bims-microg 2026-06-14 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–06–14
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

Semaglutide attenuates neuroinflammation in male mice.
Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.
Single-cell proteome atlas of aging mouse microglia reveals subpopulation-specific phagoproteome.
Intrinsically Mitochondria-Targeting Nanozyme via Coordination-Assembly of Natural Quercetin for Cascade Antioxidant Therapy of Cerebral Ischemia-Reperfusion Injury.
Targeting Dnmt3a/m5C/RelA Axis Attenuates Microglia Inflammatory Response and Improves Postoperative Recovery in Chronic Compressive Cervical Spinal Cord Injury.
Porphyromonas gingivalis disrupts hippocampal circadian clock via PI3K/AKT pathway, exacerbating Alzheimer-like pathology.
Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease.
Infiltrating monocyte-derived macrophages does not survive long term in stroke brain despite their dominance in the acute ischemic core and myeloid derived IGF-1 play dichotomous roles in stroke recovery.
Psilocybin restores behavior and 5-HT2A signaling while reducing microglial density after chronic traumatic brain injury in rats.
Cel-LDH dual-functional nanotherapy simultaneously promotes microglial efferocytosis and alleviates neuronal apoptosis for spinal cord injury recovery.
Microcystin-LR induces dopaminergic neurodegeneration by MyD88-dependent neuroinflammation in zebrafish (Danio rerio).
The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention.
Targeting the cGAS-STING pathway mitigates Huntington disease pathogenesis in a knock-in mouse model.
C1q-CD44 interactions regulate microglial phagocytosis, proliferation, and migration.
Ischemic injury triggers a protective microglial phenotype in models of Aβ pathology.
A Polarity-Sensitive Lipid Droplet Probe Reveals Aβ Species-Dependent Lipid Droplet Remodeling in Microglia.
Meta-analysis of brain and blood transcriptional signatures of neuroimmune dysregulation in Schizophrenia: convergent evidence for excessive complement system activity and CX3CL1-CX3CR1 axis disruption.
Chronic central-targeted Interleukin-6 overexpression promotes hippocampal and cortical neuropathology in the Tg2576 mouse model of Alzheimer's disease.
An integrated nano-delivery platform via baicalein-loaded polydopamine-MOF for enhanced neuroprotection against retinal ischemia reperfusion injury.
Long-term polystyrene nanoplastics exposure aggravates retinal inflammation and photoreceptor degeneration through microglial SPP1 signaling and neutrophil extracellular traps formation.

Nat Commun. 2026 Jun 09.

Semaglutide attenuates neuroinflammation in male mice.

Dylan M Belmont-Rausch, Mette Q Ludwig, Marie A Bentsen, Stine N Hansen, Anna Secher, Dorte Holst, Jaime Moreno, Vivek Das, Kristoffer L Egerod, Anne-Mette Bjerregaard, Kristoffer Niss, Sarah Bau, Charles Pyke, Kevin Dalgaard, Myrte Merkestein, Franziska Wichern, Charlotte Thim Hansen, Joseph Polex-Wolf, Lotte Bjerre Knudsen, Tune H Pers.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have shown promise in preclinical models of neurodegeneration, with emerging evidence suggesting these effects may be driven by modulation of neuroinflammation. However, the cellular mechanisms underlying GLP-1RA effects on neuroinflammation remain poorly understood. Here we show, using a mouse model of lipopolysaccharide-induced neuroinflammation, how semaglutide coordinates cellular responses to resolve neuroinflammation. We find that semaglutide in male mice prevents brain infiltration of neutrophils, excessive cytokine release, and suppresses neuroinflammation-associated transcriptional signatures specifically in microglia, endothelial cells, and a subset of pericytes. Mechanistically, we identify a subset of Glp1r-expressing neurons in the dorsal vagal complex that, upon semaglutide treatment, regulate genes involved in anti-inflammatory signaling. Semaglutide-modulated pathways overlap with inflammatory signatures found in human neurodegenerative diseases, including Alzheimer's disease, suggesting broad relevance for conditions involving neuroinflammation. Together, these findings reveal how GLP-1R signaling in male mice orchestrates resolution of neuroinflammation through coordinated multi-cellular programs.

DOI: https://doi.org/10.1038/s41467-026-74038-4
Neuron. 2026 Jun 09. pii: S0896-6273(26)00386-7. [Epub ahead of print]

Epigenetic control of microglial mitochondrial immunity by KAT7 drives Alzheimer's disease pathogenesis.

Yongqing Liu, Yingzhi Ye, Minghua Fan, Henry Yi Cheng, Shuying Sun, Zhaozhu Qiu.

  Mitochondrial DNA (mtDNA)-driven innate immune signaling sustains chronic neuroinflammation in neurological diseases such as Alzheimer's disease (AD), yet how this pathway is regulated in microglia remains poorly understood. Here, we identify the histone acetyltransferase KAT7 (HBO1) as a central epigenetic regulator that links chromatin remodeling to mitochondrial immune activation. KAT7 and its histone mark H3K14ac are elevated in microglia from 5×FAD mice and human AD brains. Integrative transcriptomic and epigenomic analyses reveal that KAT7 activates transcription of cytidine/uridine monophosphate kinase 2 (Cmpk2), a mitochondrial kinase essential for mtDNA synthesis. Loss of KAT7 reduces Cmpk2 expression, impairs mtDNA replication and release, and consequently suppresses cyclic guanosine monophosphate-AMP synthase (cGAS)-stimulator of interferon genes (STING) and NLRP3 signaling. Importantly, both microglia-specific deletion and pharmacological inhibition of KAT7 mitigate cytosolic mtDNA-induced neuroinflammation, decrease β-amyloid burden, restore synaptic plasticity, and improve cognitive function in 5×FAD mice. Together, these findings uncover an epigenetic-mitochondrial axis sustaining microglial pathogenicity and establish KAT7 as a potential therapeutic target for AD.

Keywords:  Alzheimer’s disease; CMPK2; KAT7; cGAS-STING; microglia; mitochondrial DNA; neuroinflammation

DOI:  https://doi.org/10.1016/j.neuron.2026.05.015
Neuron. 2026 Jun 11. pii: S0896-6273(26)00385-5. [Epub ahead of print]

Single-cell proteome atlas of aging mouse microglia reveals subpopulation-specific phagoproteome.

Haoran Zhang, Zhen Liu, Bijia Chen, Guangxin Zhang, Longteng Wang, Changsheng Wei, Xiaohui Zhang, Yuxiang Luo, Ting Peng, Qing Fang, Lei Gu, Ruicheng Ge, Jiangning Zhu, Ruiying Yang, Weiguo Shen, Zhujun Jiang, Yufang Sun, Weixun Duan, Jincheng Liu, Tingting Li, Jing Wang, Zhihua Gao, Xiang Yu, Hebing Chen, Zilu Ye, Xiaomeng Shi, Cheng Li.

  Microglia are brain-resident immune cells with complex physiological functions. Exploring their proteomic heterogeneity at the single-cell level has remained technically challenging. Here, we optimized a label-free single-cell proteomics (SCP) workflow using Orbitrap Astral mass spectrometry (MS) and applied it to fluorescence-activated cell sorting (FACS)-sorted microglia from the hippocampus and prefrontal cortex of young, middle-aged, and aged mice. This yielded one of the largest SCP datasets to date, comprising 3,085 single cells, with an average of 1,153 protein groups identified per cell. Compared with single-cell transcriptomic data, the SCP dataset showed higher expression completeness and moderate cross-modality correlation. This dataset revealed spatiotemporal proteomic heterogeneity of microglia during aging. Notably, we defined the microglial "phagoproteome," uncovering state-specific phagocytic preferences, and verified these results by imaging. This study underscores the potential of SCP to reveal subpopulation-specific proteomic dynamics and provides a new resource for studying microglial state transitions during aging.

Keywords:  brain aging; mass spectrometry; microglia heterogeneity; single-cell proteomics

DOI:  https://doi.org/10.1016/j.neuron.2026.05.014
Adv Sci (Weinh). 2026 Jun 11. e76038

Intrinsically Mitochondria-Targeting Nanozyme via Coordination-Assembly of Natural Quercetin for Cascade Antioxidant Therapy of Cerebral Ischemia-Reperfusion Injury.

Wenxuan Zheng, Zhicheng Wang, Xin Zhou, Shuya Wang, Xiaojing Shi, Tingli Xiong, Ruishi Li, Yuting Lin, Zhen Chen, Jiawen Wei, Fei Li, Jinwen Ge, Kelong Ai, Chong Liu, Guiming Deng.

  Mitochondrial dysfunction, culminating in oxidative stress-driven release of mitochondrial DNA (mtDNA) and subsequent inflammatory activation, constitutes a central pathogenic axis in cerebral ischemia-reperfusion injury. Disrupting this axis requires precise antioxidant delivery to neuronal mitochondria, a major therapeutic hurdle. Here, we uncover that the natural flavonoid quercetin (Quer) possesses an intrinsic ability to bind mitochondrial outer membrane proteins, revealing its unexploited potential as a natural mitochondrial-targeting ligand. Leveraging this discovery, we engineered an ultrasmall mitochondria-targeting cascade nanozyme through coordination-driven self-assembly of the natural flavonoid Quer with Fe3+. MCN currently generates Fe2+/Fe3+ dual-valence centers that confer potent, superoxide dismutase-catalase cascade catalytic enzyme activities. We further confirmed that the MCN traverse the compromised blood-brain barrier, localize within the ischemic brain, and are selectively delivered to neuronal mitochondria in a rodent stroke model. Through its cascade elimination of key ROS, MCN stabilizes mitochondrial function and prevents mtDNA leakage. By blocking the released mtDNA from activating the cGAS-STING pathway in microglia, MCN reprograms the neuroinflammatory microenvironment and robustly attenuates brain injury, leading to significant functional recovery. This work establishes a paradigm of transforming inherent bioactivity of natural products into targeted catalytic nanomedicines, offering a precise therapeutic strategy for mitochondrial-centric diseases.

Keywords:  cGAS‐STING pathway; cerebral ischemia/reperfusion injury; mitochondria‐targeting nanozymes; mtDNA; neuroinflammation

DOI:  https://doi.org/10.1002/advs.76038
Adv Sci (Weinh). 2026 Jun 09. e75995

Targeting Dnmt3a/m5C/RelA Axis Attenuates Microglia Inflammatory Response and Improves Postoperative Recovery in Chronic Compressive Cervical Spinal Cord Injury.

Tianyu Qin, Yuan Jiang, Yongheng Xie, Huanwei Qu, Wenbin Yan, Jingle Chen, Yining Chen, Huayi Li, Naibo Feng, Jiajun Wu, Chao Zhang, Zhengqi Huang, Ming Shi, Zhihuai Deng, Guozhi Xiao, Houqing Long.

  Chronic compressive cervical spinal cord injury (cCSCI) is a major cause of adult spinal cord dysfunction. Surgical decompression is the primary treatment; however, microglia-driven neuroinflammation often hampers postoperative recovery. This study was conducted to investigate the role of 5-methylcytosine (m5C) in sustaining pro-inflammatory microglial states following decompression. Using a mouse cCSCI model, we performed single-nucleus RNA sequencing (snRNA-seq) to map microglial states, calculated an m5C-regulator activity score, and validated m5C changes via dot blot. We examined the Dnmt3a-RelA pathway in primary microglia through siRNA knockdown, m5C-RIP, and mRNA stability assays. Therapeutic potential was assessed with intrathecal AAV-shDnmt3a. SnRNA-seq revealed a dominant pro-inflammatory microglial subpopulation (C1) post-decompression, enriched for NF-κB signaling. The C1 subset exhibited an elevated m5C score and increased Dnmt3a expression. Dnmt3a knockdown reduced m5C enrichment on RelA transcripts, destabilized RelA mRNA, and suppressed NF-κB activation. In vitro, Dnmt3a silencing reduced pro-inflammatory marker expression and cytokine release, and microglia-targeted AAV-shDnmt3a improved neurological recovery in cCSCI mice. These findings underscore the potential of targeting the microglia Dnmt3a/m5C/RelA axis to enhance postoperative recovery.

Keywords:  Dnmt3a; chronic compressive spinal cord injury; gene therapy; m5C; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/advs.75995
Alzheimers Dement. 2026 Jun;22(6): e71543

Porphyromonas gingivalis disrupts hippocampal circadian clock via PI3K/AKT pathway, exacerbating Alzheimer-like pathology.

Chunmei Huang, Qin Cai, Zeru Feng, Chenze Zhang, Zhiqiang Luo, Xingqun Cheng, Hongkun Wu.

   INTRODUCTION: Periodontal pathogen Porphyromonas gingivalis is epidemiologically linked to Alzheimer's disease (AD), yet how oral infection disrupts the central circadian clock to drive hippocampal neurodegeneration remains unknown.
METHODS: C57BL/6 mice received oral P. gingivalis for 6 months; hippocampal clock gene oscillations, phosphorylated protein kinase B (p-AKT), glial fibrillary acidic protein (GFAP)/Ionized calcium-binding adapter molecule 1 (Iba1), and amyloid beta (Aβ) load were quantified. C8-D1A astrocytes and BV2 microglia were infected with P. gingivalis ± phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT inhibitor or agonist; Bmal1 (brain and muscle ARNT-like 1)/Clock (circadian locomotor output cycles kaput) were knocked down by lentivirus.
RESULTS: P. gingivalis-induced periodontitis dampened hippocampal Bmal1 rhythms, lowered p-AKT, activated glia, and elevated Aβ and interleukin 1β (IL-1β). In glial cells, P. gingivalis flattened Bmal1 oscillation; PI3K blockade mimicked these effects, whereas AKT agonist restored rhythms and suppressed GFAP/Iba1/IL-1β. Bmal1 knockdown alone triggered glial activation and cytokine release.
DISCUSSION: P. gingivalis oral infection suppresses PI3K/AKT signaling, destabilizing glial circadian clocks and unleashing neuroinflammation that fosters hippocampal AD-like pathology; rescuing PI3K/AKT or clock function may mitigate the oral-brain axis in AD.

Keywords:  Alzheimer's disease; PI3K/AKT signaling pathway; astrocyte activation; circadian clock; microglial activation; neuroinflammation; periodontitis

DOI:  https://doi.org/10.1002/alz.71543
Alzheimers Dement. 2026 Jun;22(6): e71579

Early microglial response to amyloid plaques drives sleep loss in Alzheimer's disease.

Nicholas J Constantino, Riley E Irmen, Matthew J Lanning, Sierra M Turner, Clair C Ashley, Caitlin M Carroll, Evan M Neary, Dave Rubinow, J Andy Snipes, Shannon L Macauley.

   INTRODUCTION: Sleep disruption is an early feature of Alzheimer's disease (AD), but the cellular mechanisms linking amyloid pathology to sleep loss remain unclear.
METHODS: Electroencephalography/electromyography (EEG/EMG) recordings, quantitative EEG analysis, and sleep deprivation were performed in APPswe/PSEN1dE9 (APP/PS1) mice at different stages of pathology relative to normal aging. Amyloid burden and microglial density were quantified with whole-brain light-sheet microscopy. CSF1R-mediated microglial depletion explored effects of microglia on sleep loss.
RESULTS: Amyloid plaques caused non-rapid eye movement (NREM) sleep loss that did not worsen with increased plaque burden. Aging reduced REM sleep and eliminated sleep rebound. Amyloid pathology was associated with cortical hyperexcitability, network desynchrony, and microglial expansion extending beyond plaque-bearing regions into thalamocortical and white matter networks governing sleep-wake dynamics. Microglial depletion restored > 2 hours of sleep per day without altering amyloid burden.
DISCUSSION: Microglia are a causal, reversible driver of amyloid-associated sleep loss, positioning sleep and EEG-based metrics as sensitive biomarkers of presymptomatic AD.

Keywords:  aging; amyloid plaques; amyloid‐beta; microglia; sleep

DOI:  https://doi.org/10.1002/alz.71579
Genome Med. 2026 Jun 10.

Infiltrating monocyte-derived macrophages does not survive long term in stroke brain despite their dominance in the acute ischemic core and myeloid derived IGF-1 play dichotomous roles in stroke recovery.

Hongli Ma, Nicolas Hugues, Kirsten Voice, Joshua Peter, Aleksandr Taranov, Christina Thapa, Krishna Roskin, Yu Luo.

   BACKGROUND: Ischemic stroke elicits a strong neuroinflammatory response characterized by activation of microglia and infiltration of monocytes-derived macrophages (iMM), which have been speculated to have differential functions in stroke. However, because the gene expression profiles of microglia and iMM overlap in the injured brain, distinguishing these two cell populations has posed a challenge for the field.
METHODS: Using a recently characterized microglia-specific TMEM119CreER-Ai14 tdTomato reporter mouse model and single cell RNA sequencing (scRNA-seq) analysis, we prelabeled microglia in the brain prior to stroke, enabling detailed characterization of the transcriptomic and spatial distributions of microglia vs. iMM across different stages of post-stroke. ScRNA-seq findings were validated through immunohistochemistry, RNAscope, and animal models.
RESULTS: Here, we report that microglia and iMM are enriched at distinct locations and exhibit differential temporal dynamics in the stroke brain. Our genetic tracing data reveals that iMM does not survive in the chronic stroke brain past 30 days in our model. Additionally, scRNA-seq further revealed distinct transcriptomic states between microglia and iMM at D7 and D14 in the stroke brain. Genetic tracing also allowed us to identify novel markers for activated microglia vs. iMM in the acute stroke brain such as Gm21188. Finally, our data also showed that Igf1 is up-regulated in both microglia and iMM after stroke. Cx3cr1ERT2 Igf1fl/fl mediated myeloid-specific Igf1 gene deletion at 5-9 Days after stroke lead to decreased CD8+ T-cell infiltration in the stroke brain. Functionally, myeloid specific Igf1 iKO mice show expedited sensorimotor function recovery but worsened anxiety-like behavior.
CONCLUSIONS: In summary, Tmem119CreER-Ai14 tdTomato reporter mouse line is a useful tool for the field to clearly delineate the cellular dynamics and transcriptomic profiles of microglia vs. iMM in a variety of central nervous system pathological conditions, which could have broad implications beyond stroke studies. Moreover, we have characterized novel subtypes and markers for activated microglia and iMM, as well as a possible novel role for myeloid cell-derived IGF-1 in driving T-cell infiltration and/or survival in the post-stroke brain. This study provides valuable insights for future investigations aimed at modulating microglia vs. iMM to promote stroke resolution and functional recovery in vivo.

Keywords:  Infiltration of monocytes-derived macrophages (iMM); Ischemic stroke; Igf1 ; Microglia; Single-cell RNA sequencing

DOI:  https://doi.org/10.1186/s13073-026-01687-x
Cell Rep Med. 2026 Jun 12. pii: S2666-3791(26)00284-3. [Epub ahead of print] 102867

Psilocybin restores behavior and 5-HT2A signaling while reducing microglial density after chronic traumatic brain injury in rats.

Josh Allen, Bianca Jupp, Tamara L Baker, Mohammad B Haskali, Robert Brkljača, Zoe Plummer, Mujun Sun, Justin Brand, Brian R Christie, Chantel T Debert, Stuart J McDonald, Terence J O'Brien, Pablo M Casillas-Espinosa, Sandy R Shultz.

  Traumatic brain injury (TBI) causes persistent neurobehavioral deficits and increases the risk of psychiatric disorders, including depression, anxiety, and cognitive dysfunction linked to disrupted neuroplasticity, neuroinflammation, and serotonergic (5-HT) signaling. No effective pharmacotherapies exist for chronic TBI. Psilocybin, a psychedelic 5-HT2A receptor agonist, shows promise due to its neuroplasticity-enhancing, anti-inflammatory, and antidepressant effects. Here, male rats received fluid-percussion or sham injury, followed one year later by a single psilocybin (1 mg/kg) or saline injection. Behavioral testing began 24 h later, and positron emission tomography assessed 5-HT2A binding after two weeks. TBI produced persistent sensorimotor, learning and memory, and affective deficits; reduced 5-HT2A binding; and microglial alterations in the medial prefrontal cortex characterized by decreased process branching and enlarged soma size. Psilocybin treatment could improve sensorimotor function, restore 5-HT2A binding, and reduce microglial cell counts. These findings highlight psilocybin's therapeutic potential in chronic TBI and support further investigation of psychedelic treatments.

Keywords:  IBA1; PET; concussion; fluid-percussion injury; microglia; positron emission tomography; psychedelic; serotonin receptor

DOI:  https://doi.org/10.1016/j.xcrm.2026.102867
J Nanobiotechnology. 2026 Jun 11.

Cel-LDH dual-functional nanotherapy simultaneously promotes microglial efferocytosis and alleviates neuronal apoptosis for spinal cord injury recovery.

Nuo Chen, Lufeng Yao, Le Zou, Qiuchen Wang, Yaning Li, Junjun Luo, Mengting Zhan, Kailiang Zhou, Jian Xiao, Songlin Tong, Hongyu Zhang, Liangliang Yang, Lu Ge.

  Traumatic spinal cord injury (SCI) can cause severe central nervous system damage. Efferocytosis, an intrinsic regulatory mechanism through which microglia eliminate apoptotic cells, is suppressed because of the local ischaemic and hypoxic microenvironment after spinal cord injury (SCI). In addition, hypoxia and reoxygenation (H/R) trigger mitochondrial respiratory chain electron leakage, leading to the massive generation of mitochondrial reactive oxygen species (mtROS), impairing the energy supply and causing oxidative stress damage in neurons, which induces neuronal apoptosis. Synergistic therapies targeting efferocytosis and neuronal apoptosis are important for recovery after SCI. In this study, by loading celastrol in a layered double hydroxide, a multifunctional nanoparticle, Cel-LDH, was developed to facilitate SCI recovery by concurrently normalizing efferocytosis homeostasis and inhibiting neuronal apoptosis. Cel-LDH composite nanoparticles strongly scavenged ROS and preserved mitochondrial homeostasis, thus regulating apoptosis-related proteins, including Bax and Bcl-2, and effectively inhibiting the apoptotic process of neurons. Furthermore, Cel-LDH nanoparticles promoted autophagy, inhibited the cyclic GMP-AMP (cGAMP) synthase (cGAS)-stimulator of interferon genes (Sting) pathway to modulate the anti-inflammatory phenotypic transformation of microglia, and subsequently restored the efferocytosis homeostasis of microglia, thus suppressing inflammatory cascades and creating favourable microenvironments for the repair of SCI. This approach not only remodels the dysfunctional efferocytosis capacity but also inhibits neuronal apoptosis, providing a new therapeutic strategy for SCI.

Keywords:  Apoptosis; Celastrol; Efferocytosis; Mitochondria; Spinal cord injury

DOI:  https://doi.org/10.1186/s12951-026-04641-6
J Hazard Mater. 2026 Jun 08. pii: S0304-3894(26)01618-3. [Epub ahead of print]514 142640

Microcystin-LR induces dopaminergic neurodegeneration by MyD88-dependent neuroinflammation in zebrafish (Danio rerio).

Ya He, Kang Ou-Yang, Hui Yang, Liangmou Wang, Mengya Li, Dapeng Li, Li Li.

  Microcystin-LR (MC-LR) is a potent neurotoxin released by cyanobacterial blooms, posing significant threats to aquatic ecosystems and human health. However, the molecular mechanisms driving its dopaminergic neurodegeneration remain elusive. Herein, we demonstrated that chronic MC-LR exposure (60 days, 10 μg/L) to zebrafish exhibited motor deficits and anxiety-like behaviors. MC-LR also disrupted Nissl body integrity, reduced dopamine (DA) and its metabolites (HVA, DOPA), and suppressed key dopaminergic markers (TH, DAT and DRD1). These changes collectively impaired DA synthesis, transport and signaling cascades. Pathologically, MC-LR triggered robust neuroinflammation, evidenced by neuronal phagocytosis, microglial proliferation and elevated pro-inflammatory cytokines (TNF-α and IL-1β). Transcriptomic profiling, combined with computer simulation and CESTA, identified MyD88 as a master regulator of MC-LR-induced neuroinflammation. This finding was validated using both in vitro co-culture models (HMC3 microglia/SH-SY5Y neurons) and in vivo myd88 knockdown experiments. Notably, MC-LR promoted microglial M1 polarization via the MyD88/NFκB pathway, directly damaging dopaminergic neurons. Crucially, echinacoside (ECH) exerted potent neuroprotection by suppressing microglia activation, inhibiting MyD88/NFκB signaling, and restoring DA levels to controls. Together, these findings unveil a previously unrecognized pathway linking MC-LR exposure to inflammation-driven neurodegeneration, positioning MyD88 as a novel therapeutic target and ECH as a promising candidate against cyanotoxin-induced neurotoxicity.

Keywords:  Behavior; Dopamine neurons; Echinacoside; Microcystin-LR; Neuroinflammation

DOI:  https://doi.org/10.1016/j.jhazmat.2026.142640
EBioMedicine. 2026 Jun 09. pii: S2352-3964(26)00207-0. [Epub ahead of print]129 106325

The complement C3-microglial axis in depression of Parkinson's disease: from mechanism to therapeutic intervention.

Qiao Yin, Mengyang Ding, Yurui Tang, Yuwan Qi, Yuan Qin, Hong Jin, Yang Li, Jili Bao, Shuyang Ma, Ying Li, Haozhe Ding, Xinyu An, Enyou Qiao, Yan Tang, Qilin Zhang, Linna Wang, Jianfeng Shao, Jianfeng Feng, Li-Fang Hu, Jing Wang, Pan Fang, Weifeng Luo, Qifei Cong.

   BACKGROUND: Depression is a common and early non-motor symptom of Parkinson's disease (PD) with significant sexual dimorphism, yet its underlying molecular mechanisms remain poorly understood. This study aimed to elucidate the sex-specific plasma proteomic profiles of depression in patients with PD (DPD) and to investigate the role of complement-mediated synaptic pruning in its pathophysiology.
METHODS: Plasma proteomic analysis was performed on data from the Parkinson's Progression Markers Initiative (PPMI) and an independent validation cohort, stratified by sex. Functional enrichment analyses identified dysregulated pathways. A chronic MPTP/probenecid-induced mouse model of PD was used to validate findings. Behavioural tests assessed motor and depressive-like phenotypes. Proteomic, biochemical, and imaging techniques were used to evaluate protein expression, synapse density, and microglial phagocytosis. The therapeutic mechanism of Botulinum Neurotoxin A (BoNT/A) on DPD was investigated in wild-type, C3-/- and C3aR-/- mice and in microglial cultures.
FINDINGS: Proteomic profiling revealed both conserved complement-driven immune dysfunction and profound sex-divergent molecular perturbations underlying PD and DPD. Complement and coagulation cascades were consistently upregulated in both sexes. In MPTP-treated male and female mice, hippocampal complement components (C1Q, C3, C3aR) and downstream signalling (p-STAT3, p-P65) were elevated, accompanied by microglial synapse phagocytosis and depressive-like behaviours. Genetic deletion of C3 rescued both MPTP-induced motor and depressive-like behavioural deficits and prevented hippocampal synaptic loss associated with microglial synaptic engulfment. BoNT/A treatment alleviated depressive-like behaviours and reduced microglial synaptic engulfment in an MPTP model; these therapeutic effects were abolished in C3-/- and C3aR-/- mice. Single-cell RNA sequencing and in vitro phagocytosis assay confirmed that BoNT/A modulated phagocytosis-related microglial subclusters.
INTERPRETATION: DPD exhibits distinct sex-specific immune signatures, with convergent complement pathway activation driving microglial synaptic pruning and depressive symptoms. The antidepressant effect of BoNT/A is mediated through inhibition of the C3-C3aR signalling axis. These findings highlight the potential for sex-stratified diagnostics and complement-targeted therapies for depression in patients with PD. A key limitation is that our clinical analyses were constrained by limited validation cohort sizes, and mechanistic studies were limited to male mice, which may restrict the generalisability of our findings to female populations.
FUNDING: National Natural Science Foundation of China, Key Project of the Natural Science Foundation of Jiangsu Provincial Higher Education Institutions, Project of Biomedical Basic Research Center (BBRC) of Jiangsu, Clinical Research Center of Neurological Disease in The Second Affiliated Hospital of Soochow University, Project of MOE Key Laboratory of Geriatric Diseases and Immunology, Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases; The Lingang Laboratory fund; Shanghai Science and Technology Innovation Sailing Special Project, and Shanghai Municipal Science and Technology Major Project; Zhejiang Provincial Natural Science Foundation of China.

Keywords:  Botulinum neurotoxin A; C3–C3aR signalling; Depression in Parkinson's disease; Microglia; Plasma proteomics; Synaptic pruning

DOI:  https://doi.org/10.1016/j.ebiom.2026.106325
Proc Natl Acad Sci U S A. 2026 Jun 16. 123(24): e2535879123

Targeting the cGAS-STING pathway mitigates Huntington disease pathogenesis in a knock-in mouse model.

Anuradha Kesharwani, Sunayana Dagar, Isabella Zuniga, Marianne Charlene Monet, Ganesh Halade, Gunjan Upadhyay, Uri Nimrod Ramírez-Jarquín, Violeta Gisselle Lopez-Huerta, Emaad Mirza, Ning Quan, Srinivasa Subramaniam.

  Cyclic GMP-AMP synthase (cGAS) and its downstream effector, stimulator of interferon genes (STING), form a key cytosolic DNA-sensing pathway that drives innate immune activation and proinflammatory signaling. We previously showed that cGAS is upregulated in Huntington disease (HD) cellular models, where it regulates autophagy and inflammation; however, its in vivo role remained unclear. Here, we genetically ablated cGAS in Q175DN knock-in HD mice and performed longitudinal behavioral assessments from 2 to 14 mo of age. cGAS deletion significantly improved HD-associated motor deficits, including rotarod performance and beam-walk coordination, and mitigated progressive body-weight loss. Histological analyses revealed reduced lateral ventricle enlargement and decreased striatal astrogliosis and microgliosis. While minimal effects were observed in wild-type littermates, transcriptomic profiling of HD brains lacking cGAS showed downregulation of genes involved in development and cell-cell communication, along with upregulation of genes linked to ion transport and synaptic function. Lipidomic analysis further demonstrated increased levels of immunoregulatory lipids, particularly 12-HETE and 12-HEPE, indicating a shift toward a protective lipid profile. Importantly, pharmacological inhibition of STING using H-151 improved age-dependent motor performance, reduced striatal atrophy, and attenuated glial cell activation in Q175DN mice. Collectively, these findings identify the cGAS-STING pathway as a critical driver of HD progression and support its inhibition as a promising therapeutic strategy.

Keywords:  DNA damage; cGAS-STING; gene regulation; microglial polarization; neuronal vulnerability

DOI:  https://doi.org/10.1073/pnas.2535879123
J Neuroinflammation. 2026 Jun 12.

C1q-CD44 interactions regulate microglial phagocytosis, proliferation, and migration.

Pooja S Sakthivel, Alyssa J Villegas, Anita Lakatos, Meghana Kaipa, Julian M Lopez, Ashley Ling, Zeina H Elrachid, Josh Karam, Aileen J Anderson.

Microglia, the immune cells of the central nervous system (CNS), quickly respond to neurodegeneration by proliferating and migrating to areas of disease, phagocytosing debris, and releasing cytokines to initiate inflammation. Critically, the mechanisms underlying these microglial functions remain only partly understood. One molecular regulator of interest is complement protein C1q, the initiator molecule of the complement cascade that increases 300-fold in healthy aging and accumulates with neurodegeneration. We have previously reported that exogenous C1q treatment alters inflammatory gene expression and cell function in human induced pluripotent stem cell-derived microglia (iMG). Here, we test the hypothesis that C1q induced cell changes are modulated by novel C1q receptor, CD44. We first confirmed expression of five novel C1q receptors at the RNA and protein levels, and then validated C1q-receptor binding on the iMG cell surface using proximity ligation assay. Based on these results, we selected CD44 as an initial target and generated CD44 knockout iMG to test the role of CD44 in the iMG response to C1q. We demonstrate that C1q-CD44 interactions regulate changes in microglial phagocytosis, proliferation, and migration. These data suggest C1q interacts with CD44 to modulate microglial functions that are critical to health and disease, thus informing future directions to test whether these interactions are altered in neurodegenerative disease.

DOI: https://doi.org/10.1186/s12974-026-03892-2
J Neuroinflammation. 2026 Jun 09.

Ischemic injury triggers a protective microglial phenotype in models of Aβ pathology.

Michael Candlish, Jan Hofmann, Desirée Brösamle, Annika Haessler, Murphy DeMeglio, Angelos Skodras, Georgi Tushev, Eloah S De Biasi, Stefan Günther, René Wiegandt, Heidi Theis, Elena De Domenico, Nina Sofia Hermann, Peter Breunig, Christina Sauerland, K Peter R Nilsson, Marc D Beyer, Mario Looso, Maike Windbergs, Sigrun Roeber, Jochen Herms, Jonas J Neher, Andreas G Chiocchetti, Jasmin K Hefendehl.

  Microglia are highly plastic cells that are capable of integrating subsequent insults. As the majority of Alzheimer's Disease (AD) patients also show cerebrovascular pathology, we here aimed to dissect the interactions between AD and ischemic brain injury on the microglial response to amyloid beta (Aβ) pathology. Unexpectedly, ischemic stroke in the context of cerebral β-amyloidosis drives the emergence of a neuroprotective microglial phenotype characterized by an ApoE-enriched transcriptional state and enhanced lipid handling. These microglia promote the rapid formation of highly compact Aβ plaques that are relatively inert and strikingly reminiscent of those observed in cognitively resilient AD patients. Our findings thus reveal that the microglial response to Aβ pathology is not a fixed trajectory toward dysfunction, but retains a capacity for beneficial reprogramming when engaged by the appropriate stimulus. Beyond characterizing this comorbid state, our data identify specific molecular pathways, centered on ApoE, complement activation, and lysosomal processing, that may be amenable to therapeutic targeting to promote protective microglial function in AD.

Keywords:  Alzheimer’s disease; Co-morbidity; Microglia; Stroke

DOI:  https://doi.org/10.1186/s12974-026-03897-x
ACS Sens. 2026 Jun 09.

A Polarity-Sensitive Lipid Droplet Probe Reveals Aβ Species-Dependent Lipid Droplet Remodeling in Microglia.

Panyi Hu, Shuo Guo, Youxiang Ren, Rui Zhao, Liping Su, Jiahan Cheng, Xiaohe Tian.

  Microglial lipid metabolic alterations are increasingly implicated in Alzheimer's disease (AD), yet the specific β-amyloid (Aβ) species involved in lipid droplet (LD) remodeling remain unclear. Precise visualization of LD morphology in complex biological systems is limited by the availability of selective and photostable probes. Herein, we report a polarity-sensitive LD probe, BODIPY-LD, constructed with a donor-π-acceptor-π-donor (D-π-A-π-D) framework that enables hydrophobic targeting and intramolecular charge transfer (ICT)-based fluorescence activation in low-polarity environments. The probe allows high-contrast visualization and quantitative assessment of LD morphology in cells and brain tissues. Using BODIPY-LD, we observed increased LD burden in hippocampal microglia of APP/PS1 mice and systematically compared the effects of different Aβ25-35 assembly states on LD accumulation in BV2 microglia. Among monomeric, oligomeric, and fibrillar Aβ25-35 forms, the monomer-treated BV2 cells showed the most pronounced LD enrichment under our experimental conditions. This LD-rich phenotype was associated with reduced phagocytic capacity and was partially reversible upon inhibition of LD synthesis using the long-chain acyl-CoA synthetases (ACSL) inhibitor Triacsin C. Together, these findings suggest that monomeric Aβ25-35 is associated with an LD-rich microglial phenotype and impaired phagocytic function in vitro model. Beyond this biological observation, BODIPY-LD provides a useful tool for studying lipid remodeling in neuroinflammatory contexts.

Keywords:  Alzheimer's disease; Aβ species; fluorescent probe; lipid droplet; microglial metabolism

DOI:  https://doi.org/10.1021/acssensors.6c01055
Brain Behav Immun. 2026 Jun 11. pii: S0889-1591(26)00613-6. [Epub ahead of print] 106865

Meta-analysis of brain and blood transcriptional signatures of neuroimmune dysregulation in Schizophrenia: convergent evidence for excessive complement system activity and CX3CL1-CX3CR1 axis disruption.

Mohamed-ElMehdi Boughanmi, Louis-Ferdinand Lespine, Marion Leboyer, Caroline Demily, Romain Rey.

   BACKGROUND: Schizophrenia pathogenesis may involve aberrant synaptic pruning mediated by excessive complement system activity (CSA) and altered microglial function. Microglia and CSA are tightly regulated by neuro-immune regulators (NIREGs) which regulate adverse innate response and play a critical role in the regulation of the synaptic pruning process. This study investigated transcriptional alterations of NIREGs in the brain and blood tissues of individuals living with schizophrenia (SZ individuals) vs. healthy controls (HC).
METHODS: Meta-analyses were performed on gene expression data from 532 SZ individuals and 623 HC in postmortem brain tissue, and 197 SZ individuals and 164 HC in peripheral blood. In addition to C4 gene, 9 NIREGs coding genes were analyzed: 3 genes encoding complement regulators (CD46, CD55, CD59), 3 genes encoding "don't eat me signals" (CX3CL1, CD200, CD47) and a further 3 genes encoding their microglial counter-receptors (CX3CR1, CD200R, SIRPα). Exploratory network analysis was performed in brain datasets.
RESULTS: In brain tissue, SZ was associated with C4 overexpression and underexpression of CD46 and CX3CL1. Sex-specific transcriptional differences emerged for CD200 (female-specific) and CD59, CX3CR1 (male-specific). In the peripheral blood, CD46, CD55 and CD59 were overexpressed, while CX3CR1 was underexpressed. Brain and blood showed distinct altered expression patterns. However, disruption of the CX3CL1-CX3CR1 axis was observed in both tissues. Network analyses suggested altered co-regulations between astrocytes and microglia or neurons in SZ individuals.
CONCLUSIONS: Transcription of NIREGs encoding genes is altered in the brain and blood of SZ individuals, suggesting that immune dysregulation in schizophrenia arises from a combination of C4 overexpression and an altered expression of NIREGS. In SZ individuals, blood CX3CR1 underexpression in the peripheral blood may serve as a peripheral biomarker of the brain CX3CR1-CX3CL1 axis disruption.

Keywords:  Blood; Brain; Complement system; Gene expression; Meta-analysis; Microglia; Neuro-immune regulators; Postmortem; Schizophrenia

DOI:  https://doi.org/10.1016/j.bbi.2026.106865
Alzheimers Res Ther. 2026 Jun 09.

Chronic central-targeted Interleukin-6 overexpression promotes hippocampal and cortical neuropathology in the Tg2576 mouse model of Alzheimer's disease.

Carla Canal, Kevin Aguilar, Gemma Comes, Elisenda Sanz, Mercedes Giralt, Paula Sanchis, Juan Hidalgo.

   BACKGROUND: Interleukin-6 (IL-6) is a cytokine detected in the brains and peripheral fluids of both Alzheimer's disease (AD) patients and mouse models, where its levels correlate with amyloid-beta (Aβ) burden and plaque deposition. Interestingly, IL-6 deficiency ameliorates cognitive deficits and attenuates hippocampal neuroinflammation, whereas astrocyte-targeted IL-6 signaling via its soluble receptor accentuates pathological features in AD mouse models. These findings suggest that central IL-6 overexpression may actively drive disease manifestations. However, because IL-6 can also signal through its classical membrane-bound receptor pathway, the overall impact of central IL-6 on AD pathophysiology is still not fully elucidated.
MAIN TEXT: To explore the contribution of central IL-6 overexpression in modulating AD-related mortality, metabolic, behavioral and neuroinflammatory changes in the hippocampus and cortex, we crossed a transgenic mouse model (Tg2576) of Aβ-driven amyloidosis with mice expressing IL-6 under the Glial Fibrillary Acidic Protein promoter (GFAP-IL6), which predominantly targets astrocytes. Chronic IL-6 overexpression reduced inguinal white adiposity in both males and females and decreased body weight in females. Early behavioral alterations were observed in Tg2576 mice, with central-targeted IL-6 overexpression regulating behavior in an age- and sex-dependent manner. Increased cortical and hippocampal Aβ42/Aβ40 ratios, along with gliosis, were observed in aged female and male Tg2576 mice. Interestingly, chronic central-targeted IL-6 overexpression increased cortical and hippocampal Aβ42/Aβ40 ratios while inducing a differential distribution and/or reactivity of astrocytes and microglia in aged Tg2576 mice. In particular, central-targeted IL-6 overexpression resulted in increased overall gliosis in the cortical and hippocampal parenchyma but reduced gliosis in the vicinity of cortical and hippocampal amyloid plaques. Finally, cortical transcriptomic profiling in Tg2576 mice revealed widespread changes in immune, synaptic, and stress response pathways in response to chronic IL-6 overexpression, with cortical neuroinflammatory and neurotransmission-associated gene networks showing sex-dependent differences.
CONCLUSIONS: Our findings emphasize that chronic central-targeted IL-6 overexpression shapes the cortical and hippocampal molecular landscape underlying amyloidosis in both male and female Tg2576 mice. Thereby, we propose IL-6 as a potential target for future AD therapeutic strategies.

Keywords:  Alzheimer’s disease (AD); Amyloid precursor protein (APP); Amyloid-β peptides (Aβ); Glial reactivity; Interleukin-6 (IL-6); Neuroinflammation; Tg2576

DOI:  https://doi.org/10.1186/s13195-026-02101-9
Mater Today Bio. 2026 Jun;38 103239

An integrated nano-delivery platform via baicalein-loaded polydopamine-MOF for enhanced neuroprotection against retinal ischemia reperfusion injury.

Xin Liu, Keke Huang, Zhiqing Lin, Min Tang, Qianyi Lin, Wangdu Luo, Jiaguo Yuan, Junlong Yu, Yujie Rao, Peizeng Yang, Lin Xie.

  Retinal ischemia reperfusion injury (RIRI) presents a complex pathological mechanism involving oxidative stress, neuroinflammation, and retinal ganglion cell (RGC) apoptosis, with current therapies limited by their inability to address these multifaceted cascades. To address this challenge, we engineered microenvironment-responsive nanoparticles, pZIF-8@Bai, by encapsulating baicalein (Bai) within a polydopamine-coated zeolitic imidazolate framework (ZIF-8), The pZIF-8@Bai nanoparticles achieved targeted combination therapy through a sustained-release mechanism, resulting in comprehensive retinal protection: attenuating oxidative damage, promoting microglial M2 polarization, and significantly inhibiting RGC apoptosis. Importantly, functional assessments demonstrated substantial recovery of a-wave and b-wave amplitudes in electroretinography (ERG) and enhanced P1-wave amplitudes in flash visual evoked potential (FVEP) recordings. Mechanistically, proteomic analysis revealed suppression of Nogo-A expression, which modulated NF-κB signaling and the intrinsic apoptotic pathway, involving caspase-8 inhibition and BCL-2/BAX balance restoration. These actions preserved retinal structural integrity and restored visual function, as confirmed by electroretinography, with excellent biosafety profiles, offering a promising multi-target therapeutic strategy for neurodegenerative retinal diseases.

Keywords:  MOF; Oxidative stress; Polydopamine; Retinal ganglion cells; Retinal ischemia reperfusion injury

DOI:  https://doi.org/10.1016/j.mtbio.2026.103239
J Transl Med. 2026 Jun 11.

Long-term polystyrene nanoplastics exposure aggravates retinal inflammation and photoreceptor degeneration through microglial SPP1 signaling and neutrophil extracellular traps formation.

Wenchuan Zhou, Xuanyi Chen, Jiagen Li, Jincan He.

   BACKGROUND: Micro/nanoplastics (MNPs), as emerging environmental contaminants, present a growing concern for human health. This study aims to investigate the effects of polystyrene nanoplastics (PS-NPs) exposure on retinal pathology and underlying mechanisms.
METHODS: Retinal detachment (RD) model was established on adult mice following PS-NPs exposure (10 and 50 mg/L) through drinking water for two months. In vitro, oxygen glucose deprivation (OGD) model was established on BV2 microglia-661W photoreceptor co-culture system following PS-NPs exposure (100 mg/L) for 24 h. SPP1 neutralizing antibody and recombinant protein were administrated by subretinal injection. DNase I and Cl-amidine were utilized to achieve neutrophil extracellular traps (NETs) inhibition. Electroretinogram was used to assess retinal function. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), immunofluorescent staining, western blot analysis and enzyme activity assays were used to analyze photoreceptor apoptosis, microglial responses and oxidative stress. Microglia were purified with CD11b MicroBeads. Transcriptomic profiles of PS-NPs-exposed microglia and human retinas of proliferative vitreoretinopathy (PVR) were analyzed.
RESULTS: PS-NPs were able to breach the blood-retina barrier, disrupt phototransduction, aggravate oxidative stress and apoptosis in RD-induced photoreceptor degeneration model dose-dependently. Mechanistically, PS-NPs exposure triggered retinal inflammation, microglial activation and microglial SPP1-mediated peripheral neutrophil recruitment. SPP1 neutralization mitigated PS-NPs-aggravated chemokine secretion, neutrophil infiltration and NETs formation. Recombinant SPP1 protein treatment heightened neutrophil-driven retinal damage, while this could be partially reversed by chemokine receptor inhibition. NETs inhibition alleviated PS-NPs-exacerbated microglial proinflammatory activation and photoreceptor degeneration. Furthermore, transcriptomic profiling showed parallels between PS-NPs-exposed microglia and human PVR specimens in SPP1 signaling and stress/stimulus response pathways.
CONCLUSIONS: Our findings demonstrated that PS-NPs exposure aggravated retinal inflammation and photoreceptor degeneration by microglial SPP1 signaling activation and NETs formation, underscoring new insights into the effects and potential targets of MNPs exposure on retinal disorders.

Keywords:  Micro/nanoplastics; Microglia; Neutrophil extracellular traps; Retinal degeneration; SPP1

DOI:  https://doi.org/10.1186/s12967-026-08405-6