bims-microg Biomed News
on Microglia in health and disease
Issue of 2026–05–17
twenty papers selected by
Marcus Karlstetter, Universität zu Köln
  1. Sustaining microglial reparative function enhances stroke recovery.
  2. Nanozyme-Switched Efferocytosis Initiation Platform Orchestrates Pathological Network Reprogramming to Promote Functional Recovery after Spinal Cord Injury.
  3. α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
  4. Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
  5. Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination.
  6. Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.
  7. Interplay of glioblastoma cells with microglia shape invasive phenotypes during long-distance invasion.
  8. Nervonic Acid from Malania oleifera Reverses Parkinson's Disease by Regulating Oxidative Stress, Neuroinflammation, and Gut Microbiota.
  9. Pulmonary microbiota-associated formononetin modulates microglial activation in asthma-related anxiety.
  10. IL-1-mediated vitreous inflammation as an early indicator of retinal ganglion cell loss following acute optic nerve injury.
  11. A CSF disease-associated macrophage signature defines progressive multiple sclerosis.
  12. SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
  13. Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota-butyrate-mTORC1-ISR relay along the gut-brain axis.
  14. ABCA1-mediated lipid efflux restrains oxidative stress and neuroinflammation after spinal cord injury.
  15. Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.
  16. Gut microbiota and SCFA dysregulation drive MDPV-induced behavioral and neuroimmune adaptations in male mice.
  17. Exposure to SARS-CoV-2 Spike protein during development induces astrogliosis, synapse loss and long-term cognitive dysfunction in mice.
  18. The natural β-glucan polysaccharide laminarin ameliorates microglial inflammation by metabolic reprogramming through the sirtuin 1/AMP-activated protein kinase axis.
  19. Prostaglandin signaling drives peripheral inflammation-induced reduction of hypothalamic oxytocin-positive neurons.
  20. Single-Cell Sequencing Analysis Reveals Dysregulated Energy Metabolism and Altered Synaptic Connectivity in the Mouse Retina Following Dark Rearing.
  1. Nature. 2026 May 13.
    Sustaining microglial reparative function enhances stroke recovery.
    Jun Tsuyama, Seiichiro Sakai, Kumiko Kurabayashi, Ayaka Nakamura, Eri Tanaka, Yuichiro Hara, Ito Kawakami, Makoto Tsuda, Takahiro Masuda, Marco Prinz, Hideya Kawaji, Takashi Shichita.
      Neurological symptoms after brain injury can remain as lifelong detrimental sequelae because most of the spontaneous recovery response disappears within a few months after the injury1,2. Microglia have an essential role in this process; however, the cellular and molecular mechanisms that diminish spontaneous functional recovery in the brain remain unclear. Here using cellular fate analysis, we show that reparative microglia persist in the brain after a stroke even after losing their beneficial functions. In these cells, ZFP384 is identified as a pivotal transcriptional regulator that diminishes the expression of genes associated with the recovery phase, turning them into dysfunctional microglia that lose their reparative functions. Mechanistically, ZFP384 diminishes the YY1-mediated chromatin interaction necessary to induce the expression of these genes in microglia. The use of antisense oligonucleotides that target Zfp384 can sustain the broad range of neural repair effects of microglia and enhance recovery after stroke, even in the chronic phase of ischaemic stroke. Thus, therapeutics that prevent the loss of reparative immunity-the beneficial restorative functions of immune cells-can prolong functional recovery in the brain.
    DOI:  https://doi.org/10.1038/s41586-026-10480-0
  2. ACS Nano. 2026 May 12.
    Nanozyme-Switched Efferocytosis Initiation Platform Orchestrates Pathological Network Reprogramming to Promote Functional Recovery after Spinal Cord Injury.
    Chang Li, Zheng Cheng, Yanwei He, Chuchu Ma, Yinzhe Sun, Weili Han, Jianing Gong, Xiaoying Xie, Peiqi Huang, Fenfen Ma, Zhihua Wang, Honglian Zhao, Sijian Pan, Shiqiang Tong, Jun Chen.
      Nerve regeneration after spinal cord injury (SCI) is severely hindered by a hostile microenvironment, where excessive reactive oxygen species (ROS) and uncontrolled inflammation form a vicious cycle, triggering secondary injury cascades. However, most current treatments are single-target strategies, obtaining marginal benefits for the intricate pathological mechanisms after SCI. Herein, we developed a nanozyme-switched efferocytosis initiation platform, termed CM-ApoV, by integrating mesenchymal stem cell-derived apoptotic vesicles (ApoVs) with cerium-melatonin nanozymes (Ce-MT). As a distinct subtype of extracellular vesicles, ApoVs are enriched with functional proteins that mediate immunomodulation. Besides, phosphatidylserine (PtdSer) exposed on the surface of ApoVs serves as a critical "eat me" signal that enables targeted recognition and efferocytosis by microglia, thereby promoting microglial repolarization and modulating their functions. Ce-MT nanozymes were anchored onto ApoVs to enhance their ROS scavenging capacity. In the meanwhile, the reversible attachment and detachment of Ce-MT mask PtdSer during systemic circulation and enable re-exposure of PtdSer in an oxidative microenvironment at the injured site. Consequently, the CM-ApoV system comprehensively remodels the pathological network and establishes a favorable microenvironment for neuronal repair. In a rodent model of SCI, CM-ApoV promoted neuronal survival, modulated microglial function, and reduced glial scar formation, ultimately leading to a significant improvement in motor function. Overall, this system highlights the synergistic therapeutic potential of the nanozyme-ApoV hybrid platform and provides a feasible strategy for multidimensional treatment of SCI.
    Keywords:  ROS scavenging; apoptotic vesicles; efferocytosis; mesenchymal stem cells; metal-natural drug nanozymes; spinal cord injury
    DOI:  https://doi.org/10.1021/acsnano.6c05701
  3. Nat Commun. 2026 May 15.
    α-Synuclein aggregates induce mitochondrial damage and trigger innate immunity to drive neuron-microglia communication.
    Ranabir Chakraborty, Stephanie Maya, Veronica Testa, Jara Montero-Muñoz, Takashi Nonaka, Masato Hasegawa, Antonella Consiglio, Chiara Zurzolo.
      Tunneling nanotubes (TNTs) enable direct intercellular transfer of macromolecules, organelles, and pathogenic protein aggregates. While α-synuclein (α-Syn) aggregates are known to promote TNT formation, the underlying mechanisms remain poorly defined. Here, using human neuronal and microglial cell lines, as well as iPSC-derived dopaminergic neurons and microglia, we show that α-Syn aggregates induce severe mitochondrial damage, leading to cytosolic release of mitochondrial DNA (mtDNA) and activation of the cGAS-STING-NF-κB-IRF3 pathway. This innate immune response drives actin cytoskeleton remodeling and the formation of TNT-like structures, promoting intercellular transfer of α-Syn from neurons to microglia. Additionally, neuronal cells transfer damaged mitochondria to microglia, where they undergo lysosome-mediated degradation. Neuron-to-microglia communication under α-Syn-induced stress also triggers a bystander inflammatory response in microglia, suggesting a neuroimmune activation. Our findings identify mitochondrial damage and STING-mediated inflammation as key drivers of TNT formation and α-Syn propagation, highlighting potential targets to modulate disease progression in Synucleinopathies.
    DOI:  https://doi.org/10.1038/s41467-026-73136-7
  4. Nat Commun. 2026 May 12.
    Gpnmb defines a phagocytic state of microglia linked to cell death in prion disease mouse model.
    Davide Caredio, Giovanni Mariutti, Lisa Polzer, Beatrice Gatta, Martina Cerisoli, Yasmine Laimeche, Giulia Miracca, Jeanne Droux, Mohamad El Amki, Marc Emmenegger, Marian Hruska-Plochan, Susanne Wegener, Magdalini Polymenidou, Matthias Schmitz, Inga Zerr, Elena De Cecco, Adriano Aguzzi.
      Neurodegenerative disorders display brain region tropism accompanied by the emergence of distinct cellular states that contribute to disease pathogenesis, with molecular alterations occurring predominantly in glial cells. Here we show the emergence of a microglial state with distinct spatial distribution in the brains of terminally sick prion-infected mice characterized by high expression of Gpnmb (glycoprotein non-metastatic melanoma protein B), transcriptional signatures consistent with phagocytic activity, and increased expression of lysosomal genes in regions undergoing pronounced cell death. We find that this cellular state is not induced by pathological protein aggregates but by soluble factors released by dying cells regardless of the initiating insult. This work defines Gpnmb⁺ microglia as a distinct phagocytic state that links cell death to microglial activation and reveals a generalizable mechanism by which microglia respond to cell loss.
    DOI:  https://doi.org/10.1038/s41467-026-73003-5
  5. Nat Commun. 2026 May 11.
    Neuregulin-1 facilitates myelin regeneration through microglia-mediated mechanisms in a mouse model of chronic demyelination.
    Seyyed Mohyeddin Ziaee, Shiva Nemati, Hardeep Kataria, Elisabet Jakova, Seyed Mojtaba Hosseini, Pejman Ghelich, Graham McLeod, Ali Tamayol, V Wee Yong, Soheila Karimi-Abdolrezaee.
      Impaired myelin repair, or remyelination, is a hallmark of progressive multiple sclerosis (MS) that drives brain degeneration and enduring neurological disabilities. Microglia crucially support remyelination through myelin phagocytosis and lipid metabolism. However, in chronic demyelinated MS lesions, microglia lose their reparative function by acquiring a foamy dysfunctional phenotype characterized by accumulation of lipid droplets due to impaired cholesterol processing of myelin debris. Here, we show a positive correlation between dysregulation of neuregulin-1 and impaired oligodendrocyte remyelination in mice with chronic demyelination. Therapeutic restoration of neuregulin-1 fosters myelin regeneration through microglia-dependent mechanisms. We demonstrate that Nrg-1 signaling supports microglia integrity and function in chronic demyelinated lesions by exploiting their capacity for the clearance of myelin debris and cholesterol recycling, biosynthesis and efflux. These findings signify the promise of neuregulin-1 as an endogenous target to facilitate microglia mediated-repair in progressive MS in which there is an unmet need for new treatments.
    DOI:  https://doi.org/10.1038/s41467-026-72639-7
  6. Neuron. 2026 May 12. pii: S0896-6273(26)00328-4. [Epub ahead of print]
    Secreted GPNMB enhances uptake of fibrillar alpha-synuclein in a non-cell-autonomous process that can be blocked by anti-GPNMB antibodies.
    Marc Carceles-Cordon, Eliza M Brody, Masen L Boucher, Michael D Gallagher, Robert T Skrinak, Travis L Unger, Cooper K Penner, Adama J Berndt, Sromona Das, Katie Lam, Rudolf Jaenisch, Vivianna Van Deerlin, Edward B Lee, Kurt Brunden, Kelvin C Luk, Alice S Chen-Plotkin.
      Glycoprotein nonmetastatic melanoma B (GPNMB) is critical to cellular uptake of pathological forms of alpha-synuclein (aSyn), the hallmark disease protein in Parkinson's disease (PD). Here, we demonstrate that the non-membrane-anchored, extracellular domain of GPNMB can function in a non-cell-autonomous manner. In the human brain, GPNMB is widely expressed in neurons and microglia. In induced pluripotent stem cell-derived microglia (iMicroglia), GPNMB expression and secretion increase with exposure to apoptotic neurons. In the aSyn fibril-seeded model of PD, iMicroglia-derived GPNMB enhances neuronal aSyn uptake and development of aSyn pathology, including in GPNMB knockout neurons. Conversely, anti-GPNMB antibodies rescue neurons from developing aSyn pathology. Finally, in 1,675 human postmortem cases, GPNMB genotypes conferring higher GPNMB expression are associated with more widespread aSyn pathology. Our data suggest a positive feedback loop, where neurodegeneration triggers increased microglial GPNMB secretion, leading to increased neuronal aSyn pathology and neurodegeneration. Importantly, this cycle can be therapeutically interrupted by anti-GPNMB antibodies.
    Keywords:  GPNMB; Parkinson’s disease; aSyn; alpha-synuclein; anti-GPNMB antibody; microglia; neuroinflammation
    DOI:  https://doi.org/10.1016/j.neuron.2026.04.033
  7. Cancer Res. 2026 May 12.
    Interplay of glioblastoma cells with microglia shape invasive phenotypes during long-distance invasion.
    Roland H Friedel, Hongyan Zou.
      Glioblastoma (GBM) infiltration poses a formidable therapeutic challenge, but the mechanisms enabling long distance tumor invasion remain poorly defined. In a recent study, Nebeling and colleagues have leveraged longitudinal three-photon intravital microscopy to visualize the migratory behavior of invading GBM cells and their interactions with microglia. Using an immunocompetent autochthonous murine GBM model for live imaging of contralateral cortex and corpus callosum, the team demonstrated that the migration velocity of GBM cells varied by anatomical location, with tumor cells moving faster in corpus callosum than in cortex. Furthermore, GBM cells with less tumor microtubules (TMs) exhibited higher motility and traveled longer distances than TM-rich cells. Interestingly, the authors also uncovered a stage-dependent, biphasic microglial response to invading GBM cells: enhanced surveillance during sparse infiltration, followed by suppressed surveillance as tumor burden increases. Functional analyses identified chemokine receptor CX3CR1 as a key regulator of microglial reactivity and a requirement of microglia to drive GBM invasiveness. These findings align with earlier evidence that spatial constraints and microglial organization influence GBM invasion. Together, these works highlight a critical role of microglia and the tumor microenvironment in shaping invasive GBM phenotypes and offer new avenues for therapeutic strategies to limit GBM invasion.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-26-2075
  8. Biomater Res. 2026 ;30 0349
    Nervonic Acid from Malania oleifera Reverses Parkinson's Disease by Regulating Oxidative Stress, Neuroinflammation, and Gut Microbiota.
    Yuwen Li, Xiao Peng, Yang Xu, Jingyu Zhao, Yong Chen, Xuesong Liu, Lihua Peng.
      Parkinson's disease (PD) is a neurodegenerative disease characterized by the progressive loss of dopaminergic neurons in the substantia nigra, accompanied by oxidative stress and neuroinflammation. While nervonic acid (NA) is recognized as an essential component of myelin sphingolipids, its specific therapeutic mechanisms in PD have not been thoroughly elucidated. In this study, we investigated the neuroprotective potential of NA derived from Malania oleifera and elucidated its underlying multimechanistic effect. We demonstrated that NA targets the core drivers of neuronal injury by restoring PTEN-induced kinase 1-Parkin-mediated mitophagy to alleviate mitochondrial dysfunction and oxidative stress. Concurrently, NA reprograms microglia from the pro-inflammatory M1 to the anti-inflammatory M2 phenotype, thereby inhibiting cytokine secretion and resolving neuroinflammation. Beyond these central protective effects, metabolomics analysis revealed that NA serves as a direct biosynthetic precursor for long-chain ceramides, facilitating myelin regeneration. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced PD mice, these synergistic mechanisms collectively preserved dopaminergic neurons and improved motor function substantially. Furthermore, 16S ribosomal RNA amplicon sequencing revealed an associative remodeling of the gut microbiota, specifically enriching beneficial genera such as Akkermansia. Collectively, this study establishes NA as a potent multitarget therapeutic that concurrently regulates oxidative stress, neuroinflammation, and myelin regeneration to alleviate PD pathology.
    DOI:  https://doi.org/10.34133/bmr.0349
  9. J Neuroinflammation. 2026 May 11.
    Pulmonary microbiota-associated formononetin modulates microglial activation in asthma-related anxiety.
    Yanbo Liu, Haoyue Zhang, Ying Zhou, Haotian Chen, Xuanyuan Pan, Juan Zhi, Qianyu Wang, Kaixuan Zhao, Weipeng Xia, Dong Yang.
      Asthma is frequently accompanied by anxiety disorders, yet the mechanisms linking asthma to neuropsychiatric symptoms remain poorly defined. Here, we investigated the contribution of the pulmonary microbiota and its metabolites to anxiety-like behavior in an ovalbumin-induced asthma mouse model. Behavioral testing and resting-state functional magnetic resonance imaging revealed anxiety-like phenotypes and altered hippocampal function in a subset of asthmatic mice that were susceptible to anxiety-like behavior. These mice exhibited hippocampal neuroinflammation and neuronal damage, accompanied by dysbiosis of the pulmonary microbiota. Intratracheal transplantation of lung microbiota from anxiety-susceptible donors induced similar behavioral changes in recipient mice, indicating a causal role of the pulmonary microbiota. Untargeted metabolomics identified formononetin as a candidate metabolite positively correlated with the relative abundance of Acidobacteria. Intratracheal administration of formononetin alleviated anxiety-like behaviors, reduced hippocampal inflammation and injury, and restored hippocampal BDNF/TrkB signaling. However, these effects were abolished by the TrkB antagonist ANA-12. Transcriptomic and immunofluorescence analyses suggested that formononetin acts through modulation of hippocampal microglia. In vitro and small RNA sequencing analyses further demonstrated that formononetin promotes BDNF production by downregulating miR-1912-3p, thereby relieving its translational repression in microglia. Together, these findings reveal a lung-brain axis in which a pulmonary microbiota-associated metabolite modulates microglial function to alleviate asthma-related anxiety.
    Keywords:  Anxiety; Asthma; Lung-brain axis; Microglia; Pulmonary microbiota
    DOI:  https://doi.org/10.1186/s12974-026-03863-7
  10. J Neuroinflammation. 2026 May 14.
    IL-1-mediated vitreous inflammation as an early indicator of retinal ganglion cell loss following acute optic nerve injury.
    Shichu Chang, Weijia Fan, Jiahui Wu, Lei Xu, Virginia A Lee, Charlotte Zhang, Edward P Kronenberg, Wenjin Xu, Hu Yang, Hao F Zhang, Xiaorong Liu.
       BACKGROUND: Retinal ganglion cell (RGC) degeneration in optic neuropathies is often preceded by neuroinflammatory changes, yet the earliest in vivo indicators of this process remain poorly defined. Vitreous hyperreflective foci (VHRFs) emerging within 24 h following optic nerve crush (ONC) might represent a promising early in vivo indicator of RGC loss.
    METHODS: VHRFs were longitudinally tracked by visible-light optical coherence tomography (vis-OCT) imaging post-ONC. Whole-eye sectioning, immunohistochemistry, and confocal imaging revealed the identity and migration of the VHRFs. RNAscope in situ hybridization detected cytokine mRNA expression, and IL-1 signaling was pharmacologically inhibited by intracameral administration of an IL-1 receptor antagonist: Anakinra post-ONC. Statistical differences between experimental groups were assessed by Student's t-test, one-way and two-way ANOVA.
    RESULTS: Longitudinal vis-OCT imaging revealed that VHRFs emerged as early as 6 h post-injury and peaked before the significant RGC loss. The VHRFs corresponded to activated amoeboid cells undergoing vertical migration from the outer to inner retina and horizontal movement toward the optic nerve head area. Similar amoeboid cells were also observed in the anterior segment, suggesting a global ocular inflammatory response to the ONC injury. Elevated IL-1β expression was detected in vitreous amoeboid cells, and blockade of IL-1 signaling significantly reduced VHRFs, suppressed microglial migration, and delayed RGC loss.
    CONCLUSIONS: Our findings identify VHRFs as a previously unrecognized early danger signal for RGC degeneration and highlight IL-1-mediated inflammation as a tractable early therapeutic target for preventing RGC degeneration and vision loss.
    Keywords:  Neuroinflammation; Optic nerve crush; Retinal ganglion cell; Retinal microglia; Visible-light optical coherence tomography; Vitreous hyperreflective foci
    DOI:  https://doi.org/10.1186/s12974-026-03860-w
  11. J Neuroinflammation. 2026 May 13. pii: 156. [Epub ahead of print]23(1):
    A CSF disease-associated macrophage signature defines progressive multiple sclerosis.
    Anna-Lena Börsch, Frederike Riethues, Andreas Schulte-Mecklenbeck, Xuesong Wang, Michael Heming, I-Na Lu, Louisa Müller-Miny, Heinz Wiendl, Catharina C Gross, Raphaël Bernard-Valnet, Gerd Meyer Zu Hörste.
       OBJECTIVE: Progression in multiple sclerosis (MS) often corresponds to irreversible disability in MS patients. Cellular changes in the cerebrospinal fluid (CSF) have provided biomarkers and mechanisms in relapsing-remitting MS (RRMS) but remain understudied in primary and secondary progressive MS (summarized herein as PMS).
    METHODS: We combined retrospective flow cytometry of CSF cells from RRMS (n = 169), PMS (n = 56), and non-inflammatory controls (n = 74) with prospective CSF single-cell transcriptomics of 35 individuals (11 controls, 12 RRMS, and 12 PMS) and with confirmatory CSF ELISA. Available CSF single-cell data from age-matched and Alzheimer's disease (AD) patients served as additional controls.
    RESULTS: Proportions of CD14+ monocytes in CSF are increased in PMS and correlated with clinical surrogate markers of progression. Transcriptionally, these monocytes resembled border-associated macrophages (BAM)-like cells with a chronically activated antigen-presenting phenotype. Additionally, these monocytes shared some features with disease-associated microglia/macrophages (DAM), previously identified in neurodegeneration. Induction of DAM-associated molecules, including transcribed and soluble TREM2 (sTREM2), characterized secondary progressive MS (SPMS) and supported its differential diagnosis.
    INTERPRETATION: We thus identified MS stage-specific CSF signatures and shared cellular features of degeneration detectable in CSF of PMS patients.
    Keywords:  Cerebrospinal fluid; Progressive multiple sclerosis; Single-cell RNA-seq
    DOI:  https://doi.org/10.1186/s12974-026-03861-9
  12. J Neuroinflammation. 2026 May 13.
    SLC27A3-dependent lipid metabolic reprogramming by trilobatin suppresses microglial mtDNA/TLR9-driven inflammatory activation in traumatic brain injury.
    Hui-Wen Zhang, Xue-Jie Wang, Mao-Mao Chu, Guang-Yuan Xing, Kai Qiu, Yu-Ge Zhang, Wen-Feng Zhang, Yu-Tong Zhang, Xue Liu, Lei Li, Xiao-Wei Lu, Xin-Xin Huang, Lei-Yang Zhang, Zhi-Yuan Zhang.
      Peri-lesional microglia are particularly sensitive to traumatic brain injury (TBI)-induced disruption of brain lipid homeostasis. This disruption is characterized by elevated levels of acylcarnitines and phospholipids in acute lipidomic profiling, reflecting global lipid alterations. Under physiological conditions, microglial lipid processing involves fatty acid uptake, storage, and mitochondrial oxidation. However, following TBI, excessive fatty acid uptake promotes lipid droplet accumulation, mitochondrial stress, and pro-inflammatory activation. In this study, we investigated whether modulating this process confers therapeutic benefits. Trilobatin (Tri), a natural flavonoid glycoside with potent immunometabolic modulatory activity, markedly reduced neuroinflammation and neuropathological damage while improving motor and cognitive performance in a mouse model of TBI. Integrated transcriptomic and metabolomic analyses revealed that Tri reduced excessive mitochondrial lipid accumulation, alleviated mitochondrial damage, and inhibited mitochondrial DNA release, thereby blocking the TLR9/MyD88/P-P65 pro-inflammatory pathway. Further screening and validation identified that Tri downregulates the lipid transporter SLC27A3, limits excessive lipid uptake, and consequently alleviates microglial pro-inflammatory responses driven by lipid overload. Collectively, these findings establish a link between microglial lipid metabolism and inflammatory activation and support trilobatin as a promising therapeutic agent targeting metabolic-inflammatory crosstalk in acute neural injury.
    Keywords:  Lipid reprogramming; Microglial immunometabolism; Mitochondrial lipotoxicity; Neuroprotection; SLC27A3; Trilobatin
    DOI:  https://doi.org/10.1186/s12974-026-03826-y
  13. J Neuroinflammation. 2026 May 13.
    Butyrate-producing gut bacteria restrain PBAT microplastic-triggered brain microglial lipotoxicity via a microbiota-butyrate-mTORC1-ISR relay along the gut-brain axis.
    Ming-Zhu Wang, Ze-Bang Du, Wen-Qi Xu, Yu-Han Xie, Lei-Lei Wang, Xin-Xin He, Yu-Han Wang, Han-Ying Zheng, You-Liang Yao, Ya-Bin Song, Zhong-Ning Lin, Yu-Chun Lin.
      Eco-friendly poly(butylene adipate-co-terephthalate) (PBAT) is widely marketed as biodegradable, yet the neurotoxicity of derived PBAT microplastics (PBAT-MPs) and their underlying mechanisms remain poorly characterized. Here we identify a previously unrecognized "gut microbiota-butyrate-neuro-lipid" axis linking intestinal PBAT-MPs exposure to hippocampal microglial lipotoxicity and cognitive impairment. By integrating fecal microbiota transplantation (FMT) with multi-omics analyses, we demonstrate that orally administered PBAT-MPs preferentially accumulate in the colon, impair epithelial barrier integrity, deplete butyrate-associated taxa, including Muribaculaceae and Alloprevotella, and enrich Escherichia-Shigella. Butyrate depletion elevates systemic lipopolysaccharide (LPS) levels and, via the gut-brain inflammatory route, activates mTORC1-integrated stress response (ISR) signaling in microglia. Consequently, microglia acquire a lipotoxic phenotype characterized by transcriptional up-regulation of DGAT- and ACSL-dependent lipid droplet (LD) biogenesis genes, accumulation of toxic lipids and inflammatory mediators, synaptic stripping, and memory loss. In vivo butyrate supplementation in PBAT-MP-exposed mice alleviates hippocampal pathology, normalizes microglial lipid accumulation, suppresses neuroinflammation, reduces ceramide levels, and improves cognitive performance. Mechanistically, butyrate inhibits mTORC1, attenuates eIF2α-ATF4-dependent ISR signaling, and represses DGAT/ACSL-dependent LD biogenesis, whereas microglial Rptor overexpression abolishes these protective effects, identifying mTORC1 as an upstream metabolic checkpoint. Collectively, our findings establish the microbiota-butyrate-mTORC1-ISR relay as a core driver of PBAT-MPs-induced neurotoxicity and highlight restoration of butyrate signaling as a promising microbiota-based strategy for preventing microplastic-induced brain lipotoxic injury.
    Keywords:  Butyrate; Gut–brain axis; Microglial lipotoxicity; PBAT microplastics; mTORC1–ISR signaling
    DOI:  https://doi.org/10.1186/s12974-026-03869-1
  14. J Neuroinflammation. 2026 May 15.
    ABCA1-mediated lipid efflux restrains oxidative stress and neuroinflammation after spinal cord injury.
    Yuqi Shao, Jiayun Liu, Jiangyu Zhao, Kaixiao Xue, Xincan Wu, Heng Cao, Rui Bao, Qiancheng Sun, Yuanzhen Zhang, Peng Gao, Mingran Luo, Jian Chen, Guoyong Yin.
      Spinal cord injury (SCI) triggers a persistent inflammatory microenvironment that contributes to secondary tissue damage and neurological dysfunction. However, the metabolic mechanisms sustaining activation of lesion-associated phagocytes remain incompletely understood. Here, we identify lipid-laden microglia/macrophages as a metabolically stressed inflammatory state that emerges after SCI and investigate the role of lipid efflux in regulating this process. Single-nucleus and immune-enriched transcriptomic analyses revealed coordinated upregulation of cholesterol transport and inflammatory pathways in lesion-associated phagocytes. Among lipid transporters, the ATP-binding cassette transporter ABCA1 was consistently induced across post-injury stages. Conditional deletion of ABCA1 in Cx3cr1-lineage cells led to excessive lipid droplet accumulation, enhanced reactive oxygen species production, sustained pro-inflammatory cytokine expression, and impaired locomotor recovery following SCI. To therapeutically target this pathway, we performed structure-guided virtual screening and identified the small molecule Z231 as an ABCA1-binding compound. Pharmacological activation of ABCA1 reduced lipid accumulation, suppressed oxidative stress and inflammatory gene expression, and partially restored mitochondrial metabolic balance in microglia exposed to myelin debris. In vivo, systemic Z231 administration attenuated inflammatory signaling and improved functional recovery after SCI. Together, these findings identify ABCA1-mediated lipid efflux as a key regulator of microglial metabolic stress and neuroinflammation after spinal cord injury, and suggest that targeting lipid handling pathways may represent a potential therapeutic strategy for SCI.
    Keywords:  ABCA1; Lipid efflux; Lipid-laden microglia/macrophages; Redox–inflammatory coupling; Spinal cord injury
    DOI:  https://doi.org/10.1186/s12974-026-03859-3
  15. J Neuroinflammation. 2026 May 12.
    Porcine plasma-derived extracellular vesicles orchestrate multi-target neuroimmune reconfiguration to alleviate Alzheimer's disease pathology in a 5×FAD mouse model.
    Xiaoyang Lu, Yiling Jiang, Xiuqing Lin, Yuanxing Zhang, Qin Liu, Shouwen Chen.
       BACKGROUND: Systemic factors found in young blood possess the capacity to revitalize the aging brain, yet the clinical translation of human-derived therapeutics is severely limited by donor scarcity. We hypothesized that porcine plasma-derived small extracellular vesicles (PpSEVs) could serve as a scalable, cross-species alternative by leveraging evolutionarily conserved bioactive cargoes.
    RESULTS: In this study, we demonstrate that PpSEVs efficiently penetrate the blood-brain barrier and show relative enrichment in the hippocampus CA3 region of 5×FAD mice. Transcriptomic profiling and functional assays reveal that PpSEVs reverse AD pathology by reconfiguring the dysregulated neuroimmune network rather than through broad immune suppression. Specifically, PpSEVs exert a dual-action effect on microglia by blocking caspase-1/GSDMD axis-mediated pyroptosis, while simultaneously enhancing CD68-dependent amyloid-β clearance. This microglial modulation occurs in tandem with the reprogramming of reactive astrocytes, characterized by the downregulation of neurotoxic C3 and the upregulation of neuroprotective S100A10. Furthermore, we identify a direct, glia-independent neurotrophic pathway in which PpSEVs activate neuronal BDNF signaling to rescue synaptic integrity and cognitive function.
    CONCLUSIONS: By demonstrating robust cross-species efficacy without provoking immunotoxicity, our study positions PpSEVs as a potent, multi-target intervention that decouples therapeutic benefits from human donor reliance, paving the way for sustainable, xenogeneic exosome-based AD therapies.
    Keywords:  Alzheimer’s disease; Cross-species therapy; Microglia; Neuroinflammation; Porcine plasma; Reactive astrocyte; Small extracellular vesicles
    DOI:  https://doi.org/10.1186/s12974-026-03866-4
  16. Brain Behav Immun. 2026 May 09. pii: S0889-1591(26)00548-9. [Epub ahead of print]137 106800
    Gut microbiota and SCFA dysregulation drive MDPV-induced behavioral and neuroimmune adaptations in male mice.
    Jincen Liu, Yuying Bai, Yue Feng, Xilin Shao, Haotian Ma, Xinyue Yan, Yudian Ye, Shuguang Wei, Jianghua Lai, Peng Yan.
       BACKGROUND: 3,4-methylenedioxypyrovalerone (MDPV), a synthetic cathinone-derived novel psychoactive substance, exhibits potent stimulant effects and high abuse potential. However, the neurobiological mechanisms underlying MDPV dependence, particularly those involving the gut microbiota, remain unclear.
    METHODS: Male C57BL/6 mice were used to establish an MDPV-induced behavioral sensitization model. Gut microbiota composition and short-chain fatty acids (SCFAs) were analyzed by 16S rRNA sequencing and metabolomics. Antibiotics and fecal microbiota transplantation (FMT) were employed to manipulate microbiota, while valeric acid supplementation was used to assess functional effects. Microglial activation and inflammatory cytokines in the VTA were evaluated.
    RESULTS: Repeated MDPV administration (1 mg/kg) induced robust behavioral sensitization, accompanied by alterations in gut microbiota and SCFA profiles. Antibiotic-induced microbiota depletion abolished sensitization. FMT from control donors attenuated sensitization, whereas FMT from MDPV-treated donors restored it in antibiotic-treated mice. Valeric acid was significantly associated with behavioral outcomes, and its supplementation mitigated sensitization, reduced microglial activation in the VTA, and decreased pro-inflammatory cytokines (IL-1β, IL-6, TNF-α).
    CONCLUSIONS: Gut microbiota and their metabolites, particularly valeric acid, regulate MDPV-induced behavioral sensitization by modulating neuroinflammation and microglial activation. Targeting microbiota-SCFA signaling may offer a potential therapeutic strategy for MDPV -induced neurobehavioral effects.
    Keywords:  Behavioral sensitization; Gut microbiota; MDPV; Microglia; Short-chain fatty acids; Valeric acid
    DOI:  https://doi.org/10.1016/j.bbi.2026.106800
  17. Brain Behav Immun. 2026 May 12. pii: S0889-1591(26)00547-7. [Epub ahead of print] 106799
    Exposure to SARS-CoV-2 Spike protein during development induces astrogliosis, synapse loss and long-term cognitive dysfunction in mice.
    Débora M Portela, Bruna Andrade, Emanuelle V De Lima, Vitor Gayger-Dias, Daniel F Messor, Larissa Daniele Bobermin, Lídia G Paúra, Marcos Romário Matos de Souza, Sanclayver Araujo, Isadora Alonso Corrêa, Beatriz Oliveira de Campos, Vanessa-Fernanda Da Silva, Thomas Michel Sobottka, Daniele Schauren da Costa, Luiz Ricardo Berbert, Luciana J da Costa, Carlos-Alberto Gonçalves, Leda Castilho, Renato S Carvalho, André Quincozes-Santos, Claudia P Figueiredo, Raissa R Christoff, Patrícia P Garcez, Julia R Clarke.
      Exposure to pathogens can be extremely harmful to the developing brain. Even though the Coronavirus Disease-19 (COVID-19) pandemic has subsided, the actual impact of exposure to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during neurodevelopment remains poorly understood. Although vertical transmission of SARS-CoV-2 is rare, the viral Spike protein has been detected in the placenta and fetus even without detectable viral RNA. Here, we investigated whether exposure to SARS-CoV-2 Spike protein during neurodevelopment compromises brain function and behavior. We found that a single neonatal injection of the Spike protein in mice increases seizure susceptibility, induces astrogliosis, and triggers a significant loss of excitatory and inhibitory synapses in the cortex and hippocampus within 10 days. Remarkably, 60 days post-Spike protein exposure, male mice exhibited persistent, sex-specific cognitive impairments. This behavioral phenotype correlated with a chronic, sex-specific neuroinflammatory footprint, suggesting that a failure to resolve glial reactivity may drive the long-term deficits observed specifically in Spike-injected male mice. Cognitive deficits were replicated using a live SARS-CoV-2 infection model in wild-type mice, confirming that cognitive disruption occurs independently of robust viral replication. Our findings underscore the vulnerability of the developing brain to viral components and highlight the need to monitor long-term outcomes following perinatal COVID-19 exposure.
    Keywords:  Ancestral SARS-CoV-2 strain; Astrocytes; Autism; Brain development; COVID-19; Coronavirus; Memory; Microglia; Spike protein
    DOI:  https://doi.org/10.1016/j.bbi.2026.106799
  18. Int J Biol Macromol. 2026 May 12. pii: S0141-8130(26)02415-3. [Epub ahead of print] 152488
    The natural β-glucan polysaccharide laminarin ameliorates microglial inflammation by metabolic reprogramming through the sirtuin 1/AMP-activated protein kinase axis.
    Chae Young Moon, Subin Shin, Jinho Lee, Suji Kim, Sooyeun Lee, Hyunju Kang.
      Neuroinflammation, driven by the activation of immune cells such as microglia, is tightly linked to metabolic reprogramming, thereby emerging as a key therapeutic target. This study investigated the potential of laminarin, a natural β-glucan polysaccharide, to ameliorate immunometabolic dysfunction in lipopolysaccharide (LPS)-stimulated microglia. Laminarin potently suppressed the production of pro-inflammatory cytokines, reduced oxidative stress, and ameliorated metabolic dysfunction through the activation of sirtuin 1 (SIRT1), which was identified as a key molecular target. Molecular docking simulations predicted a high-affinity binding of its representative unit, laminarihexaose, to the SIRT1 allosteric activation site, leading to its effective activation. In LPS-challenged microglia, laminarin's ability to enhance cellular NAD+ levels via the NAD+ salvage pathway also contributed to SIRT1 activation. Furthermore, the promotion of SIRT1 activation was linked to laminarin's capacity to promote the phosphorylation of AMP-activated protein kinase (AMPK), suggesting a potential positive feedback loop that reinforces the integrity of the SIRT1-AMPK axis. Laminarin prevented LPS-induced abnormal flux of the TCA cycle by regulating the related genes and the concentration of intermediates like aconitic acid and 2-hydroxyglutaric acid. Laminarin's efficacy also extended to suppressing the compensatory glycolytic switch and to ameliorating mitochondrial dysfunction by restoring the mitochondrial membrane potential and regulating genes involved in mitochondrial respiration. Collectively, these results suggest that laminarin ameliorates microglial inflammation and metabolic dysregulation by activating the SIRT1-AMPK axis to restore metabolic homeostasis. These findings position laminarin as a promising therapeutic candidate for neuroinflammatory disorders by targeting the crucial link between immunity and metabolism.
    Keywords:  Immunometabolism; Laminarin; Microglia; Neuroinflammation; Sirtuin 1
    DOI:  https://doi.org/10.1016/j.ijbiomac.2026.152488
  19. Cell Mol Life Sci. 2026 May 12.
    Prostaglandin signaling drives peripheral inflammation-induced reduction of hypothalamic oxytocin-positive neurons.
    Yibing Li, Hao Xu, Hongzhi Guo, Mingrui Zhai, Li Cao, Lei Xiao.
      Oxytocin (OXT) is a pleiotropic neuropeptide with diverse physiological functions, including anti-inflammatory effects. Endogenous OXT, primarily produced by neurons in hypothalamic paraventricular nucleus (PVN) and supraoptic nucleus (SON), is known to be reduced in various pathological states, particularly during peripheral inflammatory infections. However, the mechanisms by which peripheral inflammation leads to reduced OXT signaling remain poorly understood. In a mouse model of lipopolysaccharide (LPS)-induced chronic inflammation, we observed a selective reduction in the number of magnocellular (Magno) OXT-immunopositive neurons in the PVN, with no significant changes in PVN parvocellular (Parvo) or SON OXT-immunopositive neurons. Electrophysiological recordings revealed hyperexcitability of PVN OXT Magno neurons after LPS treatment, whereas Parvo neurons showed reduced activity. Microglial activation was preferentially localized to Magno neurons-dominant PVN subregions after LPS treatment. Single-cell transcriptomic analysis indicated higher expression of the Ptger4 gene in Magno OXT neurons, and bulk RNA sequencing of PVN and SON tissues highlighted enrichment of prostaglandin-related pathways following LPS challenge. Pharmacological inhibition and genetic knockdown experiments confirmed that prostaglandin E2 (PGE2)-EP4 signaling mediates the reduction of PVN OXT-immunopositive neurons and drives microglial phagocytosis of Magno OXT neurons under inflammatory conditions. Thus, these results not only identify the specific impact of peripheral inflammation on PVN Magno OXT neurons but also uncover the involvement of prostaglandin signaling in this process.
    Keywords:  Microglia; Oxytocin; Peripheral inflammation; Prostaglandin signaling
    DOI:  https://doi.org/10.1007/s00018-026-06248-4
  20. Invest Ophthalmol Vis Sci. 2026 May 01. 67(5): 35
    Single-Cell Sequencing Analysis Reveals Dysregulated Energy Metabolism and Altered Synaptic Connectivity in the Mouse Retina Following Dark Rearing.
    Zehui Zhu, Er Mo, Sihan Dong, Yuanyuan Li, Siyan Li, Hongzhe Li, Xinyu Zhang, Yun-E Zhao.
       Purpose: In this study, single-cell RNA sequencing (scRNA-seq) was applied to retinas from dark-reared and normally reared mice to resolve how each cell type contributes to retinal alterations under visual deprivation.
    Methods: C57BL/6J mice were reared in complete darkness from birth to postnatal day 36 (P36), when visual function and retinal morphology were evaluated. At P36, retinas were isolated for scRNA-seq, followed by transcriptomic profiling, cell clustering, differential expression, and cell-cell communication analyses. Key findings were validated by immunofluorescence, qPCR, Seahorse metabolic assays, flow cytometry, and targeted biochemical measurements. To determine the functional significance of Müller glia-derived DIO2, pharmacological inhibition was performed using iopanoic acid, followed by exogenous T3 supplementation.
    Results: Dark rearing markedly reduced visual function, as shown by attenuated optomotor responses and decreased electroretinogram a- and b-wave amplitudes. Photoreceptors exhibited downregulation of mitochondrial genes, accompanied by decreased oxygen consumption rate, reduced mitochondrial membrane potential, lower ATP levels, and progressive upregulation of Hif1α, collectively indicating impaired energy metabolism under visual deprivation. At the synaptic level, the presynaptic vesicle-priming protein UNC13A (Munc13-1) was selectively downregulated in ON-bipolar cells, whereas amacrine cells showed enhanced GABAergic signaling. Notably, dark rearing induced both systemic and local thyroid hormone fluctuations, triggering a dynamic compensatory upregulation of DIO2 specifically in Müller glia. Inhibiting DIO2 exacerbated visual dysfunction and retinal thinning, whereas T3 supplementation successfully rescued these deficits.
    Conclusions: This study reveals that dark rearing elicits metabolic dysregulation and synaptic remodeling in the retina. Müller glia-derived DIO2 acts as a critical compensatory mechanism to stabilize local thyroid hormone homeostasis, which is essential for preserving retinal structure and function.
    DOI:  https://doi.org/10.1167/iovs.67.5.35
This page is being maintained by Thomas Krichel. It was last updated on 2026‒05‒17 at 15:10.