Glia最新文献

{"title":"A Microglia–Astrocyte Signaling Axis Regulates Astrocyte Piezo1 Expression and Inflammatory Responses","authors":"Yanyang Bai,&nbsp;Hyun B. Choi,&nbsp;Stefan Wendt,&nbsp;Morgan Towriss,&nbsp;Ada J. Lin,&nbsp;Christopher J. Groten,&nbsp;Ivy Cui,&nbsp;Haakon B. Nygaard,&nbsp;Brian A. MacVicar","doi":"10.1002/glia.70199","DOIUrl":"10.1002/glia.70199","url":null,"abstract":"<p>Structural tissue alterations in numerous brain disorders can initiate mechanosensory signaling pathways and influence neuropathology. Astrocytes are highly mechanosensitive cells that play essential roles in maintaining brain homeostasis; however, the molecular mechanisms underlying astrocyte mechanosensation during pathological conditions remain largely unexplored. In this study, we investigated how the expression of the mechanosensitive ion channel Piezo1 in astrocytes is modulated by inflammatory triggers. We found that direct exposure of primary astrocyte cultures to inflammatory stimuli, including lipopolysaccharide (LPS) or oligomeric amyloid-β (oAβ), had minimal impact on astrocytic Piezo1 expression. In contrast, when LPS or oAβ were applied to primary microglia cultures, Piezo1 expression was increased in microglia, and conditioned media from these microglia cultures significantly upregulated Piezo1 expression in astrocytes. We further identified that microglia released pro-inflammatory cytokines (IL-1α, IL-1β, and TNF-α) that can directly enhance Piezo1 expression and Piezo1-mediated Ca²⁺ signaling in both rodent and human astrocytes. Microglial depletion in 5xFAD mice consistently and substantially reduced astrocytic Piezo1 expression in vivo, supporting the physiological relevance of this microglia–astrocyte signaling axis during pathology. Activation of Piezo1 with Yoda2 did not alter astrocytic inflammatory gene expression under basal conditions but reduced TNF-α, CCL2, and C3 expression following cytokine pretreatment. Conversely, Piezo1 knockdown increased GFAP expression at baseline and enhanced pro-inflammatory gene expression under cytokine stimulation, indirectly promoting microglial activation. These findings demonstrate that astrocytic Piezo1 expression is regulated by microglia-derived inflammatory signals and plays a context-dependent role in modulating astrocyte reactivity and neuroinflammatory responses.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13401733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148589733","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cdk7 Regulates Myelin Sheath Morphology and Lipid Homeostasis in Schwann Cells","authors":"Nathalie Schumacher,&nbsp;Alexandra Pieltain,&nbsp;Pierre Tocquin,&nbsp;Nicolas Thelen,&nbsp;Arnaud Lavergne,&nbsp;Nathalie Masar,&nbsp;Romano Terrasi,&nbsp;Romane Leloup,&nbsp;Giulio Muccioli,&nbsp;Philippe Gailly,&nbsp;Peter Arthur-Farraj,&nbsp;Renaud Vandenbosch,&nbsp;Rachelle Franzen","doi":"10.1002/glia.70194","DOIUrl":"10.1002/glia.70194","url":null,"abstract":"<div>\u0000 \u0000 <p>Schwann cells (SC) are responsible for myelination in the peripheral nervous system (PNS). Myelin allows saltatory transmission of action potentials along axons and functionally relies on its unique constitution. We previously reported that Cdk7, a regulator of cell cycle progression and transcription, regulates myelin gene expression in oligodendrocytes and contributes to myelin maintenance in the central nervous system. Using mice with conditional Cdk7 knock-out in SCs, we provide evidence that Cdk7 is dispensable for myelin initiation but needed for the correct myelin thickness of larger caliber fibers in young mice, as well as for myelin elongation and rapid nerve conduction throughout age. We report that Cdk7 loss results in disturbed myelin stoichiometry, with significant dysregulation of lipid-related genes in SCs and a reduction in myelin protein zero. Finally, we demonstrate that Rxrγ, a nuclear receptor involved in lipid metabolism, is significantly downregulated in the absence of Cdk7. However, although Cdk7 regulates myelin segment length, our results indicate that this effect occurs independently of Rxrγ in myelinating dorsal root ganglion explants.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148576405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Quantifying Heteromer Partitioning Reveals Inflammation-Dependent Redistribution of Microglial Adenosine A2A and Cannabinoid CB2 Receptors","authors":"Rafael Franco,&nbsp;Jaume Lillo,&nbsp;Christian Griñán-Ferré,&nbsp;Mercè Pallàs,&nbsp;Rafael Rivas-Santisteban","doi":"10.1002/glia.70200","DOIUrl":"10.1002/glia.70200","url":null,"abstract":"<p>G protein–coupled receptor (GPCR) heteromerization represents a key organizational mechanism in cell signaling, but it remains difficult to determine, in native cells, how receptor-associated signals are distributed between non-interacting and heteromer-associated states. Here, we address this limitation by combining proximity ligation assay (PLA) with the newly applied MolBoolean methodology, enabling in situ quantification of the partitioning of adenosine A_2A and cannabinoid CB₂ receptor-associated signals between non-interacting fractions and A_2A–CB₂ heteromeric complexes in primary microglia. We show that resting microglia contain detectable A_2A–CB₂ heteromers together with a substantial non-interacting A_2A-associated signal fraction. Selective activation of either receptor promotes redistribution of the detectable receptor-associated signal toward the heteromer-associated fraction. Ligand-induced redistribution also occurred in HEK-293T cells expressing the two receptors. In contrast, pro-inflammatory activation of primary microglia with LPS/IFN-γ markedly changes the basal organization of the receptor system, increasing the proportion of MolBoolean-detectable signal associated with A_2A–CB₂ complexes, with approximately 70% of the detectable receptor-associated signal corresponding to heteromeric complexes. In this inflammatory context, further agonist-induced repartitioning is strongly limited compared with that observed in resting microglia. These findings identify inflammation-dependent receptor partitioning as a quantitatively measurable feature of microglial A_2A and CB₂ receptor organization and provide a framework for interpreting how receptor context may influence future studies of A_2A–CB₂ pharmacology under neuroinflammatory conditions.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13389093/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148547100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Satellite Glial Cells Synthesize and Release GABA to Activate Extrasynaptic GABAA Receptors That Modulate Dorsal Root Ganglia Neuron Excitability","authors":"Natalie Jiménez-Barrios,&nbsp;Ricardo González-Ramírez,&nbsp;Francisco Javier Paz-Bermúdez,&nbsp;Guadalupe Raya-Tafolla,&nbsp;José Segovia Vila,&nbsp;Ricardo Felix,&nbsp;Rodolfo Delgado-Lezama,&nbsp;Benjamín Florán Garduño","doi":"10.1002/glia.70190","DOIUrl":"10.1002/glia.70190","url":null,"abstract":"<p>Sensory neurons express extrasynaptic GABA_A receptors in their soma and axon, tonically activated by ambient GABA, modulating their excitability. However, the specific glial or neuronal origin of endogenous GABA that modulates this excitability has yet to be identified. We investigated the expression and function of enzymes involved in GABA synthesis via the ornithine-putrescine and glutamic acid pathways, and the effects of inhibiting these enzymes on the compound action potential (cAP) of primary afferent fibers. PCR analysis revealed that the dorsal root ganglia (DRG) express transcripts for ornithine decarboxylase (ODC), monoamine oxidase B (MAOB), diamine oxidase (DAO), and GAD65/67. Immunofluorescence assays confirmed the expression of ODC, MAOB, DAO, and GAT-3 proteins, as well as GABA in satellite glial cells (SGC). In contrast, neurons express DAO and ODC. However, despite the presence of GAD65 and GAD67 mRNAs, their corresponding proteins were not detected. Inhibition of ODC and MAOB, but not DAO or GAD, prevented the accumulation of GABA induced by the GABA transaminase (GABA-T) inhibitor aminooxy acetic acid in SGC cultures. Additionally, the Best1 channel blocker CaCCinh suppressed the K⁺-induced release of [³H]GABA in DRG and SGC cultures. Blocking GABA_A receptors with picrotoxin, inhibiting MAOB, and blocking Best1 all increased cAP. However, allylglycine, a GAD inhibitor, failed to elicit this effect. Likewise, the use of selegiline and CaCCinh on cAP occluded the effects of picrotoxin. These results support that GABA synthesized and released by satellite glial cells activates extrasynaptic GABA_A receptors, thereby modulating the excitability of sensory neurons.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13385656/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148534662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of Astrocytic TNFR1 Attenuates Hyperexcitability and Initiation of Epileptogenesis","authors":"Lukas Henning,&nbsp;Ioannis Zalachoras,&nbsp;Giovanni Carriero,&nbsp;Gerald Seifert,&nbsp;Peter Bedner,&nbsp;Christian Steinhäuser,&nbsp;Andrea Volterra","doi":"10.1002/glia.70205","DOIUrl":"10.1002/glia.70205","url":null,"abstract":"<p>Temporal lobe epilepsy (TLE), the most common form of adult focal epilepsy, is highly resistant to current medical therapy. Cytokine signaling, including via tumor necrosis factor-alpha (TNFα), has been implicated not only as an accompanying factor but as a key aspect in the initiation of the disease. TNFα, through its type-1 receptor (TNFR1) in astrocytes, controls excitatory circuits in the hippocampus, yet it remains unknown whether this astrocyte pathway specifically contributes to epilepsy. Here, we used a conditional cell-specific knockout mouse line to induce TNFR1 deletion selectively in astrocytes and test its roles in the initiation and progression of TLE. Mice lacking astrocyte TNFR1 showed decreased basal spectral power, longer latency to first seizure following treatment with kainic acid, and a less severe phenotype up to 4 weeks later. Thus, abrogation of astrocyte TNFR1 signaling may be beneficial in TLE and could provide a new therapeutic target for this disease.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13382600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148519652","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VPS35 Regulates Microglial Lipid Droplet Accumulation in Parkinson's Disease via Rab7","authors":"Yue Liang,&nbsp;Tong Chang,&nbsp;Leping Yan,&nbsp;Jiayi Li,&nbsp;Yihe Zhang,&nbsp;Jianhua Ding,&nbsp;Yinquan Fang,&nbsp;Gang Hu","doi":"10.1002/glia.70203","DOIUrl":"https://doi.org/10.1002/glia.70203","url":null,"abstract":"<div>\u0000 \u0000 <p>Microglial dysfunction and aberrant lipid metabolism are emerging as key contributors to Parkinson's disease (PD) pathogenesis. However, the specific role and regulation of lipid droplets (LDs) within microglia remain poorly defined. In this study, we employed MPTP- and LPS-induced PD mouse models and an in vitro system utilizing astrocyte-conditioned medium to model disease-relevant lipid stress and found enhanced LD accumulation in microglia. VPS35 expression was decreased in microglia, correlating with elevated microglial LD levels in PD mouse models. We then performed genetic manipulations (knockdown and overexpression) of VPS35, including the PD-associated D620N mutant, in primary microglia and assessed LD accumulation, phagocytic function, inflammatory responses, and integrated stress pathways. We showed that VPS35 knockdown exacerbated the accumulation of LDs in microglia. Conversely, VPS35 overexpression ameliorated LD formation, improved phagocytic function, and reduced inflammatory and integrated stress responses in microglia. The PD-related VPS35[D620N] mutation abolished these protective effects. We further found that VPS35 interacts with Rab7 to maintain lysosomal function, and the D620N mutation disrupts this interaction, leading to defective LD clearance. Our findings reveal VPS35 dysfunction as a key pathogenic mechanism in PD, where the D620N mutation disrupts microglial lipid handling to promote disease progression, thereby nominating VPS35 restoration as a promising therapeutic strategy.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148467552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A TREK-1/AQP4/TRPA1/BDNF Signaling Axis Is Associated With Astrocytic Volume Transients, Synaptic Plasticity, and Spatial Memory","authors":"Victor James Drew,&nbsp;Junsung Woo,&nbsp;Jung Moo Lee,&nbsp;Wuhyun Koh,&nbsp;Joungha Won,&nbsp;Jae-Hun Lee,&nbsp;C. Justin Lee","doi":"10.1002/glia.70195","DOIUrl":"10.1002/glia.70195","url":null,"abstract":"<p>Astrocytes, known for their support roles, are emerging as active participants in synaptic plasticity and cognitive functions. Astrocytes actively regulate synaptic plasticity and memory through dynamic volume transients. Our previous research identified several key molecules, including TREK-1, TRPA1, and Best1 ion channels, as well as the gliotransmitter BDNF, as critical components of astrocytic volume transients. However, the precise mechanisms by which these volume transients influence synaptic plasticity and memory remain poorly understood. In this study, we investigate the roles of TREK-1 and TRPA1 in astrocytic volume dynamics and their downstream effects. Our findings, based on intrinsic optical signal imaging, electrophysiology, and behavioral assays, support a model in which neuronal stimulation induces astrocytic swelling, initiated by K⁺ uptake through TREK-1 channels and regulated by Ca²⁺ influx via TRPA1 channels. This swelling is closely associated with short- and long-term potentiation (LTP), and exogenous BDNF restores LTP under conditions of calcium sequestration during astrocytic calcium clamping experiments. Disruption of ion channels associated with astrocytic volume transients leads to significant impairments in spatial memory, as demonstrated by deficits in object-place recognition and passive avoidance tasks. Moreover, these channels contribute to the regulation of synaptic plasticity. These findings implicate astrocytic volume transients and BDNF as pivotal modulators of synaptic plasticity and memory, as well as potential therapeutic targets for addressing memory dysfunctions.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70195","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Navigating Human Astrocyte Differentiation: Direct and Rapid One-Step Differentiation of Induced Pluripotent Stem Cells to Functional Astrocytes Supporting Neuronal Network Development","authors":"Imke M. E. Schuurmans,&nbsp;Annika Mordelt,&nbsp;Marta Guevara-Ferrer,&nbsp;Katrin Linda,&nbsp;Denise Duineveld,&nbsp;Sofia Puvogel,&nbsp;Marina P. Hommersom,&nbsp;Nicky Scheefhals,&nbsp;Lisa Rahm,&nbsp;Emma Dyke,&nbsp;Gijs-Jan Scholten,&nbsp;Caroline Knorz,&nbsp;Carlos Gonzalez Jimenez,&nbsp;Noelle van Egmond,&nbsp;Astrid Oudakker,&nbsp;Chantal Bijnagte-Schoenmaker,&nbsp;Hans van Bokhoven,&nbsp;Wei Wei,&nbsp;Samuel Hofmann,&nbsp;Sabine Jung-Klawitter,&nbsp;Sandra Mojica-Perez,&nbsp;Jack Parent,&nbsp;Lidia Carotenuto,&nbsp;Sarah Weckhuysen,&nbsp;Nadine Maas,&nbsp;Ype Elgersma,&nbsp;Eline van de Ven,&nbsp;Dirk Lefeber,&nbsp;Anita Lygeroudi,&nbsp;Helga E. de Vries,&nbsp;Luc Jordi,&nbsp;Magdalini Polymenidou,&nbsp;Teresa Mitchell-Garcia,&nbsp;Iulia Dragan,&nbsp;Amalia Dolga,&nbsp;Lot D. de Witte,&nbsp;Clara D. M. van Karnebeek,&nbsp;James Ellis,&nbsp;Alejandro Garanto,&nbsp;Nael Nadif Kasri","doi":"10.1002/glia.70202","DOIUrl":"10.1002/glia.70202","url":null,"abstract":"<p>Astrocytes play a pivotal role in neuronal network development. Despite the well-known role of astrocytes in the pathophysiology of neurologic disorders, the utilization of induced pluripotent stem cell (iPSC)-derived astrocytes in neuronal networks remains limited. Here, we present a streamlined one-step protocol for the differentiation of iPSCs directly into functional astrocytes without the need for ectopic gene expression or neural progenitor cell generation. We found that culturing iPSCs directly in commercial astrocyte medium, was sufficient to differentiate iPSCs into functional astrocytes within 5 weeks. More than 60 iPSC lines were successfully differentiated into astrocytes by independent researchers across 10 independent laboratories. Validation of the iPSC-astrocyte cultures demonstrated consistent astrocyte differentiation with minimal batch-to-batch variability. In dept. characterization of a subset of iPSC lines confirmed astrocyte identity and functionality of the iPSC-astrocyte monocultures by immunofluorescence, flow cytometry, RNA sequencing, glutamate uptake assays and calcium signaling recordings. Optimization of the protocol enabled co-culture of iPSC-astrocytes with Ngn2 iPSC-derived neurons (iNeurons), promoting neuronal differentiation and synapse formation. Lastly, we used single-cell electrophysiology and multi-electrode arrays, by four independent researchers, to confirm robust neuronal network development in 5-week-old iPSC-astrocyte and iNeuron co-cultures. This protocol offers a rapid and efficient method to establish all-human astrocyte-neuron co-cultures, facilitating the investigation of cell-type-specific contributions to disease pathogenesis. Its validation across numerous iPSC lines in 10 independent laboratories highlights the reproducibility of the protocol and positions it as a platform for advancing disease modeling in human neural networks.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70202","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148443499","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Young Adult Microglial Deletion of C1q Reduces Engulfment of Synapses and Partially Mitigates Cognitive Impairment in an Aggressive Alzheimer's Disease Mouse Model","authors":"Tiffany J. Petrisko,&nbsp;Shu-Hui Chu,&nbsp;Angela Gomez-Arboledas,&nbsp;Blossom Zhang,&nbsp;Andrea J. Tenner","doi":"10.1002/glia.70189","DOIUrl":"10.1002/glia.70189","url":null,"abstract":"<p>C1q is a multifunctional protein, including its role as the initiating protein of the classical complement cascade. While classical pathway activation is involved in synaptic pruning during nervous system development, it also contributes to inflammation and cognitive decline in Alzheimer's disease (AD). Constitutive genetic C1q deficiency has been shown to reduce glial activation and attenuate neuronal loss in AD mouse models, but the specific contributions of microglial C1q to AD pathology while avoiding deficits during post-natal development remain unaddressed. To dissect specific role(s) of microglial C1q in AD progression, we crossed the Cx3cr1^CreERT2 mouse model that deletes C1q from microglia in young adulthood (8 weeks of age) to the aggressive Arctic48 (Arc) amyloidosis mouse model. At 10 months, young adult microglial C1q deletion (Arc C1q^ΔMG) was associated with improved spatial memory performance, despite unchanged amyloid plaque burden. Furthermore, Arc C1q^ΔMG mice exhibited reduced hippocampal C3 protein levels without altering C3 mRNA. No changes were observed in C5aR1, astrocyte GFAP, or microglial Iba1 protein expression. However, Arc C1q^ΔMG mice demonstrated region specific reductions in microglial synaptic engulfment, alongside decreased phagolysosome-associated amyloid in both microglia and astrocytes, and reduced hippocampal amyloid compaction. These findings support a role for C1q in astrocytic C3 induction and the engulfment of both synapses and amyloid. Importantly, young adult microglial C1q inhibition confers cognitive benefits without exacerbating amyloid pathology, suggesting a therapeutic window in which targeting microglial C1q may help preserve synaptic integrity and modulate the neuroinflammatory processes during the later stages of AD.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70189","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148434514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Deletion of Adenosine A2A Receptors Attenuates Aged-Related Alterations of Glial Cells Morphology and of Inflammasome in the Hippocampus and Prefrontal Cortex of Mice","authors":"Cátia R. Lopes,&nbsp;Samira G. Ferreira,&nbsp;Rodrigo A. Cunha,&nbsp;Paula Agostinho","doi":"10.1002/glia.70197","DOIUrl":"10.1002/glia.70197","url":null,"abstract":"<div>\u0000 \u0000 <p>Although brain disorders are the major burden of disease in Western countries and their incidence increases sharply with aging, the biological basis of brain aging is still poorly explored. Glial cells, namely microglia and astrocytes, maintain brain homeostasis and mount neuroinflammation that can contribute to age-related deterioration of brain functions. The purinergic system, particularly adenosine A_2A (A_2AR) and P2X₇ (P2X₇R) receptors, modulates glial function and neuroinflammation. The present study aims to investigate how aging affects microglia and astrocytes morphology and the NRLP3 inflammasome complex, a key driver of the inflammatory process, and if the genetic deletion of A_2AR has a protective role in inflammaging. We resorted to wild-type and A_2AR knockout mice with 3- and 24- month-old to investigate alterations in microglia and astrocytes morphology, in P2X₇R, and in related NRLP3 inflammasome components in the hippocampus and prefrontal cortex. Data show that brain aging alters the tridimensional structure of microglia and astrocytes in the hippocampus and prefrontal cortex. Aging decreased the levels of P2X₇R and of inflammasome components, NLRP3 and caspase 1, in the hippocampus. Remarkably, A_2AR knockout abrogated age-related morphological changes of glial cells in both brain structures. Also, the decreased hippocampal P2X₇R levels and the alterations in NLRP3 levels in both hippocampus and cortex, were no longer present in aged A_2AR knockout mice. These findings indicate that A_2AR might bolster NRLP3 inflammasome activation associated with an age-related neuroinflammation, and A_2AR blockade might promote healthy brain aging.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"74 9","pages":""},"PeriodicalIF":5.5,"publicationDate":"2026-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429496","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}