bims-microg 2026-07-05 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–07–05
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

An integrated hydrogel-V3 interneuron therapy promotes functional repair of spinal cord injury via neural circuit reconstruction and microenvironment remodeling.
Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.
Microglial IL-27 modulates depression-like behaviors induced by postnatal immune activation.
OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation.
Structural-functional network decoupling in early stage amyotrophic lateral sclerosis reveals cell-type specific transcriptional signatures.
Ablation of microglial estrogen receptor alpha predisposes male mice to diet-induced obesity.
Raffinose targets the NQO1/NF-κB axis to attenuate DON-driven microglial activation and neuroinflammation via metabolic reprogramming.
Hereditary spastic paraplegia (HSP) gene 11 (Spg11) attenuates lipid accumulation in myeloid cells and neuroinflammation in the midbrain without affecting α-synuclein pathology.
Human umbilical cord blood mononuclear cells ameliorate vascular dementia by modulating microglial myelin debris handling and white matter injury.
SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.
Csf1r-mediated depletion of myeloid cells prevents dopaminergic neuron loss during chronic colitis.
Regional mapping of CSF1R-positive microglia in neurodegenerative diseases and progressive MS, with exploratory presynaptic marker analyses.
T cells contribute to approaching positive but potentially risky stimuli through medial prefrontal cortex immune modulation.
Microglial brain-derived neurotrophic factor (BDNF) supports the behavioral and synaptogenic effects of ketamine.
HIV Tat-activated microglial extracellular vesicles induce neuronal iron dysregulation and synaptodendritic injury.
Minocycline modulates hippocampal BDNF-PSD95 and glial inflammatory protein signaling to alleviate chronic restraint stress-induced depressive- and anxiety-like behaviors.
The pyroptosis cascade between inflammatory endothelial cells and microglia facilitates BBB disruption in bacterial meningitis.
Complement C3a induces synaptic elimination in the hippocampus and neurobehavioral deficits in later life of septic neonatal rats triggered by lipopolysaccharide.
IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage.
Myd88 Deficiency Accelerates Retinal Degeneration and Alters Microglial Dynamics in a Mouse Model of Retinitis Pigmentosa.

Bioact Mater. 2026 Nov;65 938-956

An integrated hydrogel-V3 interneuron therapy promotes functional repair of spinal cord injury via neural circuit reconstruction and microenvironment remodeling.

Wenqi Yin, Guangrui Ma, Jia Xu, Xinrong Chen, Yupeng Liu, Qiuzhi Zhou, Guoliang Tang, Zhijun Shi, Guang Yang, Hong Chen.

  Spinal cord injury (SCI) disrupts neural circuits and creates an inhibitory microenvironment, posing challenges such as low cell survival rates and limited host integration for traditional cell transplantation therapies. This study developed an injectable, self-adaptive, and self-repairing oxidized hyaluronic acid-carboxymethyl chitosan (OHA-CMCS) dual-network interpenetrating hydrogel. This hydrogel serves as a functionalized, dynamically responsive cell-matrix co-delivery platform for delivering spinal cord-specific V3 neuronal precursors derived from human pluripotent stem cells. Through tissue-mimetic mechanical design, the hydrogel closely simulates the spinal cord tissue microenvironment. Its reversibly crosslinked network exhibits excellent compliance and self-healing capabilities, forming bidirectional feedback coupling with V3 cells across mechanical and biochemical dimensions, thereby significantly enhancing cell survival and functional maturation. In rats with complete spinal cord transection, the "material-cell synergistic system" (OC0.33+V3) formed by the OHA-CMCS hydrogel and V3 cells markedly improved motor function (BBB score, grip strength, gait analysis) and remodeled the injured microenvironment. Mechanistic studies reveal that this system drives microenvironmental reprogramming through material-cell interactions, inhibiting glial scar formation, inducing M2 polarization of microglia, and promoting axonal regeneration and vascular remodeling. Chemogenetic validation further confirms that transplanted V3 neurons successfully integrate into host neural circuits and exert inhibitory regulatory functions. This study proposes a dual-engine strategy of "material-driven regulation and cell-function integration," revealing the mechanism by which biomimetic hydrogels synergize with neurons to repair spinal cord injury, establishing a new paradigm for intelligent neuroregeneration systems.

Keywords:  Microenvironment modulation; Neural regeneration; Self-healing hydrogel; Spinal cord injury; V3 interneurons

DOI:  https://doi.org/10.1016/j.bioactmat.2026.05.034
Cell Death Differ. 2026 Jun 30.

Dysregulation of the TFEB-ATP6V0C axis in microglia exacerbates α-synuclein pathology through impaired lysosomal acidification in Parkinson's disease.

Yiming Wang, Zhuoran Ma, Zongjie Jin, Liang Kou, Nian Xiong, Tao Wang, Yun Xia.

Emerging evidence suggests that microglia exhibit dual regulatory roles in the pathogenesis of Parkinson's disease (PD); however, their precise function in α-synuclein clearance remains incompletely understood. Here, we provide compelling evidence that α-synuclein preformed fibrils (α-syn PFF) impair lysosomal acidification in microglia, leading to defective autophagic flux and disrupted α-syn degradation. This dysfunction further promotes the secretion of microglial extracellular vesicles (EVs), exacerbating disease pathology. Mechanistic investigations uncover that α-syn PFF directly interacts with ATP6V0C, a pivotal V0 subunit of V-ATPase. This interaction sterically hinders V0-V1 domain assembly, disrupting proton pump complex formation and reducing ATP6V0C expression. Functionally, ATP6V0C overexpression rescues lysosomal acidification deficits and facilitates α-syn degradation in vitro, while in vivo, ATP6V0C overexpression alleviates neurotoxicity and reduces phosphorylated α-syn aggregation in α-syn PFF mouse models. Further investigation identifies the PI3K-AKT-mTOR-TFEB pathway as a key regulatory axis of ATP6V0C-mediated lysosomal acidification in microglia. Notably, both TFEB activation and mTOR inhibition restore lysosomal acidity and upregulate ATP6V0C expression, thereby enhancing α-syn clearance. These findings establish the TFEB-ATP6V0C axis as a key determinant of microglial proteostasis, proposing targeted activation of this pathway as a promising strategy to mitigate PD progression.

DOI: https://doi.org/10.1038/s41418-026-01800-y
Cell Rep Med. 2026 Jun 04. pii: S2666-3791(26)00289-2. [Epub ahead of print] 102872

Microglial IL-27 modulates depression-like behaviors induced by postnatal immune activation.

Xinghui Qiao, Naigang Li, Yuan Yao, Xinyue Zhang, Yanrong Wang, Xuan Zhang, Tiantian Zhao, Dong Wu, Shangming Liu, Jingyi Du, Dongshuang Wang, Can Diao, Liyan Wang, Fenglin Cao, Wenjuan Zhou, Aijun Hao.

  Early-life inflammation increases the risk of mental disorders later in life by altering the long-term microglial capacity for neuronal spine engulfment, highlighting a tightly regulated neuroimmune interaction. However, how local immune signals modulate microglial function remains unclear. Here, we show that microglia-associated IL-27-IL-27Rα signaling alleviates depression-like behaviors induced by postnatal immune activation (PIA). At the cellular level, IL-27 treatment suppresses excessive microglial phagocytic activity, thereby preserving synaptic density and preventing synaptic loss. Notably, its beneficial effects extend beyond the PIA model, as IL-27 also ameliorates behavioral deficits in prenatal stress-exposed mice. Importantly, animal safety evaluations support the tolerability of IL-27 administration. These effects are mediated, in part, through the STAT1-Trem2-dependent mechanism. Collectively, these findings support IL-27 as a protective immunoregulatory factor and highlight its therapeutic potential for mood disorders associated with neurodevelopmental immune dysregulation.

Keywords:  IL-27; Trem2; microglia; phagocytosis; postnatal immune activation

DOI:  https://doi.org/10.1016/j.xcrm.2026.102872
EMBO Mol Med. 2026 Jul 02.

OTUB1 non-canonically inhibits TAB2 ubiquitination to govern microglia-mediated neuroinflammation.

Zijun Cao, Zhenhu Zhu, Ping Zeng, Fuqi Mei, Deqi Wang, Jun Xu, Yanqi Xu, Kangmin Chen, Chushan Wei, Jiangyun Shen, Keshuo Jin, Jiaqing Chen, Zhongding Li, Baohua Liu, Dirk Schlüter, Jingyong Huang, Xu Wang.

Microglia contribute to detrimental neuroinflammation under pathological conditions and thereby drive the pathogenesis and development of various diseases of the central nervous system (CNS). Here, the deubiquitinating enzyme OTUB1 is identified as a regulator of microglial activation and CNS inflammation. In mice, microglia-specific OTUB1 deletion significantly ameliorates ischemic brain injury by reducing the pro-inflammatory activation of microglia. OTUB1 enhances Toll-like receptor (TLR) signaling through stabilizing UBC13 and TAB2, leading to the increased induction of cytokines. Notably, OTUB1 reduces the proteasomal degradation of TAB2 by reducing its K48 ubiquitination in a catalytic activity-independent manner. Moreover, microglia-confined OTUB1 deficiency also alleviates lipopolysaccharide-induced sickness behavior and experimental autoimmune encephalomyelitis in mice due to decreased neuroinflammation. Pharmacological inhibition of OTUB1 significantly mitigated ischemic stroke injury in mice. These findings reveal an important role of OTUB1 in potentiating microglial activation and neuroinflammation, providing a proof-of-principle observation for targeting OTUB1 in the treatment of TLR-associated neuroinflammatory diseases.

DOI: https://doi.org/10.1038/s44321-026-00473-x
BMC Med. 2026 Jul 02.

Structural-functional network decoupling in early stage amyotrophic lateral sclerosis reveals cell-type specific transcriptional signatures.

Jixin Luan, Yan Yun, Yichang Jiao, Yao Wang, Mingjie Ma, Didi Shan, Hongxu Wang, Xinbo Ji, Yao Tang, Jianing Li, Zexin Zhan, Xiaohan Sun, Ninglu Gao, Pengfei Lin, Chuanzhu Yan, Dexin Yu, Shuangwu Liu, Fuchen Liu.

   BACKGROUND: Amyotrophic lateral sclerosis (ALS) involves widespread brain network dysfunction, yet the molecular mechanisms linked to these alterations remain poorly understood. We investigated macroscopic structural-functional coupling abnormalities in early-stage ALS (ALS-ES) and their underlying transcriptomic signatures.
METHODS: We analyzed multimodal MRI data from 73 patients with sporadic ALS-ES and 74 age- and sex-matched healthy controls. Structural-functional (SC-FC) coupling was quantified using diffusion tensor imaging and resting-state functional MRI. Machine learning models were constructed to distinguish patients from controls based on network features. Coupling alterations were spatially correlated with neurotransmitter receptor maps and gene expression profiles from the Allen Human Brain Atlas. Key transcriptomic findings were validated using independent single-cell RNA sequencing datasets.
RESULTS: While structural connectivity remained largely preserved, functional connectivity was significantly reduced in the somatomotor network (SMN). This mismatch manifested as significant SC-FC network decoupling, particularly within the SMN (pFDR = 0.001). A gradient boosting machine model accurately classified patients, identifying SC-FC coupling in the left precentral gyrus as a primary statistical contributor to the classification model. Decoupling spatially correlated with 5-HT2A and mGluR5 receptor distributions. Imaging-transcriptomics linked network failure to a gene signature enriched for synaptic pathways and microglial markers. Single-cell analysis identified FMN1 as a candidate gene whose glial expression spatially associates with network decoupling.
CONCLUSIONS: Early-stage ALS is characterized by significant structural-functional network decoupling, primarily in motor systems. This macroscopic failure is linked to specific microglial dysregulation, particularly FMN1 downregulation, providing a multiscale framework bridges statistical neuroimaging signatures with potential cellular pathology.

Keywords:  Amyotrophic lateral sclerosis; Microglia; Single cell; Structural-functional coupling; Transcriptional patterns

DOI:  https://doi.org/10.1186/s12916-026-04932-7
Metabolism. 2026 Jul 02. pii: S0026-0495(26)00200-3. [Epub ahead of print] 156689

Ablation of microglial estrogen receptor alpha predisposes male mice to diet-induced obesity.

Inmaculada Velasco, Jeremy M Frey, Vladislav Baglaev, Tristan Jafari, Thomas Huang, Sophia Schwie, Olivia D Santiago, Rachael D Fasnacht, Joshua P Thaler, Mauricio D Dorfman.

  Estrogen receptor alpha (ERα) signaling has metabolic and anti-inflammatory properties in addition to its impact on reproductive function. Compared to females, male mice generally exhibit greater inflammatory activation of microglia and increased susceptibility to diet-induced obesity (DIO). Given the established metabolic protective effects of estrogen, these observations raise the possibility that sex differences in microglial estrogen signaling contribute to this sexual dimorphism. In this study, we assessed metabolic and CNS histopathological properties in a mouse model with inducible microglia-specific ablation of ERα (MG-ERαKO). Male MG-ERαKO mice developed increased weight gain and insulin resistance relative to controls during high-fat diet (HFD) feeding. Indirect calorimetry and food intake analysis revealed that reduced energy expenditure, coupled with an inadequate compensatory reduction in food intake, was the primary driver of the obese phenotype. In contrast, female MG-ERαKO mice fed HFD developed mild insulin resistance, with no change in body weight gain compared to controls, despite a similar reduction in energy expenditure. Immunohistochemical analyses of the microglial activation marker IBA1 in the mediobasal hypothalamus (MBH) revealed that female MG-ERαKO mice had an increased number of microglia without showing morphological signs of activation. In contrast, MBH microglial number was unchanged in MG-ERαKO male mice, but the cells adopted more activated morphological profiles. Finally, HFD-fed MG-ERαKO male mice had increased POMC neuron-microglia interactions but fewer overall hypothalamic POMC neurons, suggesting microglia may disrupt POMC neuron integrity to promote DIO. Together, these findings indicate that sex-specific actions of estrogen in microglia limit the metabolic complications of HFD feeding.

Keywords:  Estrogen receptor alpha; Microglia; Neuroinflammation; Obesity; POMC neurons

DOI:  https://doi.org/10.1016/j.metabol.2026.156689
Metabolism. 2026 Jul 01. pii: S0026-0495(26)00199-X. [Epub ahead of print] 156688

Raffinose targets the NQO1/NF-κB axis to attenuate DON-driven microglial activation and neuroinflammation via metabolic reprogramming.

Jiexing Zhang, Yuwei Zheng, Haoyan Li, Yuanyuan Chen, Junfeng Gao, Xuming Deng, Chongshan Dai, Hongming Lv.

  Deoxynivalenol (DON), a prevalent mycotoxin in grain crops, can cross the blood-brain barrier (BBB) and cause neuroinflammation and neurobehavioral deficits in humans and animals. To date, the precise molecular mechanisms remain incompletely understood. Herein, we showed that DON triggers neurotoxicity by reprogramming microglial glycolysis via activation of the NQO1/NF-κB pathway. Raffinose (Raf), a natural trisaccharide, effectively attenuated DON-induced neuroinflammation in vivo and in vitro. Mechanistically, Raf upregulated NQO1 transcription by selectively binding to Nrf2 at Val-514 and Cys-368, thereby reinforcing the NQO1-IκBα interaction, possibly through NQO1-associated regulatory interfaces. This interaction inhibited NF-κB hyperactivation, suppressed glycolysis, and restored oxidative phosphorylation, thereby attenuating DON-induced pro-inflammatory microglial activation. Furthermore, NQO1 knockdown or Nrf2 knockout weakened the inhibitory effect of Raf on the NF-κB signaling pathway and inflammatory activation state of microglia. In conclusion, our findings revealed that Raf supplementation could efficiently alleviate DON exposure-induced neuroinflammation and neurobehavioral deficits by modulating NQO1/NF-κB-associated metabolic remodeling. These findings suggested that Raf may represent a potential therapeutic strategy against DON-induced neuroinflammation.

Keywords:  Deoxynivalenol; Glycolysis; Neuroinflammation; Neurotoxicity; Raffinose

DOI:  https://doi.org/10.1016/j.metabol.2026.156688
J Neuroinflammation. 2026 Jun 27.

Hereditary spastic paraplegia (HSP) gene 11 (Spg11) attenuates lipid accumulation in myeloid cells and neuroinflammation in the midbrain without affecting α-synuclein pathology.

Margaret Hayne, Joanna Lipka, Tawaun A Lucas, Allison L Soung, Max Adrian, Soumitra Ghosh, Han Lin, Sarah Chu, Kimberly Stark, Hai Ngu, Oded Foreman, Joshua Kaminker, Casper C Hoogenraad.

  Hereditary spastic paraplegia type 11 (SPG11-HSP) is a neurodegenerative disorder caused by mutations in SPG11, which encodes the large scaffolding protein spatacsin, involved in lysosomal and autophagosomal trafficking. A portion of patients with SPG11 mutations present with parkinsonism features. While spatacsin dysfunction is linked to neurodegeneration, the underlying cellular mechanisms, especially in the midbrain, remain largely unclear. Here, we demonstrate that loss of Spg11 in mice results in neuroinflammation and lipid accumulation in myeloid cells. Bulk RNA sequencing revealed a strong upregulation of microglial genes in the midbrain of Spg11 knockouts, supported by increased CD68 and CLEC7A expression and morphological changes consistent with microglial activation. Spg11 depletion in two in vivo models of synucleinopathy revealed no enhancement of phosphorylated α-synuclein-positive inclusions or dopaminergic neuron loss; however, the mice did exhibit Spg11-dependent microglial reactivity. Further in vitro studies using primary bone-derived macrophages revealed increased phagocytic capacity and neutral lipid accumulation under basal and stress conditions. These findings support a model where SPG11 is a critical regulator of microglial activation and myeloid lipid metabolism, contributing to neurodegeneration through pathways distinct from α-synuclein-mediated pathology.

Keywords:  Hereditary spastic paraplegia; Lipid metabolism; Microglia; Neuroinflammation; SPG11; Synucleinopathy

DOI:  https://doi.org/10.1186/s12974-026-03910-3
J Neuroinflammation. 2026 Jul 03.

Human umbilical cord blood mononuclear cells ameliorate vascular dementia by modulating microglial myelin debris handling and white matter injury.

Xueyi Wen, Kejing He, Cheng Huang, Congying Shi, Wei Wei, Yusheng Zhang, Zhenguo Yang, Keshen Li.

  Vascular dementia (VaD), characterized by white matter damage and cognitive decline, currently lacks effective therapeutic options. Human umbilical cord blood mononuclear cells (hUCB-MNCs) have shown neuroprotective and immunomodulatory properties; however, their therapeutic efficacy and underlying mechanisms in VaD remain incompletely understood. In this study, we investigated the effects of hUCB-MNCs treatment in a mouse model of VaD induced by bilateral common carotid artery stenosis (BCAS). Behavioral assessments showed that hUCB-MNCs treatment improved cognitive performance, affective-like behaviors, and motor coordination in BCAS mice. Histopathological analyses demonstrated that hUCB-MNCs treatment attenuated white matter injury, preserved myelin integrity, and mitigated neuronal and synaptic damage. Integrated transcriptomic and proteomic analyses of corpus callosum (CC) tissues revealed enrichment of immune-regulatory, phagocytosis-related, and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)-associated pathways after hUCB-MNCs treatment. In vivo and in vitro analyses further indicated that hUCB-MNCs helped preserve microglial homeostatic features and improved myelin debris-handling responses. Collectively, these findings suggest that hUCB-MNCs ameliorate VaD-associated pathology, at least in part, by modulating microglial myelin debris-handling responses and PI3K/AKT-related signaling, highlighting hUCB-MNCs as a promising cell-based therapeutic candidate for VaD.

Keywords:  Human umbilical cord blood mononuclear cells; Microglia; Myelin debris handling; PI3K/AKT signaling; Vascular dementia; White matter injury

DOI:  https://doi.org/10.1186/s12974-026-03929-6
J Neuroinflammation. 2026 Jul 02.

SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis.

Meijun He, Chaoran Wu, Mengqiu Hu, Xiayi Shi, Ruiqi Liu, Yujie Tong, Heng Wang, Haoran Hu, Hong Liao.

  Alterations in microglial function and transcriptomic profiles are major pathological hallmarks of amyotrophic lateral sclerosis (ALS). However, the dynamics and regulatory mechanisms underlying microglial phagocytic activity during disease progression remain unclear. In this study, we observed stage-dependent alterations in microglial phagocytic activity during disease progression in SOD1G93A mice. Single-cell RNA sequencing suggested that this change was associated with a reduced abundance of microglial subpopulations enriched for phagocytosis-related pathways. Transcriptomic analysis identified serum- and glucocorticoid-regulated kinase 1 (SGK1) as a potential mediator of this process. Notably, sgk1 knockout in SOD1G93A mice was associated with improved microglial clearance of myelin debris and reduced aberrant engulfment of neuronal material after disease onset. Our results further showed that, after disease onset, the accumulation of myelin debris and apoptotic neurons induced SGK1 upregulation in microglia from SOD1G93A mice. Mechanistically, SGK1 appeared to promote lipid accumulation in microglia by suppressing lipophagy, thereby impairing the ability of microglia to clear cellular debris. Moreover, pharmacological inhibition of SGK1 with GSK650394 attenuated motor deficits and prolonged survival in SOD1G93A mice. Together, our findings provide evidence for a previously unrecognized role of SGK1 in regulating microglial phagocytosis in ALS models and support SGK1 as a potential therapeutic target in SOD1 mutation-associated ALS models.

Keywords:  ALS; Lysosomal dysfunction; Microglia; Motor deficits; Phagocytic activity; SGK1

DOI:  https://doi.org/10.1186/s12974-026-03925-w
J Neuroinflammation. 2026 Jun 27. pii: 214. [Epub ahead of print]23(1):

Csf1r-mediated depletion of myeloid cells prevents dopaminergic neuron loss during chronic colitis.

Rebecca Katharina Kutscherauer, Marie Andert, Iris Stolzer, Emely Elisa Neumaier, Mark Dedden, Pavel Kielkowski, Wei Xiang, Alexander Grotemeyer, Marco Prinz, Takahiro Masuda, Klaus-Peter Knobeloch, Veit Rothhammer, Sebastian Zundler, Johannes C M Schlachetzki, Jürgen Winkler, Claudia Günther, Patrick Süß.

  Inflammatory bowel disease (IBD) predisposes to neuropsychiatric comorbidity and increases the risk of Parkinson's Disease (PD). Although the gut-immune-brain axis was proposed as a link between IBD and PD and a driver of PD immunopathogenesis, the regional pattern and single-cell landscape of the brain immune response during colitis and its contribution to PD pathology remain poorly defined. Here, we observe a loss of dopaminergic neurons and synuclein pathology in the substantia nigra pars compacta of adult mice with chronic colitis. By confocal microscopy and integrated multi-omics, we reveal a complex midbrain-specific immune response to chronic colitis. Single-cell mapping of the midbrain immune landscape showed an inflammatory shift of microglial clusters including an expansion of interferon-response microglia, CD8+ T cell extravasation, and increased numbers of vessel-associated neutrophils. Selective myeloid cell depletion using a colony stimulating factor 1 receptor (Csf1r) inhibitor after colitis onset reduced midbrain microglia by 67% and led to a complete rescue of dopaminergic neuron loss, without affecting mucosal pathology or T cell and neutrophil migration to the midbrain. Collectively, within the complex midbrain immune response to chronic colitis, we demonstrate a causal role of Csf1r-dependent myeloid cells for dopaminergic neurodegeneration. Thus, Csf1r inhibition in IBD may not locally ameliorate colitis, but provide neuroprotection to dopaminergic neurons.These results reveal a novel cellular link between chronic gut-derived peripheral inflammation and midbrain vulnerability and thereby substantially enhance our understanding of the risk for PD related to the gut-immune-brain axis.

Keywords:  Colony-stimulating factor 1 receptor; Gut-immune-brain axis; Inflammatory bowel disease; Microglia; Parkinson’s Disease

DOI:  https://doi.org/10.1186/s12974-026-03926-9
J Neuroinflammation. 2026 Jul 04.

Regional mapping of CSF1R-positive microglia in neurodegenerative diseases and progressive MS, with exploratory presynaptic marker analyses.

Mahsa S Bavarsad, Felipe L Pereira, Marina M Reinhardt, Abhijit Satpati, Salvatore Spina, William W Seeley, William Jagust, Gil D Rabinovici, Ari Green, Lea T Grinberg.

   BACKGROUND: Microglial colony-stimulating factor-1 receptor (CSF1R) is a therapeutic and imaging target, yet the regional, disease-specific distribution of CSF1R-positive microglia in the human brain remains incompletely defined, limiting interpretation of emerging CSF1R-PET signals. We sought to build a cross-disease, multi-region, quantitative map of CSF1R-positive microglia in neurodegenerative conditions and progressive multiple sclerosis (MS) lesions, with an exploratory comparison to presynaptic marker burden.
METHODS: CSF1R mRNA‑positive microglia were quantified by RNAscope across six cortical regions (MFG, IFG, ITG, AG, CA1, EC) in early‑onset Alzheimer's disease (EOAD), late‑onset AD (LOAD), progressive supranuclear palsy (PSP), and frontotemporal lobar degeneration with TDP-43 inclusions due to progranulin mutation (FTLD‑GRN), and in primary and secondary progressive MS (PPMS, SPMS) within cortical gray‑matter plaques, plaque-adjacent gray matter and white matter. Positivity was defined a priori as ≥ 3 puncta with housekeeping‑probe pass and negative‑control verification, counting blinded, and densities were cortical‑thickness corrected. Iba-1 immunolabeling verified microglial identity. Western blot provided protein‑level verification. We explored ROI‑level associations of CSF1R with SV2A and synaptophysin previously measured in the same regions/cases.
RESULTS: In neurodegeneration, increases were smaller and region‑specific (e.g., EOAD-ITG/CA1; LOAD-AG; PSP-AG; FTLD‑GRN-IFG/ITG/AG/EC), with minimal white‑matter change. In progressive MS, gray-matter CSF1R-positive microglia densities did not differ from controls, whereas SPMS white matter was increased. Exploratory analysis showed that CSF1R and SV2A were positively associated across ROIs in neurodegenerative diseases (e.g., PSP approximately ρ = 0.66), and weakest in LOAD; synaptophysin showed similar patterns, suggesting that regions with higher CSF1R-positive microglia density can coincide with relative preservation of presynaptic markers.
CONCLUSIONS: A cross‑disease, region‑resolved map reveals region‑specific changes in CSF1R + cell density in neurodegeneration, but only white matter in MS. These findings provide the histological context needed to interpret future CSF1R‑PET. Prospective studies pairing CSF1R‑PET with SV2A‑PET and multiplex tissue profiling are warranted to define microglial states and synaptic outcomes in vivo.

Keywords:  Alzheimer’s Disease; CSF1R; Frontotemporal Dementia; Microglia; Multiple Sclerosis; Synapse/synaptic

DOI:  https://doi.org/10.1186/s12974-026-03945-6
Brain Behav Immun. 2026 Jun 30. pii: S0889-1591(26)00633-1. [Epub ahead of print] 106885

T cells contribute to approaching positive but potentially risky stimuli through medial prefrontal cortex immune modulation.

Anna Panuccio, Juliette Gimenez, Marta Tiberi, Carlo Fabrizio, Andrea Termine, Francesca Balsamo, Giuseppe Sciamanna, Giulia Carrera, Alessandro Matteocci, Marco De Bardi, Silvia Caioli, Luana Saba, Sofia Nutarelli, Maria Teresa Viscomi, Valerio Orlando, Laura Petrosini, Valerio Chiurchiù, Daniela Laricchiuta.

  Avoidance behaviour, a core feature of the "Behavioural Immune System," minimizes exposure to pathogens but limits social and environmental engagement. For some individuals, the benefits of approaching attractive but risky stimuli may outweigh the costs of avoiding them. In spontaneously approaching (AP) mice, we identified the neuronal and immune correlates that contribute to individual differences in approach to positive yet potentially risky stimuli. AP mice displayed enhanced excitatory synaptic transmission and excitability in the pyramidal neurons of the medial prefrontal cortex (mPFC), a neuronal transcriptomic profile enriched for immune pathways, and an increased abundance of T lymphocytes in both the mPFC and peripheral blood. Microglia in AP mice exhibited a pro-inflammatory shift with reduced anti-inflammatory markers. Modulating lymphocyte trafficking with fingolimod abolished the approach phenotype and reduced cerebral T cells, whereas microglial inhibition with minocycline did not affect approach behaviour. These findings reveal that T-cell-associated immune modulation plays a critical role to maintain risk-oriented approach behaviour, suggesting a functional coupling between adaptive immunity and prefrontal circuits. We propose an "Approaching Immune System" that complements the classical Behavioural Immune System in regulating the flexibility of approach-avoidance behaviours. The findings provide ground-breaking insight into neuronal and immune circuits orchestrating adaptive behaviours, offering broad translational relevance for psychiatric, infectious, and chronic inflammatory disorders.

Keywords:  Approach-avoidance motivation; High-dimensional flow cytometry; Immune gene pathways; Inflammatory responses; T-cells; Transcriptomic profiling

DOI:  https://doi.org/10.1016/j.bbi.2026.106885
Brain Behav Immun. 2026 Jul 02. pii: S0889-1591(26)00634-3. [Epub ahead of print] 106886

Microglial brain-derived neurotrophic factor (BDNF) supports the behavioral and synaptogenic effects of ketamine.

Samuel C Woodburn, Alexander Kuhn, Kelly Bosis, David T Dadodsky, Etienne Mueller, Justin L Bollinger, Rosa Maria Salazar Gonzalez, J Elliott Robinson, Lauren Larke Vollmer, Eric S Wohleb.

  Ketamine promotes spine growth on the apical dendrites of pyramidal neurons in the prefrontal cortex (PFC), which are critical for its behavioral effects. Follow-up studies show that brain-derived neurotrophic factor (BDNF) signaling is critical for these effects. In this context, we sought to determine if microglial BDNF contributes to the synaptic and behavioral effects of ketamine. Thy1-GFP(M) mice were administered ketamine (10 mg/kg, i.p.) and assessed for behavior as well as dendritic spine density and microglial morphology in the PFC. Fluorescence-activated cell sorting (FACS) was used to isolate PFC microglia for gene expression analyses. Further studies used mice with depletion of microglial Bdnf (Cx3cr1Cre/+:Bdnffl/fl) and genotype controls (Cx3cr1Cre/+:Bdnf+/+) to examine synaptosome protein levels and behavioral responses to ketamine. An AAV-PHP.eB construct was injected systemically to enable analyses of dendritic structures. As expected, mice show reduced FST immobility and increased dendritic spine density on PFC pyramidal neurons after ketamine. These effects were associated with reduced microglia ramification in the PFC and increased Bdnf expression in sorted PFC microglia. Subsequent studies revealed that Cx3cr1Cre/+:Bdnffl/fl mice had decreased GluN2B levels in PFC synaptosomes and attenuated behavioral responses following ketamine administration. Consistent with this, we found that Cx3cr1Cre/+:Bdnffl/fl mice show no change in dendritic spine density in the PFC following ketamine. These results implicate microglia in the neurobiological and behavioral effects of ketamine, and highlights the neurotrophic capacity of microglia.

Keywords:  Bdnf; Dendrites; Depression; Ketamine; Microglia; PFC; Synaptogenesis

DOI:  https://doi.org/10.1016/j.bbi.2026.106886
Cell Commun Signal. 2026 Jun 29.

HIV Tat-activated microglial extracellular vesicles induce neuronal iron dysregulation and synaptodendritic injury.

Uma Maheswari Deshetty, Frida L Martínez-Cuevas, Poojashree Chettiar, Shashank M Dravid, Palsamy Periyasamy, Susmita Sil, Shilpa Buch.

  Extracellular vesicles (EVs) are membrane-enclosed, nanoscale structures released by cells and play a key role in intercellular communication under both normal physiological and pathological conditions. They serve as conduits for transferring molecular cargo between neighboring cells, thereby modulating recipient cell function. While the HIV Transactivator of transcription (Tat) protein has been shown to induce ferroptosis in microglia, the role of Tat-activated microglia-derived EVs (Tat-MEVs) in transferring iron-handling and ferroptosis-associated cargo to neurons and promoting neuronal injury remains unexplored. In this study, we sought to evaluate the impact of cargo derived from Tat-MEVs on neuronal synaptodendritic degeneration. Rat primary cortical and hippocampal neurons were exposed to either control MEVs or Tat-MEVs and subsequently assessed for synaptodendritic degeneration, expression of key ferroptotic mediators, and mitochondrial dysfunction associated with neuronal injury. Neurons exposed to Tat-MEVs demonstrated increased expression of the key iron-handling and ferroptosis-associated proteins (transferrin, TF; transferrin receptor 1, TFR1; Six-Transmembrane Epithelial Antigen of the Prostate 3, STEAP3; divalent metal transporter 1, DMT1; and ferritin heavy chain 1, FTH1); inhibitory synaptic markers (GAD65, Gephyrin), Fe2+/total iron content, neuronal cytotoxicity and mitochondrial reactive oxygen species (ROS) compared to neurons exposed to control MEVs. These findings suggest a link between mitochondrial dysfunction and neuronal iron accumulation. The expression of these mediators was downregulated in neurons exposed to MEVs derived from iron chelator, deferoxamine (DFO)-pretreated BV2 cells. Electrophysiological recordings further revealed reduced miniature excitatory postsynaptic currents in neurons exposed to Tat-MEVs, an effect that was attenuated in neurons exposed to DFO-derived MEVs. Additionally, dendritic spine analyses of neurons exposed to Tat MEVs revealed a reduction in mushroom and stubby spine subtypes, suggesting synaptodendritic injury.Collectively, these findings demonstrate that Tat-MEVs transfer iron-handling and ferroptosis-associated cargo that promotes neuronal iron dysregulation, oxidative stress, mitochondrial dysfunction, and synaptodendritic degeneration. These changes are consistent with ferroptosis-associated neuronal stress and contribute to functional impairment in recipient neurons. This EV-based communication axis provides mechanistic insight into how HIV Tat-induced microglial dysfunction propagates iron-dependent neurotoxic signaling within the central nervous system and identifies EV-mediated iron dysregulation as a potential therapeutic target in NeuroHIV.

Keywords:  Extracellular vesicles; HIV-1 Tat; Iron dysregulation; Mitochondrial dysfunction; Synaptodegeneration

DOI:  https://doi.org/10.1186/s12964-026-03032-6
Int J Biol Macromol. 2026 Jun 28. pii: S0141-8130(26)03188-0. [Epub ahead of print]374 153248

Minocycline modulates hippocampal BDNF-PSD95 and glial inflammatory protein signaling to alleviate chronic restraint stress-induced depressive- and anxiety-like behaviors.

Adeel Ahmed Abbasi, Hamid Khan, Shishi Xu, Yanwen Zhao, Keying Zhang, Yin Shen, Jianan Lv, Xinyu Zhu, Xiaoqin Fu, Peijun Li.

  Chronic restraint stress (CRS) is a widely used experimental model for investigating the neurobiological mechanisms underlying stress-related mood disorders, including depression and anxiety. Increasing evidence suggests that neuroinflammation and impaired synaptic plasticity contribute to the development of these behavioral abnormalities; however, the underlying molecular pathways remain incompletely understood. In the present study, we investigated the effects of CRS on hippocampal brain-derived neurotrophic factor (BDNF)-postsynaptic density protein 95 (PSD95) signaling and glial inflammatory protein expression and evaluated the therapeutic potential of minocycline. CRS exposure induced depressive- and anxiety-like behaviors, as evidenced by increased immobility in the forced swim and tail suspension tests, reduced sucrose preference, and anxiety-related behavioral deficits. At the molecular level, CRS significantly increased microglial and astrocytic activation while reducing the expression of BDNF and PSD95 in the hippocampus, indicating impaired neurotrophic support and synaptic integrity. Treatment with minocycline markedly attenuated glial activation, restored hippocampal BDNF and PSD95 expression, and improved both depressive- and anxiety-like behaviors. These findings demonstrate that CRS-induced behavioral abnormalities are associated with dysregulation of hippocampal BDNF-PSD95 signaling and enhanced glial inflammatory responses. Furthermore, minocycline exerts neuroprotective and behavioral benefits by modulating glial inflammatory protein signaling and preserving neurotrophic and synaptic plasticity pathways. Collectively, these results highlight the therapeutic potential of minocycline for stress-related mood disorders and identify hippocampal BDNF-PSD95 and glial inflammatory signaling as important targets underlying its beneficial effects.

Keywords:  Astrocytes; Chronic restraint stress; Depressive like behavior; Microglia; Minocycline; Neuroinflammation

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.153248
Cell Rep. 2026 Jun 30. pii: S2211-1247(26)00712-6. [Epub ahead of print]45(7): 117634

The pyroptosis cascade between inflammatory endothelial cells and microglia facilitates BBB disruption in bacterial meningitis.

Yangyang Zheng, Zhiyue Wu, Fei Wu, Hanyu Hu, Jiaxiu Ma, Guokun Zhang, Hao Sun, Xiaoya Li, Hui Cheng, Haiqing Xiong.

  Neonatal meningitis-causing Escherichia coli (NMEC) is a primary etiological agent of neonatal meningitis. Inflammatory cell death triggered by NMEC infection has been implicated as a critical determinant of blood-brain barrier (BBB) disruption and neuroinflammation. However, the mechanisms underlying inflammatory BBB breakdown and the propagation of inflammation within the neuroinflammatory milieu remain poorly understood. Here, we show that brain endothelial cells (ECs) undergo GSDMD-dependent pyroptosis in response to NMEC infection. Through integrated spatiotemporal single-cell transcriptomic, epigenomic, and proteomic analyses, we identify Gbp5 as a key regulator of pyroptosis in brain ECs. Moreover, we uncovered a homeostasis-to-inflammation transition in both ECs and microglia (MG), whereby pyroptotic ECs promote microglial pyroptosis via Angptl4-Sdc4 signaling. This intercellular communication establishes a "pyroptosis cascade" between BBB ECs and microglia in the central nervous system (CNS), providing mechanistic insight into inflammatory BBB disruption and revealing potential therapeutic targets within the CNS immune microenvironment.

Keywords:  BBB disruption; CP: immunology; CP: neuroscience; endothelial cell; microglia; neonatal meningitis-causing Escherichia coli; pyroptosis cascade

DOI:  https://doi.org/10.1016/j.celrep.2026.117634
Free Radic Biol Med. 2026 Jul 01. pii: S0891-5849(26)00918-4. [Epub ahead of print]

Complement C3a induces synaptic elimination in the hippocampus and neurobehavioral deficits in later life of septic neonatal rats triggered by lipopolysaccharide.

Peixian Huang, Shuqi Jiang, Zhuo Chen, Nan Liu, Haiyan Li, Anhui Wang, Lifang Luo, Wei Huang, Shenglong Chen, Yiyu Deng.

  Neonatal septic encephalopathy is a severe complication of sepsis, yet its underlying neuropathological mechanisms remain poorly understood. This study investigated the role of the complement component C3a in mediating synaptic elimination and neurobehavioral deficits in later life of a lipopolysaccharide (LPS)-induced neonatal sepsis model. We found that activated hippocampal astrocytes upregulated C3a expression, while its receptor, C3aR, was elevated in both microglia and neurons. Blocking the C3a/C3aR axis with a C3a receptor antagonist (C3aRA) attenuated cognitive impairments, synaptic loss, and microglial engulfment of synapses. C3a led to downregulated expression of neurofilament medium (NF-M) and an increased accumulation of phosphorylated Tau (p-Tau) in primary neurons in vitro. Mechanistically, C3a activated the ERK signaling pathway in primary neurons. Inhibition of ERK with ASN007 mitigated C3a-induced synaptic elimination, neuronal damage, and behavioral deficits both in vivo and in vitro. Our results suggest that astrocyte-derived C3a may contributes to hippocampal synaptic elimination and cognitive deficits through C3a/C3aR/ERK pathway in later life of neonatal septic rats. These findings highlight the C3a/C3aR/ERK axis as a potential therapeutic target for preventing synaptic and cognitive deficits in neonatal septic encephalopathy.

Keywords:  Complement C3a; ERK signaling; Neonatal sepsis; Neuroinflammation; Synaptic pruning; Tau pathology

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.003
Aging Dis. 2026 Jun 23.

IRG1/Itaconate Inhibits Microglial Senescence-Like Transition by Modulating Mitochondrial Dynamics through Rhoa Alkylation in Subarachnoid Hemorrhage.

Zeyu Zhang, Yanlin Chen, Weizhen Gao, Fengchen Zhang, Yichao Jin, Jie Li, Jiaqi Wang, Tao Lv, Feng Jia, Xiaohua Zhang.

Aging is a potent risk factor for poor prognosis in subarachnoid hemorrhage (SAH), yet the molecular mechanisms underlying the age-related exacerbation of early brain injury remain incompletely understood. This study investigates the immunometabolic regulation of the microglial senescence-like transition following SAH, focusing on the immune-responsive gene 1 (IRG1)/itaconate axis. We observed that the endogenous upregulation of IRG1 and itaconate is a protective response to hemorrhagic stress that is significantly blunted in aged mice. Microglia-specific IRG1 deficiency exacerbated SAH-induced brain injury, characterized by an accelerated senescence-like transition and the secretion of senescence-associated secretory phenotype (SASP) factors. Mechanistically, we demonstrate that IRG1 deficiency leads to excessive mitochondrial fission and dysfunction via the hyperactivity of Dynamin-related protein 1 (Drp1). Using click chemistry-based proteomics and site-directed mutagenesis, we identified that itaconate exerts its neuroprotective effects by directly alkylating the small GTPase RhoA at the cysteine 107 (C107) residue. This specific post-translational modification inhibits RhoA-GTP binding and downstream ROCK1 activation, thereby suppressing Drp1-mediated mitochondrial fragmentation. Importantly, treatment with the cell-permeable itaconate derivative 4-octyl itaconate (4-OI) rescued mitochondrial dynamics and attenuated microglial senescence and neurological deficits, whereas the RhoA-C107S mutation abolished these protective effects. Collectively, our findings unveil a novel metabolic-mitochondrial checkpoint involving the IRG1/itaconate-RhoA-Drp1 axis. Restoring this pathway represents a promising therapeutic strategy to combat the age-related exacerbation of neuroinflammation and improve outcomes in SAH patients.

DOI: https://doi.org/10.14336/AD.2025.1527
Invest Ophthalmol Vis Sci. 2026 Jul 01. 67(8): 3

Myd88 Deficiency Accelerates Retinal Degeneration and Alters Microglial Dynamics in a Mouse Model of Retinitis Pigmentosa.

Shotaro Shimokawa, Sakurako Shimokawa, Huanyu Zhao, Jun Funatsu, Takahiro Hisai, Kaho Yamamoto, Shunji Nakatake, Kohta Fujiwara, Ayako Okita, Yoshito Koyanagi, Shoji Notomi, Keijiro Ishikawa, Nobuyo Yawata, Noriko Yoshida, Yasuhiro Ikeda, Kensuke Shibata, Koh-Hei Sonoda, Yusuke Murakami.

Purpose: Neuroinflammation is triggered by the recognition of damage-associated molecular patterns (DAMPs) by pattern recognition receptors (PRRs). Toll-like receptors (TLRs)/MyD88 is the PRR pathway that mediates inflammatory signaling. We investigated the functions of Myd88 in retinal degeneration and neuroinflammation in a mouse model of retinitis pigmentosa (RP).
Methods: Rd10 mice were crossed with Myd88-/- mice to produce rd10; Myd88-/- mice. The retinal phenotype was assessed by TUNEL, hematoxylin and eosin (H&E) staining, and electroretinography. Retinal microglia were immunostained with Iba-1. Retinal mRNA profiles associated with neuroinflammation were analyzed using a NanoString Neuroinflammation panel.
Results: Myd88 deficiency increased the number of TUNEL-positive cells in the outer nuclear layer (ONL) and exacerbated ONL thinning at postnatal day 18 and 21 (P < 0.01, each). Consistent with these findings, the scotopic electroretinogram (ERG) showed lower b-wave amplitudes in rd10; Myd88-/- mice compared with rd10 mice (P < 0.01). Microglial infiltration into the outer retina showed an early but transient increase at P18, followed by a reduction at P21 in rd10; Myd88-/- mice. Retinal mRNA profiling revealed increased expression of Ifitm3 and Serpina3n, markers of astrocytic glia, in rd10; Myd88-/- mice. Immunostaining confirmed the upregulation of IFITM3 and SERPINA3N in astrocytes and Müller cells in rd10; Myd88-/- mice.
Conclusions: Myd88 deficiency accelerates retinal degeneration in rd10 mice, accompanied by an earlier onset of microglial infiltration and altered glia-related gene expression.

DOI: https://doi.org/10.1167/iovs.67.8.3