gal-3 upregulation to PV interneuron-dependent network desynchronization and highlight Gal-3 as a promising therapeutic target for inflammation-associated cognitive disorders.

Keywords:  Cognitive impairments; Galectin-3; Hippocampal oscillations; Microglia; Neuroinflammation; PV interneurons

DOI:  https://doi.org/10.1186/s12974-026-03889-x
J Neuroinflammation. 2026 Jun 02.

GPNMB modulates neutrophil extracellular trap formation: therapeutic implications for ischemic stroke.

Ningning Zong, Jian Chen, Yang Geng, Lixuan Yang, Shengnan Xia, Haiyan Yang, Xinyu Bao, Yun Xu.

  Microglia are key immune-competent cells responding immediately to manipulate post-stroke neuroinflammation to shape the prognosis of stroke. GPNMB was reported to be upregulated after ischemic stroke and might influence the outcome. However, its detailed biological function and mechanism remain elusive. Here, we found that GPNMB was remarkably elevated in the ischemic brain and mainly distributed in microglia. Combining GPNMB knockout mice and recombinant GPNMB protein, we found that GPNMB could alleviate ischemic brain injury. Recombinant GPNMB (rGPNMB) administration could reduce neutrophil extracellular traps (NETs) formation, while knockout of GPNMB promoted NET formation in ischemic stroke. In addition, we found that CD44 functioned importantly in mediating the role of GPNMB inhibiting NET formation and alleviating ischemic brain injury. Depletion of neutrophils or inhibition of NET formation with DNase I could reduce the neuroprotective impact of GPNMB. Mechanistically, GPNMB might inhibit NET formation partly via modulating the Rac-ROS pathway after binding to the CD44 receptor. Finally, our data indicated that delayed rGPNMB administration retained neuroprotective impact in ischemic stroke. Our study revealed the importance of GPNMB in modulating NET formation and suggested a potential target for manipulating post-stroke neutrophil-associated neuroinflammation.

Keywords:  GPNMB; Ischemic stroke; Microglia; NETs; Neutrophil

DOI:  https://doi.org/10.1186/s12974-026-03894-0
Pharmacol Res. 2026 Jun 03. pii: S1043-6618(26)00195-7. [Epub ahead of print]230 108280

Microglial OTUD6A promotes neuroinflammation and Alzheimer's disease pathogenesis by deubiquitinating C/EBPβ.

Lingyu She, Mengqing Li, Fan Chen, Xiaoting Wu, Jingtao Zhang, Wei Jiang, Zefeng Sun, Luyao Li, Juan Ren, Dazhi Chen, Xia Zhao, Guang Liang.

  Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by β-amyloid (Aβ) deposition, neuroinflammation, and cognitive decline. Microglia, the brain's primary immune cells, play a central role in AD pathogenesis by driving neuroinflammatory responses. Deubiquitinating enzymes (DUBs) regulate microglial activation, but the role of the ovarian tumor domain-containing DUB OTUD6A in AD remains unclear. In this study, we demonstrate that OTUD6A is upregulated in microglia across multiple AD models, including Aβ-infused mice, 3 ×Tg mice, and APP/PS1 mice. Otud6a KO or microglia-specific knockdown Otud6a ameliorated cognitive deficits and reduced neuroinflammation in AD mice. Besides, OTUD6A binds to C/EBPβ by removing K48-linked ubiquitin chains at lysine 253 (K253), thereby leading to C/EBPβ accumulation and enhancing NF-κB signaling and proinflammatory cytokine production. Moreover, mutation of OTUD6A catalytic residue (C157A) abolished its deubiquitination activity, confirming its role in C/EBPβ stabilization. Furthermore, C/EBPβ knockdown reversed OTUD6A-mediated neuroinflammation, validating the microglial OTUD6A-C/EBPβ-NF-κB axis as a critical pathway in AD pathogenesis. Therefore, our findings highlight OTUD6A as a novel regulator of microglial activation and suggest that targeting this DUB could provide a therapeutic strategy to mitigate neuroinflammation in AD.

Keywords:  Alzheimer’s disease; C/EBPβ; Deubiquitination; Microglia; NF-κB; Neuroinflammation; OTUD6A

DOI:  https://doi.org/10.1016/j.phrs.2026.108280
Brain Behav Immun. 2026 Jun 02. pii: S0889-1591(26)00591-X. [Epub ahead of print]137 106843

Antiviral and anti-inflammatory effects of Cannabidiol in HIV/SIV infection.

Alysha L Ellison, José Javier Rosado-Franco, Labib Mamun, Stephen Knerler, Marzieh Daniali, Kiara Mehta, Sierra Williams-McLeod, Jade Alvarez, Savoya S Joyner, Ryan Vandrey, Elise M Weerts, Peter J Gaskill, Michael J Corley, Lishomwa C Ndhlovu, Dionna W Williams.

  Persistent reservoirs and chronic immune activation are hallmarks of HIV, despite the effectiveness of antiretroviral therapy (ART) in suppressing viral replication. Here, we use rhesus macaques and primary and induced pluripotent stem cell (iPSC)-derived human immune cells to evaluate the virologic and immunologic consequences of cannabidiol (CBD) exposure during HIV/SIV infection. We show that CBD, in the absence of ART, suppresses viral replication and establishment of the viral reservoir to levels comparable with first-line therapies during acute SIV infection of rhesus macaques. This antiviral effect of CBD extended to in vitro HIV infection of human macrophages, T cells, and microglia. Immunologically, we observe CBD slowed CD4 + T cell decline and polarization, decreased CD14 + CD16 + monocyte expansion, and reduced interferon-inducible cytokine release in rhesus macaques. We identify comparable effects on cytokine production with in vitro CBD treatment of human macrophages, T cells, and microglia. Importantly, we find CBD inhibits cytokines only when an immune response is elicited by HIV, suggesting it is not broadly immunosuppressive. Finally, we determine CBD regulates endocannabinoid receptors, modulators, and transporters and inhibits NF-κb and STAT1 activation when mediating its antiviral and anti-inflammatory effects. These findings show beneficial effects of CBD in laboratory models of untreated HIV, thus placebo-controlled clinical trials to evaluate the safety and effectiveness of adjunctive CBD use with ART is warranted.

Keywords:  Cannabidiol; Endocannabinoid; HIV; Inflammation; SIV

DOI:  https://doi.org/10.1016/j.bbi.2026.106843
Brain Behav Immun. 2026 Jun 01. pii: S0889-1591(26)00589-1. [Epub ahead of print] 106841

Mammary tumors-derived exosomes induce striatal NF-κB signaling, microglial reactivity, and anxiety/depression-like behaviors.

Yuan-Yuan Han, Ji-Chao Wu, Hong-Mei Yang, Zhi-Wei Guo, Chen-Qiong Gu, Ya-Wen Deng, Hui-Dong Li, Min-Hua Huang, Xue-Ping He, Qi-Jia Han, Heng Kong, Yan-Qi Xu, Jian Yao, Peng-Hui Shan, Hong-Yun Chen, Jia-Yue Wen, De-Xiang Liu, Ya-Mei Tang, Zhang Wang, Cheng Long.

  Emerging evidence links peripheral cancer growth with affective disturbances, yet the mechanisms bridging tumor biology and central dysfunction remain poorly defined. In a cohort of newly diagnosed breast cancer patients and healthy controls, patients exhibited elevated depressive and anxiety-related symptoms, accompanied by a focal reduction of amplitude of low-frequency fluctuations (ALFF) in the right caudate. The ALFF of right caudate is negatively correlated with individual affective scores, suggesting early striatal involvement in cancer-related affective vulnerability. Building on these observations, we used mammary tumor-bearing mouse models and found that mammary tumor-bearing mice developed pronounced anxiety/depression-like behaviors accompanied by microglial reactivity and heightened NF-κB signaling in the striatum. In vitro, exosomes isolated from mammary tumor-bearing cells activated BV-2 microglia and the NF-κB pathway, and enhanced pro-inflammatory cytokine production. Systemic administration of tumor cell-derived exosomes in naïve mice reproduced both behavioral abnormalities and striatal microglial/NF-κB activation, whereas pharmacological inhibition of exosome release in mammary tumor-bearing mice ameliorated behavioral abnormalities and reduced neuroinflammation. Together, these human and experimental data identify exosomes as a mechanistic conduit linking peripheral malignancy to central affective pathology. Exosome-driven NF-κB activation in striatal microglia emerges as a key driver of cancer-associated anxiety and depression. It represents a potential therapeutic point for mitigating neuropsychiatric comorbidity in cancer.

Keywords:  Anxiety and depression; Exosome; Mammary tumor; Microglia; NF-κB pathway

DOI:  https://doi.org/10.1016/j.bbi.2026.106841
Research (Wash D C). 2026 ;9 1301

Aerobic Exercise-Induced TGF-β Receptor Reprogramming Disrupts Neutrophil-Microglia Crosstalk to Attenuate Early Brain Injury after Subarachnoid Hemorrhage.

Shengming Jiang, Li Jiang, Shiqiang Zhang, Xincan Zhao, Peipei Jiang, Qi Tian, Chengli Liu, Peibang He, Zhijie Li, Guijun Wang, Zhou Sun, Minghao Du, Zhongyang Zhang, Youyu Wang, Fuhai Chao, Yang Yuan, Yuwei Jiang, Zhan Zhang, Jianming Liao, Mingchang Li.

Acute-phase neuroinflammation and early brain injury progressing rapidly is responsible for substantial severity and mortality in subarachnoid hemorrhage (SAH). While cohort studies have confirmed that aerobic exercise (AE) was associated with decreased short-term mortality, its precise mechanisms remain elusive. We employed a murine SAH model subjected to preconditioning AE to validate the above hypothesis, combining early neurological function assessment and histological staining. Whole-transcriptome profiling and single-cell RNA sequencing were performed to capture differentially expressed genes and to delineate subtype-specific differentiation. To recapitulate the neuroimmune crosstalk in vitro, we established a primary neutrophil-microglia coculture system. Targeted receptor-ligand interaction studies were employed to validate the specific environmental variables driving their synergistic activation. Our data indicated that AE significantly ameliorated neurological outcomes, cerebral edema, and neuronal apoptosis post-SAH. Sequencing data identified classical pro-inflammatory M1-like microglia, alongside a novel early-response microglial subset characterized by high expression of transforming growth factor beta 1; both populations were regulated by AE for modulating neuroinflammation and significantly correlated with infiltrating neutrophil counts. This crosstalk was mediated by mature neutrophil-derived leucine-rich alpha-2-glycoprotein 1 (Lrg1), which differentially activated the microglial transforming growth factor beta signaling pathway. Collectively, AE-mediated suppression of neutrophil infiltration rebalanced microglial differentiation, thereby attenuating neuroinflammation following SAH. We identified Lrg1 as a key immune mediator in this process, highlighting exercise-induced reprogramming at the receptor level as a potential therapeutic strategy for SAH.

DOI: https://doi.org/10.34133/research.1301
Eur J Nucl Med Mol Imaging. 2026 May 30.

The prognostic significance of TSPO-PET imaging in IDH-mutant glioma: a single-center, retrospective study.

Katharina J Müller, Roman Stürzl, Sabrina Kirchleitner, Isabelle von Polenz, Viktoria Ruf, Veit M Stoecklein, Jonas Reis, Stefanie Quach, Lena Kaiser, Julia Lorenz, Adrian Zounek, Patrick N Harter, Rainer Rupprecht, Markus J Riemenschneider, Matthias Brendel, Niklas Thon, Joerg-Christian Tonn, Louisa von Baumgarten, Nathalie L Albert.

   PURPOSE: Clinical prognostication and decision-making in IDH-mutant glioma is increasingly complex, especially with new targeted treatment options like IDH-inhibitors. Individual patient risk stratification for better treatment planning is needed; however, standard prognostic models rely on clinical and histologic parameters as well as MRI, which may not fully reflect the tumor's biological behavior. Positron emission tomography (PET) imaging of the 18 kDa translocator protein (TSPO) is known as surrogate marker of activated microglia and macrophages and enables non-invasive assessment of the tumor microenvironment and peri-/intratumoral inflammation as well as TSPO-positive tumor cells. The aim of this study was to investigate TSPO-PET imaging in IDH-mutant glioma and its association with outcome.
METHODS: In this monocentric, retrospective study, 46 patients with newly diagnosed IDH-mutant glioma who had undergone TSPO-PET imaging with [¹⁸F]GE180 prior to any therapeutic intervention were included. Quantitative PET parameters including mean and maximum standardized uptake values (SUVmax, SUVmean) and the respective PET-positive tumor volumes were evaluated for their association with clinical data and time to next intervention (TTNI), and overall survival (OS).
RESULTS: The cohort consisted of 27 patients (58.7%) with astrocytoma, IDH-mutant (median age 36 years (30-51)) and 19 patients (41.3%) with oligodendroglioma, IDH-mutant and 1p/19q-codeleted (median age 41 years (36-48)). High SUVmax on TSPO-PET imaging was associated with shorter TTNI, and OS (p = 0.0118 and p = 0.0459, respectively). In multivariate analyses adjusting for age, KPS, WHO grade, FET-PET-positive volume, and tumor volume on contrast-enhanced MRI, the TSPO-PET-positive volume was associated with TTNI (hazard ratio (HR) = 1.037, 95% CI: 1.009-1.064, p = 0.0106).
CONCLUSIONS: This study highlights the potential prognostic utility of TSPO-PET imaging in newly diagnosed IDH-mutant glioma. Our findings support the inclusion of PET imaging in future clinical trials to develop imaging-based risk models for better prognostication and individualized treatment guidance.

Keywords:  IDH-mutant glioma; Imaging; Neuroinflammation; Prognostication; TSPO-PET

DOI:  https://doi.org/10.1007/s00259-026-07926-y
Cell Death Dis. 2026 May 30. pii: 517. [Epub ahead of print]17(1):

Microglia in diffuse midline glioma contribute to extracellular matrix remodelling and cancer cell invasion.

Lily Keane, Martin Škandík, Mercedes Posada-Pérez, Raj Bose, John Desito, Esmee van der Linde, Pinelopi Engskog-Vlachos, Sandra Ceccatelli, Adam L Green, Bertrand Joseph.

Diffuse midline glioma, H3K27-altered (DMG), is an aggressive and uniformly fatal paediatric brain tumour arising in midline structures and characterised by substantial microglial infiltration. We investigated whether microglia adopt a reactive state in response to DMG cells that functionally contributes to tumour progression. Transcriptomic profiling of microglia exposed to DMG, H3K27M cells, together with analysis of tumour associated myeloid cells isolated from DMG patient biopsies, revealed a pronounced upregulation of extracellular matrix (ECM) components, including fibronectin. Single cell transcriptomic analysis further identified microglia as the primary fibronectin expressing cell population within human DMG, H3K27M tumours. Functional invasion assays using a panel of patient-derived DMG, H3K27M cells, revealed that microglia-derived fibronectin significantly enhances tumour cell invasiveness, while its chemical inhibition with RGDS peptide or Avapritinib or its genetic silencing using small-interfering RNAs effectively suppresses invasion. Across independent patient cohorts (Kids First, PNOC, and CBTTC), and in archival tissues, DMG tumours were found to exhibit elevated expression of ECM components, and high fibronectin expression that correlated with poor prognosis. These findings suggest that microglia actively contribute to DMG invasiveness through ECM component production, identifying fibronectin as a potential therapeutic target in this lethal paediatric cancer.

DOI: https://doi.org/10.1038/s41419-026-08891-y
Cell Rep. 2026 May 29. pii: S2211-1247(26)00496-1. [Epub ahead of print]45(6): 117418

Astrocyte-microglia crosstalk via CSF1 and IFN-β promotes central nervous system repair.

Tuoxin Cao, Matin Hemati-Gourabi, Yongliang Liu, Anna E Mills, Lauren Baur, Ellie P Rice, Theo Klippel, Yiwen Yan, Xiu Xu, William K Fenske, Jean X Jiang, Meifan Chen.

  Despite accumulating evidence of functional interactions between astrocytes and microglia in central nervous system (CNS) injury and disease, mechanisms coordinating their response to CNS insults remain incompletely understood. We report that injury-reactive astrocytes at the lesion border upregulate colony-stimulating factor 1 (CSF1) required for microglial proliferation, wound closure, and motor recovery after focal spinal cord injury (SCI). Intriguingly, astrocyte-targeted deletion of CSF1 also reduces the cell number of border-forming astrocytes, revealing positive feedback regulation between astrocytes and microglia. We further show that microglia produce interferon β (IFN-β), which reciprocally supports astrocyte survival. Genetic disruption of interferon signaling in astrocytes in turn impairs astrocytic border formation, coordination with microglia in wound healing, and motor recovery. This work uncovers astrocyte-microglia crosstalk via CSF1 and IFN-β that synergizes the acute injury response of these cells for neural repair, providing insights into fundamental biology of astrocyte-microglia communication and its therapeutic potential.

Keywords:  CNS injury; CNS repair; CP: neuroscience; CSF1; IFN-β; astrocyte-microglia interaction; glia crosstalk; interferon response; reactive astrocytes; spinal cord injury; wound repair astrogliosis

DOI:  https://doi.org/10.1016/j.celrep.2026.117418
Cell Rep. 2026 May 29. pii: S2211-1247(26)00489-4. [Epub ahead of print]45(6): 117411

Enhancing the specificity of microglia genetic targeting using a CSF1R inhibitor.

Isaac W Babcock, Sydney A Labuzan, Abigail G Kelly, Anne E Schuster, Seblework Alemu, Lydia A Sibley, Anne E Marchildon, Tajie H Harris.

  Microglia are the resident macrophages of the brain and are central to neuroimmunology research. The roles of microglia are often probed by pharmacological depletion with CSF1R inhibitors or by genetic manipulation using Cre-lox systems, but microglia-specific genetic targeting remains challenging due to limited specificity or efficiency of Cre lines. We confirm that Cx3cr1CreERT2 mice, widely used for microglial studies, also target multiple peripheral tissue macrophage populations that fail to turn over within the standard 4-week period intended to improve specificity. To overcome this limitation, we combined tamoxifen induction in Cx3cr1CreERT2 mice with PLX5622 treatment to accelerate peripheral macrophage turnover. In a brain infection model, this strategy increased the specificity of gene deletion in microglia in Cx3cr1CreERT2 mice and eliminated confounding contributions from peripheral macrophages. In sum, the use of a CSF1R inhibitor provides a solution to enhance the precision of microglial genetic manipulation using a common Cre line.

Keywords:  CP: immunology; CP: neuroscience; genetics; microglia; neuroimmunology; tissue-resident macrophages

DOI:  https://doi.org/10.1016/j.celrep.2026.117411
Exp Eye Res. 2026 May 29. pii: S0014-4835(26)00249-6. [Epub ahead of print]270 111093

A temporal single-cell atlas of the retina uncovers the dynamic transcriptomic landscape of sodium iodate-induced retinopathy in mice.

Zhenzhen Zhao, Ye Zhou, Ying Liu, Qian Wang, Guo-Tong Xu, Haibin Tian, Yanlong Bi, Tingting Cui, Qingjian Ou.

  Retinal degeneration involves complex interactions among diverse cell types, yet the dynamic cellular responses and intercellular communication remain incompletely characterized. Here, we generated a temporal single-cell RNA sequencing atlas of the mouse retina following sodium iodate-induced oxidative injury to characterize cell type-specific trajectories and stage-dependent interactions. Our analysis identified a distinct inflammatory-reactive Müller glia subpopulation enriched for Il1r1, Tnfrsf1a, and C3, which exhibited early activation of TNF/NF-κB/MAPK signaling and later engagement in chemokine signaling, ECM-receptor interaction, and synaptic regulation. Photoreceptor profiling further revealed two rod subclusters with differential vulnerability, in which the more susceptible Rod1 subpopulation displayed marked downregulation of phototransduction genes and selective enrichment of tumor necrosis factor (TNF) signaling. Microglia exhibited early expansion and upregulation of inflammatory gene programs, including Il1b, Tnf, and Ccr2, while in vitro assays confirmed that conditioned medium from sodium iodate-activated microglia reduced photoreceptor viability. Together, we show a conceptual model in which sodium iodate-induced oxidative stress is associated with early microglial inflammation and subsequent glia-photoreceptor crosstalk, suggesting a potential pathway that may contribute to selective rod degeneration. This study provides a comprehensive resource for dissecting retinal degenerative mechanisms and highlights critical temporal windows for therapeutic intervention.

Keywords:  Microglia; Müller glia; Photoreceptors; Retinal degeneration; Sodium iodate

DOI:  https://doi.org/10.1016/j.exer.2026.111093