bims-microg 2026-01-11 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2026–01–11
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

State-specific enhancer landscapes govern microglial plasticity.
How astrocytes regulate microglia in CNS injury: BST2-high astrocytes at the border.
Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.
Effects of lipopolysaccharide on energy metabolism and immune cell activation in different microglia model systems.
Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.
Neuropeptide SP protects against colitis and linked anxiety-like behavior through the putative roles of gut microbiota and metabolite inositol.
Microglial HVCN1 Deficiency Improves Movement and Survival of SOD1G93A ALS Mice by Enhancing Microglial Migration and Neuroprotection.
Microglial Membranes Wrapped Ultrasmall Medium-Entropy Ru Single-Atom Nanozyme: Enhanced Catalysis for Accelerating Inflammation/Redox Microenvironment Regulation in Intracerebral Hemorrhage.
Restoration of progranulin by engineered hematopoietic stem cell-derived microglia corrects phenotypes of granulin knockout mice.
Cognitive dysfunction in type 1 diabetes: role of TREM2 in microglial activation and Aβ pathology.
MicroRNA-29a-5p contributes to neuroinflammation through TLR7.
Allogeneic MHC-mismatched microglia-like cell replacement as a therapeutic approach for multiple sclerosis.
Chimeric brain models to study human glial-neuronal and macroglial-microglial interactions.
A Nanovesicle-Sericin-Based Hydrogel Scaffold for RGC Survival in Glaucoma via Regulation of Microglial Polarization.
Comparative lipidomics of iPSC-derived microglia protocols reveal lipid droplet and immune differences mediated by media composition.
Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.
Microglial Expression of Serotonin Receptors Reveals Parallel Regulation of 5-HT2b and BDNF in the Rat Hippocampus.
Spinal Microglial TLR7 Activation Drives Hyperalgesia in a Lupus Mouse Model via Upregulation of IL-1β, IL-18, and Cav2.2 and Enhanced Glutamatergic Synaptic Activity.
cGAS knockout inhibited endotoxin-induced uveitis in mice.
GPR40 Attenuates Age-Related Macular Degeneration by Suppressing Retinal Microglial NLRP3 Inflammasome Activation Via ERK Signaling.

Immunity. 2026 Jan 07. pii: S1074-7613(25)00525-4. [Epub ahead of print]

State-specific enhancer landscapes govern microglial plasticity.

Nicole Hamagami, Dvita Kapadia, Kia M Barclay, Yanlong Huang, Nora Abduljawad, Zuolin Cheng, Liam McLaughlin, Darsh Singhania, Xukai Ding, Jin Yang, Zhixin Sun, Vikram Karra, Siling Du, Peter Bayguinov, Guoqiang Yu, Yang E Li, Harrison W Gabel, Qingyun Li.

  Single-cell transcriptomic studies have identified distinct microglial subpopulations with shared and divergent gene signatures across development, aging, and disease. Whether these microglial subsets represent ontogenically separate lineages of cells or are manifestations of plastic changes in microglial states downstream of some converging signals is unknown. Furthermore, despite the well-established role of enhancer landscapes underlying the identity of microglia, the extent to which histone modifications and DNA methylation regulate microglial state switches at enhancers has not been defined. Here, using genetic fate mapping, we demonstrated the common embryonic origin of proliferative-region-associated microglia enriched in developing white matter and tracked their dynamic transitions into disease-associated microglia and white matter-associated microglia in disease and aging contexts, respectively. This study links spatiotemporally discrete microglial states through their transcriptomic and epigenomic plasticity, while revealing state-specific enhancer histone modifications and transcription regulators that govern state transitions in health and disease.

Keywords:  Alzheimer’s disease; DNA methylation; development; disease-associated microglia; enhancers; histone modifications; microglia; plasticity; proliferative-region-associated microglia; white matter

DOI:  https://doi.org/10.1016/j.immuni.2025.11.023
Neuron. 2026 Jan 07. pii: S0896-6273(25)00930-4. [Epub ahead of print]114(1): 1-3

How astrocytes regulate microglia in CNS injury: BST2-high astrocytes at the border.

Jungjoo Park, Won-Suk Chung.

In this issue of Neuron, Zhang et al.1 identified a subset of BST2-high astrocytes that emerge at the ischemic injury border and promote microglial recruitment through the C3-C3aR pathway. These findings highlight BST2 as a key modulator of astrocyte-microglia communication and a potential therapeutic target for CNS injury.

DOI: https://doi.org/10.1016/j.neuron.2025.12.003
Brain Behav Immun. 2026 Jan 04. pii: S0889-1591(26)00001-2. [Epub ahead of print] 106253

Long-term NRF2-driven microglial repopulation mitigates microgliosis, neuronal loss and cognitive deficits in tauopathy.

Lucía Viqueira, Elisa Navarro, Pilar Negredo, Juan Antonio Bernal, María Isabel Rodríguez-Franco, ElenaTortosa, Manuela G López.

  Tauopathies, including Alzheimer's disease, feature chronic microglial reactivity that drives neuroinflammation and disease progression. Pharmacological microglial depletion and subsequent repopulation using colony stimulating factor 1 receptor inhibitors have emerged as a potential therapeutic strategy to reprogram dysfunctional microglia. Despite promising short-term results, the long-term efficacy and pharmacological modulation of repopulated microglia remain poorly understood. Here, we investigated the long-term effects of microglial repopulation alone and in combination with the activation of the cytoprotective nuclear factor erythroid 2 p45-related factor 2 (NRF2) in an in vivo AAV-hTauP301L induced model. Integrating different behavioural, immunohistological and transcriptomic analysis, we evaluated cognitive function, tau pathology, neuronal survival and glial reactivity. We found that, whereas microglial repopulation alone did not significantly affect disease progression, NRF2-driven microglial replenishment sustained cognitive function, prevented hippocampal neuronal loss and restored microglial phenotype. Transcriptomic analyses further revealed that the combined treatment modulated tau- associated mitochondrial gene expression changes. These results highlight the importance of shaping the fate of self-renewed microglia and propose NRF2-mediated microglial repopulation as a potential pharmacological strategy for the treatment of tauopathies.

Keywords:  Colony-stimulating factor 1 receptor; Depletion; Microglia; Mitochondria; NRF2; PLX5622; Repopulation; Tauopathy

DOI:  https://doi.org/10.1016/j.bbi.2026.106253
Brain Behav Immun. 2026 Jan 04. pii: S0889-1591(26)00003-6. [Epub ahead of print]133 106255

Effects of lipopolysaccharide on energy metabolism and immune cell activation in different microglia model systems.

Susanne Michels, Johanna Eichberg, Fahd Alhamdan, Micha Engeser, Rafael Leite Dantas, Felix Sr Picard, Mona Mathews-Ajendra, Oliver Brüstle, Martin K-H Schäfer, Judith Alferink, Holger Garn, Markus Wöhr, Carsten Culmsee.

  Microglia, the brain's resident immune cells, constantly monitor their environment for signs of tissue damage or pathogens. Upon activation by stimuli like lipopolysaccharide (LPS), microglia undergo metabolic changes and release pro-inflammatory mediators. However, variations between human and rodent microglia, as well as differences between in vitro and in vivo conditions, likely influence microglial cellular functions and their responses to stimulation. In the present study, we compared several rodent and human model systems, including cell lines, primary cultures, induced pluripotent stem cell (iPSC)-derived cultures, and acutely isolated microglia, and revealed striking differences in LPS-induced metabolic changes and nitric oxide (NO) production. Using the murine microglial cell line BV-2, we demonstrated that NO was critical for restricting metabolism to glycolysis by blocking oxidative phosphorylation. In contrast, human iPSC-derived microglia and acutely isolated microglia from intraperitoneally injected rats maintained mitochondrial respiration upon LPS activation and did not show significant NO production and inducible nitric oxide synthase (iNOS) expression, respectively. Furthermore, we found that NO was not required for the increase in glycolysis rate or the release of pro-inflammatory cytokines upon LPS stimulation. Our results suggest that glycolysis is essential for microglial activation and cytokine production irrespective of NO production. However, the specific metabolic pathways involved may differ between species and experimental conditions. Understanding these differences is crucial for developing effective therapeutic strategies targeting microglial dysfunction in neurological diseases.

Keywords:  Energy metabolism; Glycolysis; Inducible nitric oxide synthase (iNOS); Lipopolysaccharide (LPS); Microglia; Mitochondrial respiration; Pro-inflammatory cytokines

DOI:  https://doi.org/10.1016/j.bbi.2026.106255
Nat Commun. 2026 Jan 09. 17(1): 338

Sulfatide deficiency-induced astrogliosis and myelin lipid dyshomeostasis are independent of TREM2-mediated microglial activation.

Sijia He, Namrata Mittra, Hanmei Bao, Anindita Bhattacharjee, Sherry G Dodds, Jeffrey L Dupree, Xianlin Han.

Disrupted lipid homeostasis and neuroinflammation often co-exist in neurodegenerative disorders, including Alzheimer's disease (AD). However, the intrinsic connection and causal relationship between these deficits remain elusive. Our previous studies show that the loss of sulfatide (ST), a class of myelin-enriched lipids, causes AD-like neuroinflammatory responses, cognitive impairment, bladder enlargement, and lipid dyshomeostasis. To better understand the relationship between neuroinflammation and lipid disruption induced by ST deficiency, we established a ST-deficient mouse model with a constitutive Trem2 knockout. Our study demonstrates that TREM2 regulates ST deficiency-induced neuroinflammation and astrocyte activation at the transcriptomic level but does not affect stage 1 disease-associated microglia or astrogliosis at the protein level. Additionally, ST loss-induced lipidome disruption, free water retention, and cognitive impairment persist in the absence of TREM2. Further, these phenotypes are more severe in females compared to males. Collectively, these results emphasize the essential role of TREM2 in mediating lipid loss-associated microglia-mediated neuroinflammation, but not astrogliosis or myelin lipid disruption. Moreover, we demonstrated that attenuating TREM2-mediated neuroinflammation has a limited impact on brain ST loss-induced lipidome alteration or AD-like central and peripheral disorders. Our findings suggest that preserving the lipidome and astrocyte balance may be crucial in decelerating the progression of AD.

DOI: https://doi.org/10.1038/s41467-025-66222-9
Nat Commun. 2026 Jan 08. 17(1): 295

Neuropeptide SP protects against colitis and linked anxiety-like behavior through the putative roles of gut microbiota and metabolite inositol.

Jing Lan, Jiaqi Wang, Sijuan Huang, Chenyu Li, Ziteng Deng, Zhihui Hao, Yunfei Ma.

The gut-brain axis links gut inflammation to psychiatric symptoms in inflammatory bowel disease (IBD), but the underlying mechanisms remain unclear. We demonstrate that neuropeptide substance P (SP) alleviated intestinal injury and behavioral disorders induced by dextran sodium sulfate in mice. SP mitigated hippocampal neuroinflammation and inhibited microglial activation and astrocyte loss. Furthermore, SP improved gut microbiome dysregulation, and its protective effects depended on the putative roles of microbiota. Notably, through modulating microbiota, SP dampened the NF-κB pathway in microglia, and increased GABAergic/Ca2+ signaling within astrocytes. SP elevated the microbiota-derived metabolite inositol. Supplementing inositol mimicked SP's benefits and activated GABAergic signaling, while the inositol inhibitor reversed SP's neuroprotective impacts, highlighting inositol's indispensable role. Collectively, SP exerts beneficial effects via microbiota's putative roles and inositol, involving the suppression of microglial NF-κB pathway while enhancing astrocytic GABAergic/Ca²⁺ signaling. Our findings underscore SP's potential as a therapeutic intervention for these disorders in IBD.

DOI: https://doi.org/10.1038/s41467-025-67904-0
Adv Sci (Weinh). 2026 Jan 04. e12149

Microglial HVCN1 Deficiency Improves Movement and Survival of SOD1G93A ALS Mice by Enhancing Microglial Migration and Neuroprotection.

Fan Wang, Ke-Yu Zhang, Lang-Jian Zhu, Wei-Jue Li, Yang Wu, Xiang Gao, Xiao-Ru Ma, Xiu-Hua Yin, Jian-Bin Wu, Xiao-Kang Ye, Zhao-Jun Dong, Di-Xian Wang, Zhe Zhou, Shao-Dong Wang, Lei Han, Zhi-Nong Jiang, Jing-Wei Zhao.

  Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease characterized by progressive loss of motor neurons. Current clinically available drugs targeting neurons show minor survival extension and no motor improvement in ALS patients. This shifts the focus of ALS research toward non-neuronal cells, particularly microglia, a critical driver of ALS pathogenesis. Highly druggable ion channels are key regulators of microglia function. Here, Hydrogen voltage gated channel 1 (HVCN1) was screened out as the most highly expressed ion channel in microglia, and was upregulated in microglia of SOD1G93A mice and patients. Deletion of HVCN1 in microglia increased motor neuron survival, rescued the innervated neuromuscular junctions in the muscle, reduced glial activation and decreased the level of both misfolded protein and myelin debris in the ALS mice. Importantly, these pathological improvements were translated into significant motor improvement and survival extension in the ALS mice, exhibiting better effects than the current clinical drugs. HVCN1 deletion enhanced microglia migration and their homeostatic state with elevated neurotrophic functions. Mechanistically, HVCN1 ablation promoted microglial migration via suppressing Akt signaling. Our results identify HVCN1 as a novel promising therapeutic target for ALS, opening a new avenue to further develop specific inhibitors for HVCN1 to alleviates ALS.

Keywords:  HVCN1/Hv1; amyotrophic lateral sclerosis; microglia; migration; neuroprotection; phagocytosis

DOI:  https://doi.org/10.1002/advs.202512149
Adv Sci (Weinh). 2026 Jan 04. e20714

Microglial Membranes Wrapped Ultrasmall Medium-Entropy Ru Single-Atom Nanozyme: Enhanced Catalysis for Accelerating Inflammation/Redox Microenvironment Regulation in Intracerebral Hemorrhage.

Jiebo Li, Penghui Wei, Yuanbo Pan, Hongjia Zheng, Jiajun Hu, Qianxi Chen, Zhongyuan Shen, Yongrui Hu, Jiajun Wu, Fuxin Lin, Fuxiang Chen, Chenyu Ding, Wenhua Fang, Yuanxiang Lin, Dezhi Kang, Yuxiang Gu, Yang Zhu, Dengliang Wang.

  Intracerebral hemorrhage (ICH) causes severe secondary brain injury (SBI) via excessive inflammation and reactive oxygen species (ROS), and current treatments lack effective dual-target efficacy. In this study, we designed a microglial membrane-wrapped single-atom nanozyme (PtRhIr/Ru SAN@M) by anchoring a single atom of Ru onto ultrasmall, medium-entropy PtRhIr alloys. This design integrates two underutilized strategies, single-atom nanozymes (SANs) and medium-entropy catalysts, to address critical therapeutic gaps in ICH therapy. PtRhIr/Ru SAN@M exhibited enhanced catalytic activity with superior Hydroxyl radical (•OH) scavenging and superoxide dismutase (SOD)-like and catalase (CAT)-like performances compared to Ru-free PtRhIr@M, enabled by electronically modulated active sites. Fluorescence imaging confirmed its ability to penetrate the blood-brain barrier (BBB) and accumulate in post-ICH neuroinflammatory regions. Both in vitro and in vivo experiments demonstrated that PtRhIr/Ru SAN@M repolarized microglia from the M1 to the M2 phenotype, disrupting the neuroinflammatory cycle and halting neuronal death. Therapeutic intervention with PtRhIr/Ru SAN@M significantly increased survival rates, restored neurological function, and enhanced spatial memory after ICH. This study pioneers the integration of SANs with medium-entropy alloys for ICH, offering a dual-target ROS-inflammation regulatory strategy and a generalizable platform for ROS-related degenerative disease therapies.

Keywords:  catalytic therapy; ferroptosis; intracerebral hemorrhage; medium‐entropy; single‐atom nanozyme

DOI:  https://doi.org/10.1002/advs.202520714
Sci Transl Med. 2026 Jan 07. 18(831): eadw9930

Restoration of progranulin by engineered hematopoietic stem cell-derived microglia corrects phenotypes of granulin knockout mice.

Yuri Ciervo, Pietro Rigoni, Linda Bucciarelli, Martina Lombi, Federico Pratesi, Nadia Bologna, Massimo Accardo, Chiara Recchi, Rita Milazzo, Valentina Poletti, Alessandra Biffi.

Autologous hematopoietic stem/progenitor cell (HSC)-gene therapy (GT) represents a promising therapeutic option for progranulin (PGRN)-related neurodegenerative diseases due to mutations in the PGRN encoding gene (GRN), such as frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis 11 (CLN11). These conditions are characterized by a deficiency in PGRN, have no cure, and represent an unmet medical need. We report on the efficacy and feasibility of an HSC GT approach that used a lentiviral vector encoding the human GRN complementary DNA to transduce HSCs that then were transplanted into a Grn-/- mouse model, which mirrors both FTD and CLN11 phenotypes. Two promoters, one with medium-low strength (HLA-DRA gene-based promoter regulated by inflammation) and the other with medium-high strength [ubiquitous phosphoglycerate kinase (PGK) promoter], were compared for HSC transduction. Moreover, intravenous and intracerebroventricular HSC administration were compared. Under all tested conditions, a partial reconstitution of PGRN production by microglia-like cells (MLCs) derived from genetically corrected Grn-/- HSCs was observed, which uniformly led to a correction of lipid accumulation, reduced gliosis, and improved social recognition in Grn-/- mice. Therapeutic effects were similarly achieved with either of the promoters and administration routes and particularly also when the PGRN-expressing cells and their MLC progeny had engrafted exclusively in the central nervous system (CNS) after intracerebroventricular transplantation. These findings suggest that a durable yet modest restoration of PGRN expression in the CNS is sufficient to correct pathology.

DOI: https://doi.org/10.1126/scitranslmed.adw9930
J Neuroinflammation. 2026 Jan 02.

Cognitive dysfunction in type 1 diabetes: role of TREM2 in microglial activation and Aβ pathology.

Yue Wang, Ruyue Wang, Yimeng Liu, Zhaohui Wang, Hongyan Ding, Xinyi Wei, Aikeda Aihemaitijiang, Minghan Sun, Li Zhao.

   BACKGROUND: Cognitive dysfunction associated with type 1 diabetes (T1D) is closely linked to the accumulation of amyloid-beta (Aβ) oligomers. However, the role of microglia and their underlying molecular mechanisms in this process remain unclear. Triggering receptor expressed on myeloid cells 2 (TREM2), a microglial receptor critical for clearing neurotoxic Aβ and maintaining metabolic homeostasis, is dysfunctional in Alzheimer's disease. Here, we investigated TREM2-mediated microglial dysfunction in diabetic neurodegeneration.
PURPOSE: To investigate the role of TREM2-mediated microglial dysfunction in Aβ clearance and cognitive impairment in T1D.
BASIC PROCEDURES: A total of 204 male C57BL/6J mice, aged 6-8 weeks, were used in this study. We performed single-nucleus RNA sequencing (snRNA-seq) on 59,356 cells from the prefrontal cortex and hippocampus. Aβ pathology was evaluated by western blot, immunofluorescence and ELISA. TREM2 knockout mice and the murine microglial cell line BV2 were used to study the role of TREM2 in cognitive function and Aβ clearance.
MAIN FINDINGS: T1D mice exhibited progressive memory deficits and prefrontal Aβ oligomer accumulation (36-50 kDa), with region-specific microglial activation. SnRNA-seq identified ten microglial subpopulations, with Trem2-enriched clusters (M1/M2/M3/M5) showing impaired phagocytosis and metabolic dysregulation. TREM2 knockout exacerbated cognitive deficits and Aβ accumulation in T1D mice. Mechanistically, TREM2 regulated microglial migration, phagocytosis of Aβ oligomers, and mitochondrial integrity under high-glucose conditions, potentially via the mTOR signaling pathway.
PRINCIPLE CONCLUSIONS: These findings establish TREM2 as a critical regulator of microglial Aβ clearance in T1D, operating mitochondrial and phagocytic programs via mTOR and highlighting its therapeutic potential for diabetic neurodegeneration.

Keywords:  Amyloid-beta; Microglia; TREM2; Type 1 diabetes

DOI:  https://doi.org/10.1186/s12974-025-03611-3
J Neuroinflammation. 2026 Jan 09.

MicroRNA-29a-5p contributes to neuroinflammation through TLR7.

Hugo McGurran, Eugenio Graceffo, Victor Kumbol, Marina Jendrach, Lukas Hinkelmann, Mariam Brehm, Leandre Ravatt, Christina Krüger, Thomas Wallach, Alexander Haake, Susanne Wegmann, Frank L Heppner, Markus Schülke, Seija Lehnardt.

  MicroRNAs (miRNAs) canonically regulate post-transcriptional gene expression, but they can also serve as ligands for Toll-like receptors (TLRs). These receptors and their associated signalling pathways contribute to inflammatory responses involved in various central nervous system (CNS) diseases, including Alzheimer's disease (AD). Here, we investigated the effects of extracellularly delivered miRNA in the context of neuroinflammation. We identified several miRNAs specifically dysregulated in AD and/or neuroinflammatory states, which directly activate the single-stranded RNA sensors mouse TLR7 and human TLR7/8. Among them, extracellular miR-29a-5p induced cytokine and chemokine release from murine primary microglia, altered expression of TLR signalling elements, and enhanced Aβ phagocytosis. Furthermore, this miRNA induced neuronal injury dependent on microglial TLR7 expression, but also in a cell-autonomous fashion, in vitro. Intrathecal injection of miR-29a-5p into mice led to microglial accumulation and neuronal injury in the cerebral cortex through TLR7 after 3 days. Brains of wild-type and APP/PS1 mice, an established AD mouse model, treated with multiple intrathecal miR-29a-5p injections over 120 days exhibited changes in cytokine/chemokine expression and neuronal injury. RNAseq analysis of the cerebral cortex of both miRNA-treated genotypes revealed downregulation of MAPK-associated pathways.Our study establishes AD-associated miRNAs such as miR-29a-5p as TLR7 agonists and signalling molecules for microglia, thereby altering the neuroinflammatory response.

Keywords:  Alzheimer’s disease; Cytokine expression; MicroRNA; Microglia; Neuroinflammation; Toll-like receptors

DOI:  https://doi.org/10.1186/s12974-025-03680-4
J Neuroinflammation. 2026 Jan 08.

Allogeneic MHC-mismatched microglia-like cell replacement as a therapeutic approach for multiple sclerosis.

Irene Benito-Cuesta, Jin-Hong Min, Yuxi Guo, Giulia Adriana Virgilio, Valerie Suerth, Stefan Bencina, Paula Trigo-Alonso, Keying Zhu, Shin-Yu Kung, Majid Pahlevan Kakhki, Heela Sarlus, Robert A Harris.



Keywords:  Adoptive transfer; Allogeneic; BALB/c; C3H; EAE; MHC-mismatch; Microglia replacement; Microglia-like cells; Multiple sclerosis

DOI:  https://doi.org/10.1186/s12974-025-03672-4
Cell Rep. 2026 Jan 06. pii: S2211-1247(25)01566-9. [Epub ahead of print]45(1): 116794

Chimeric brain models to study human glial-neuronal and macroglial-microglial interactions.

Mengmeng Jin, Ziyuan Ma, Haiwei Zhang, Rui Dang, Ava V Papetti, Alessandro C Stillitano, Lisa Zou, Steven A Goldman, Peng Jiang.

  Chimeric brain models generated by transplanting human pluripotent stem cell (hPSC)-derived neural cells are valuable for studying the development and function of human neural cells in vivo. To explore glial-neuronal and glial-glial interactions, we co-engraft hPSC-derived primitive neural progenitor cells and primitive macrophage progenitors into neonatal mouse brains, generating chimeric brains containing human microglia, macroglia, and neurons. Using super-resolution imaging and 3D reconstruction, we observe human microglia pruning synapses and engulfing neurons. Single-cell RNA sequencing reveals human glial progenitor populations and dynamic stages of astroglial development resembling those in the human brain. Cell-cell communication analysis identifies strong human neural interactions, including NRXN-NLGN3 signaling between neurons and astrocytes and SPP1- and PTN-MK-mediated communication between microglia and astroglia. This co-transplantation model provides a powerful approach to study complex human glial-neuronal interactions and mechanisms underlying neurological diseases.

Keywords:  CP: Neuroscience; astroglia; chimeric brain models; glia-glia interactions; human pluripotent stem cells; microglia; neuron-glia interactions; oligodendroglia

DOI:  https://doi.org/10.1016/j.celrep.2025.116794
ACS Appl Mater Interfaces. 2026 Jan 05.

A Nanovesicle-Sericin-Based Hydrogel Scaffold for RGC Survival in Glaucoma via Regulation of Microglial Polarization.

Wenxiang Zhu, Jiawei Chen, Qiuling Huang, Zhimin Liao, Xiaobo Wang, Xiaoyu Zhou, Wei Huang, Dengming Zhou, Xuanchu Duan.

  Chronic inflammation is closely linked to retinal ganglion cell (RGC) damage in glaucoma. However, naturally derived biomaterials often lack sufficient anti-inflammatory activity and fail to effectively support RGC survival. In this study, we developed a stem cell-loaded, nanovesicle-integrated sericin-based hydrogel, SerMA-PC@PNVs, designed to enhance the survival of RGCs in glaucomatous conditions. Nanovesicles (NVs) derived from periodontal ligament stem cells (PDLSCs) were obtained via ultracentrifugation and liposome extrusion. These NVs were loaded with procyanidins (PC) and functionalized with acrylate-polyethylene glycol-N-hydroxysuccinimide (AC-PEG-NHS). The modified NVs (PC@PNVs) were then covalently grafted onto methacrylated sericin (SerMA) through a photo-cross-linking reaction to form the SerMA-PC@PNVs hydrogel scaffold. In vitro studies demonstrated that the SerMA-PC@PNV scaffold enhanced the secretion of neurotrophic factors by encapsulated PDLSCs. Both in vitro and in vivo results confirmed that the SerMA-PC@PNVs/PDLSCs hydrogel effectively reprogrammed microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, thereby creating a neuroprotective microenvironment favorable for RGC survival. Mechanistically, RNA sequencing of retinal tissues revealed significant regulation of pathways associated with the "inflammatory response" and "apoptotic process". Single-cell RNA sequencing further demonstrated an increase in RGC populations and a reduction in neutrophils and microglia following treatment. Microglial subclustering analysis validated the hydrogel's regulatory effects on "inflammatory response" signaling. In conclusion, the SerMA-PC@PNVs/PDLSCs can promote the survival of glaucoma-damaged RGCs by regulating the inflammatory response.

Keywords:  RGCs; glaucoma; hydrogel; nanovesicles; sericin

DOI:  https://doi.org/10.1021/acsami.5c18589
Stem Cell Reports. 2026 Jan 08. pii: S2213-6711(25)00383-2. [Epub ahead of print] 102779

Comparative lipidomics of iPSC-derived microglia protocols reveal lipid droplet and immune differences mediated by media composition.

Aiko Toda Robert, Amanda McQuade, Sascha J Koppes-den Hertog, Lena Erlebach, Deborah Kronenberg-Versteeg, Martin Kampmann, Martin Giera, Rik van der Kant.

  Altered microglial lipid metabolism is heavily implicated in Alzheimer's disease (AD) and aging. Recently, protocols were developed to generate human induced pluripotent stem cell-derived microglia-like cells (iMGL) to study microglial function in vitro, including embryoid body-based methods and induced transcription factor (iTF)-dependent approaches. Here, we performed comparative lipidomics on iMGL from these methods and report major differences in multiple lipid classes, including triglycerides (TGs), a storage form of fatty acids implicated in microglial reactivity. TGs are strongly increased in iTF microglia due to the absence of a media supplement (B-27). Supplementing iTF microglia with B-27, or its component L-carnitine, reduces TGs and promotes a homeostatic state. B-27 also renders iTF microglia metabolically responsive to immune stimuli. Overall, our data show that iMGL differentiation methods have a major impact on microglial lipidomes and warrant attention when studying AD and neuroinflammatory processes involving lipids.

Keywords:  iPSC; lipid droplet; lipid metabolism; lipidomics; microglia; neuroinflammation; triglycerides

DOI:  https://doi.org/10.1016/j.stemcr.2025.102779
Glia. 2026 Mar;74(3): e70119

Müller Glial Kir4.1 Channel Dysfunction in APOE4-KI Model of Alzheimer's Disease.

Surabhi D Abhyankar, Yucheng Xiao, Neha Mahajan, Qianyi Luo, Theodore R Cummins, Adrian L Oblak, Bruce T Lamb, Timothy W Corson, Ashay D Bhatwadekar.

  Alzheimer's disease (AD), particularly late-onset AD (LOAD), affects millions worldwide, with the apolipoprotein ε4 (APOE4) allele being a significant genetic risk factor. Retinal abnormalities are a hallmark of LOAD, and our recent study demonstrated significant age-related retinal impairments in APOE4-knock-in (KI) mice, highlighting that retinal impairments occur before the onset of cognitive decline in these mice. Müller cells (MCs), key retinal glia, are vital for retinal health, and their dysfunction may contribute to retinal impairments seen in AD. MCs maintain potassium balance via specialized inwardly rectifying K+ channels 4.1 (Kir4.1). This study posits that Kir4.1 channels will be impaired in APOE4-KI, resulting in MC dysfunction. Additionally, we demonstrate that MC dysfunction in APOE4-KI stems from alterations in mitochondrial dynamics and oxidative stress. Kir4.1 expression and function were studied using immunofluorescence and through the whole-cell voltage clamp, respectively. In parallel, rat Müller cells (rMC-1) were used to create an in vitro model for further mechanistic studies. MitoQ was used to evaluate its potential to mitigate APOE4-induced deficits. APOE4 retinas and APOE4-transfected rMC-1 significantly reduced Kir4.1 expression, K+ buffering capacity, and increased mitochondrial damage. APOE4-transfected rMC-1 showed reduced mitochondrial membrane potential (ΔΨm) and increased mitochondrial reactive oxygen species (ROS). MitoQ treatment significantly reduced mitochondrial ROS and restored Kir4.1 expression in APOE4-expressing cells. Our results demonstrate that APOE4 causes mitochondrial dysfunction and MC impairment, which may contribute to retinal pathology in AD. MitoQ restored mitochondrial health and Kir4.1 expression in APOE4-expressing rMC-1, suggesting targeting mitochondria may offer a promising therapeutic strategy for AD.

Keywords:   APOE ; Kir4.1; Müller cells; late‐onset Alzheimer's disease; mitochondrial dysfunction

DOI:  https://doi.org/10.1002/glia.70119
Cells. 2025 Dec 30. pii: 66. [Epub ahead of print]15(1):

Microglial Expression of Serotonin Receptors Reveals Parallel Regulation of 5-HT2b and BDNF in the Rat Hippocampus.

Andrei Turkin, Maria Sidorova, Ekaterina Kurilova, Natalia Alenina, Oksana Tuchina, Friederike Klempin.

  Growing evidence suggests that psychiatric disorders are characterized by a prolonged inflammatory state, which may influence the efficacy of compounds targeting serotonin. Serotonin is a key signaling molecule in neuroplasticity of the adult hippocampus and involved in antidepressant action. Recent in vitro studies indicate the neurotransmitter may also facilitate the response to inflammation and potentially modulate microglial function towards neuroprotection. Using Tph2-/- rats depleted of brain serotonin, we examined microglial expression of various serotonin receptors (5-HTRs) in vivo in both the hippocampus and prefrontal cortex and assessed mRNA levels of cytokines and brain-derived neurotrophic factor (BDNF). We observed age-dependent and region-specific gene expression of 5-HTRs on sorted microglia, paralleling changes in BDNF signaling, especially with 5-HT2b. Notably, both 5-HT2b and BDNF expression in the hippocampus was significantly upregulated in the absence of brain serotonin. Our data indicate distinct roles of 5-HTR subtypes in early network formation (5-HT1b, 5-HT5b) and in the response to endogenous changes (5-HT2b, 5-HT5a). Understanding serotonin-microglia interplay could offer therapeutic insights into the maintenance of mood via brain-immune cell interactions.

Keywords:  5-HT2b; BDNF; Tph2; inflammation; microglia; serotonin

DOI:  https://doi.org/10.3390/cells15010066
Cells. 2025 Dec 22. pii: 20. [Epub ahead of print]15(1):

Spinal Microglial TLR7 Activation Drives Hyperalgesia in a Lupus Mouse Model via Upregulation of IL-1β, IL-18, and Cav2.2 and Enhanced Glutamatergic Synaptic Activity.

Saumya Bipin, Viacheslav Viatchenko-Karpinski, Catherine Li, Sujin Lim, Han-Rong Weng.

  Patients with systemic lupus erythematosus (SLE) often suffer from chronic pain due to a lack of effective and safe analgesics. In this study, we investigated the role of spinal TLR7 in the pathogenesis of chronic pain using female MRL lupus prone (MRL/lpr) mice, a SLE mouse model. We found that from 11 weeks of age, MRL/lpr mice exhibited thermal hypersensitivity in the hind paw, which reached plateau between 14 and 16 weeks. MRL/lpr mice with thermal hypersensitivity had increased expression of TLR7 in the spinal dorsal horn. TLR7 was located in microglia in this region. Intrathecal administration of a TLR7 antagonist attenuated the thermal hypersensitivity in MRL/lpr mice, while administration of the TLR7 agonist induced thermal hypersensitivity in control mice. Pharmacological activation of spinal TLR7 in control mice recapitulated molecular, synaptic, and cellular changes in the spinal dorsal horn of MRL/lpr mice with thermal hyperalgesia. These alterations included activation of microglia and astrocytes, increased production of IL-1β and IL-18, upregulated expression of N-type voltage-gated calcium channels (Cav2.2), enhanced glutamatergic synaptic activity, and elevated neuronal activation. Our findings suggest that targeting TLR7 or downstream effectors may represent a promising strategy to alleviate chronic pain induced by SLE.

Keywords:  EPSC; glial neuronal interaction; neuroinflammation; nociception; synaptic

DOI:  https://doi.org/10.3390/cells15010020
Genes Dis. 2026 Mar;13(2): 101786

cGAS knockout inhibited endotoxin-induced uveitis in mice.

Yue Guo, Ruiping Gu, Jiaojiao Wei, Chunhui Jiang.

  Our research focused on the impact of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of interferon genes (STING) pathway on retinal inflammation and employed an endotoxin-induced uveitis (EIU) model. EIU was provoked in mice through the intravitreal administration of lipopolysaccharide. Transcriptome analysis was performed via bulk RNA sequencing. Cytosolic mitochondrial DNA levels in the retina were quantified via PCR. Western blotting was used to assess the activation of cGAS‒STING signaling at specified times after intravitreal lipopolysaccharide injection. To understand the influence of the cGAS‒STING pathway on inflammatory retinal disorders, Cgas knockout mice were developed. Fundus imaging and fluorescein angiography were conducted to observe vitreous inflammation. Microstructural analysis of the eyes was performed, and histopathological scoring was performed. Retinal leukocytosis assays were used to evaluate retinal inflammation. Analysis of these differentially expressed mRNAs revealed activation of the cGAS‒STING signaling pathway, which was confirmed by western blotting analysis of these proteins. Using Cgas knockout mice, we observed significant inhibition of endotoxin-induced intraocular inflammation, including reduced vitreous inflammation, reduced retinal vascular leakage, decreased leukocyte adhesion, inhibited infiltration and activation of macrophages in the retina, and inhibited microglial activation. These findings suggest that cGAS might be a potential novel therapeutic target for uveitis.

Keywords:  EIU; Lipopolysaccharide; Retina; STING; cGAS

DOI:  https://doi.org/10.1016/j.gendis.2025.101786
Inflammation. 2026 Jan 06.

GPR40 Attenuates Age-Related Macular Degeneration by Suppressing Retinal Microglial NLRP3 Inflammasome Activation Via ERK Signaling.

Xin Tan, Jianshu Kang, Hongkun Zhao, Fang Fang, Yanping Xia, Chun Luo, Yue Zou, Yunqin Li.

  Retinal neuroinflammation is a key pathological feature of age-related macular degeneration (AMD), primarily driven by aberrant microglial cell activation. The expression and role of G-protein-coupled receptor 40 (GPR40), in AMD remain unclear. To investigate this pathology, we established a sodium iodate-induced mouse model of non-exudative AMD and performed in vitro experiments using LPS-stimulated microglial cells. The results showed that activation of the GPR40 receptor significantly promoted the polarization of microglial cells from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, effectively inhibiting neuroinflammation. Mechanistic studies revealed that GPR40 negatively regulates the ERK signaling pathway, inhibiting NLRP3 inflammasome activation and the release of pro-inflammatory cytokines such as IL-1β and TNF-α. In both in vivo and in vitro experiments, GPR40 activation protected photoreceptors by suppressing neuroinflammation caused by excessive microglial activation. In conclusion, this study reveals, for the first time, the critical role of GPR40 in regulating retinal neuroinflammation and its molecular mechanism. It highlights the potential therapeutic value of targeting the GPR40-ERK signaling axis to control the neuroinflammatory cascade and delay the progression of AMD and other retinal degenerative diseases.

Keywords:  Age-related macular degeneration; Caspase-1; ERK pathway; GPR40; Microglia; NLRP3; Photoreceptors

DOI:  https://doi.org/10.1007/s10753-025-02380-8