Glia最新文献

{"title":"FABP7 Expression Modulates the Response of Astrocytes to Induced Endotoxemia","authors":"Mariana Bresque,&nbsp;Daniel Esteve,&nbsp;Garret Balmer,&nbsp;Haylee L. Hamilton,&nbsp;Joshua S. Stephany,&nbsp;Mariana Pehar,&nbsp;Marcelo R. Vargas","doi":"10.1002/glia.70023","DOIUrl":"10.1002/glia.70023","url":null,"abstract":"<p>Fatty acid binding proteins (FABPs) are a family of small proteins involved in fatty acid (FA) subcellular trafficking. In the adult central nervous system, FABP7, one of the members of this family, is highly expressed in astrocytes and participates in lipid metabolism, regulation of gene expression, and energy homeostasis. Reactive astrocytes in Alzheimer's disease and amyotrophic lateral sclerosis animal models upregulate FABP7 expression. This upregulation may contribute to the pro-inflammatory phenotype that astrocytes display during neurodegeneration and is detrimental for co-cultured neurons. Here, we explore how FABP7 expression modulates astrocyte response to inflammatory stimuli. Our results showed that silencing FABP7 expression in astrocyte cultures before treatment with different inflammatory stimuli decreases the expression of a luciferase reporter expressed under the control of NF-κB -response elements. Correspondingly, FABP7-silenced astrocytes display decreased nuclear translocation of the NF-κB-p65 subunit in response to these stimuli. Moreover, silencing FABP7 decreases the toxicity of stimulated astrocytes toward co-cultured motor neurons. Similar results were obtained after silencing FABP7 in human astrocytes differentiated from induced pluripotent stem cells. Finally, knockdown of astrocytic FABP7 expression in vivo reduces glial activation in the cerebral cortex of mice after systemic bacterial lipopolysaccharide (LPS) administration. In addition, whole transcriptome RNA sequencing analysis from the cerebral cortex of LPS-treated mice showed a differential inflammatory transcriptional profile, with attenuation of NF-κB-dependent transcriptional response after FABP7 knockdown. Together, our results highlight the potential of FABP7 as a target to modulate neuroinflammation in the central nervous system.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 8","pages":"1627-1641"},"PeriodicalIF":5.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143951775","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":"The Aquaporin-4 Expression and Localization in the Olfactory Epithelium Modulate the Odorant-Evoked Responses and Olfactory-Driven Behavior","authors":"Donatella Lobraico,&nbsp;Pasqua Abbrescia,&nbsp;Maria Grazia Fioriello,&nbsp;Barbara Barile,&nbsp;Claudia Palazzo,&nbsp;Onofrio Valente,&nbsp;Grazia Paola Nicchia,&nbsp;Michele Dibattista,&nbsp;Antonio Frigeri","doi":"10.1002/glia.70024","DOIUrl":"10.1002/glia.70024","url":null,"abstract":"<p>Aquaporin-4 (AQP4) is a water-selective channel expressed in glial cells throughout the central nervous system (CNS). It serves as the primary water channel in the neuropil and plays roles in physiological functions, including regulating water homeostasis by adjusting cell volume and modulating neuronal activity. Different isoforms of AQP4 are expressed in glial-like cells known as sustentacular cells (SUSs) of the olfactory epithelium (OE). Notably, mice lacking all AQP4 isoforms exhibit impaired olfactory abilities. Therefore, we aim to uncover the physiological role of AQP4 isoforms, particularly the AQP4ex isoforms (AQP4M1ex, AQP4M23ex) and the orthogonal array of particles (OAPs)-forming isoform (AQP4M23) in the OE. We investigated the impact of AQP4 isoforms on the OE, observing a reduced number of mature olfactory sensory neurons (OSNs), SUSs, and globose basal cells (GBCs) in mice lacking AQP4ex (AQP4ex-KO) or OAPs (OAP-null). This suggests that AQP4 isoforms are involved in maintaining an optimal microenvironment in the OE, preserving cell density. Next, we explored the role of AQP4 in modulating odorant-evoked responses through electro-olfactogram recordings, where we found reduced odorant responses in mice lacking AQP4 isoforms. Assessments of olfactory ability revealed deficits in odor-guided food-seeking behavior in both AQP4ex-KO and OAP-null mice. Furthermore, AQP4ex-KO mice exhibited a diminished ability to discriminate between different odorants, while OAP-null mice were unable to recognize them as distinct. Overall, our data highlight the role of AQP4 isoforms in modulating neuronal homeostasis, influencing odorant-evoked responses and cell density in the OE, with AQP4ex emerging as a key regulator despite its low abundance.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 8","pages":"1642-1659"},"PeriodicalIF":5.4,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70024","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956054","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":"Starvation Induces Upregulation of Monocarboxylate Transport in Glial Cells at the Drosophila Blood–Brain Barrier","authors":"Andrés González-Gutiérrez,&nbsp;Jorge Gaete,&nbsp;Andrés Esparza,&nbsp;Andrés Ibacache,&nbsp;Esteban G. Contreras,&nbsp;Jimena Sierralta","doi":"10.1002/glia.70021","DOIUrl":"10.1002/glia.70021","url":null,"abstract":"<div>\u0000 \u0000 <p>Living organisms can sense and adapt to constant changes in food availability. Maintaining a homeostatic supply of energy molecules is crucial for animal survival and normal organ functioning, particularly the brain, due to its high-energy demands. However, the mechanisms underlying brain adaptive responses to food availability have not been completely established. The nervous system is separated from the rest of the body by a physical barrier called the blood–brain barrier (BBB). In addition to its structural role, the BBB regulates the transport of metabolites and nutrients into the nervous system. This regulation is achieved through adaptive mechanisms that control the transport of nutrients, including glucose and monocarboxylates such as lactate, pyruvate, and ketone bodies. In \u0000 <i>Drosophila melanogaster</i>\u0000 , carbohydrate transporters increase their expression in glial cells of the BBB in response to starvation. However, changes in the expression or activity of <i>Drosophila</i> monocarboxylate transporters (dMCTs) at the BBB have not yet been reported. Here, we show that neuronal ATP levels remain unaffected despite reduced energy-related metabolites in the hemolymph of <i>Drosophila</i> larvae during starvation. Simultaneously, the transport of lactate and beta-hydroxybutyrate increases in the glial cells of the BBB. Using genetically encoded sensors, we identified Yarqay as a proton-coupled monocarboxylate transporter whose expression is upregulated in the subperineurial glia of the BBB during starvation. Our findings reveal a novel component of the adaptive response of the brain to starvation: the increase in the transport of monocarboxylates across the BBB, mediated by Yarqay, a novel dMCT enriched in the BBB.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 8","pages":"1608-1626"},"PeriodicalIF":5.4,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143958737","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":"Astrocyte Extracellular Matrix Modulates Neuronal Dendritic Development","authors":"Joel G. Hashimoto,&nbsp;Nicholas Margolies,&nbsp;Xiaolu Zhang,&nbsp;Joshua Karpf,&nbsp;Yuefan Song,&nbsp;Natalie Gorham,&nbsp;Brett A. Davis,&nbsp;Fuming Zhang,&nbsp;Robert J. Linhardt,&nbsp;Lucia Carbone,&nbsp;Marina Guizzetti","doi":"10.1002/glia.70020","DOIUrl":"10.1002/glia.70020","url":null,"abstract":"<div>\u0000 \u0000 <p>Major developmental events occurring in the hippocampus during the third trimester of human gestation and neonatally in altricial rodents include rapid and synchronized dendritic arborization and astrocyte proliferation and maturation. We tested the hypothesis that signals sent by developing astrocytes to developing neurons modulate dendritic development in vivo. First, we altered neuronal development by exposing neonatal (third trimester-equivalent) mice to ethanol, which increased dendritic arborization in hippocampal pyramidal neurons. We next assessed concurrent changes in the mouse astrocyte translatome by translating ribosomal affinity purification (TRAP)-seq. We followed up on ethanol-inhibition of astrocyte <i>Chpf2</i> and <i>Chsy1</i> gene translation because these genes encode biosynthetic enzymes of chondroitin sulfate glycosaminoglycan (CS-GAG) chains (extracellular matrix components that inhibit neuronal development and plasticity) and have not been explored before for their roles in dendritic arborization. We report that <i>Chpf2</i> and <i>Chsy1</i> are enriched in astrocytes, and their translation is inhibited by ethanol, which also reduces the levels of CS-GAGs measured by Liquid Chromatography/Mass Spectrometry. Finally, astrocyte-conditioned medium derived from <i>Chfp2</i>-silenced astrocytes increased neurite length and branching of hippocampal neurons in vitro, mechanistically linking changes in CS-GAG biosynthetic enzymes in astrocytes to altered neuronal development. These results demonstrate that CS-GAG biosynthetic enzymes in astrocytes regulate dendritic arborization in developing neurons and are involved in ethanol-induced altered neuronal development.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 8","pages":"1589-1607"},"PeriodicalIF":5.4,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143794196","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":"Role of Cx43 and ACKR3 in Modulating Astrocytic Response and Neuronal Survival Post-Subarachnoid Hemorrhage","authors":"Jian Yan,&nbsp;Shenhao Xie,&nbsp;DianDa Chen,&nbsp;Jinlin Xiao,&nbsp;ErMing Zeng,&nbsp;Tao Hong,&nbsp;Jian Duan","doi":"10.1002/glia.70008","DOIUrl":"10.1002/glia.70008","url":null,"abstract":"<div>\u0000 \u0000 <p>Subarachnoid hemorrhage (SAH) is a devastating neurological disorder that results from the accumulation of blood in the brain's subarachnoid space, leading to significant challenges in neurological recovery. This study explores the molecular interactions between Connexin 43 (Cx43) and Atypical Chemokine Receptor 3 (ACKR3) in astrocytes following SAH, with a focus on their roles in neuroinflammation and neuronal apoptosis. Through transcriptome sequencing and a range of functional assays, we have identified crucial alterations in astrocytic gene expression triggered by the modulation of these proteins. Our results indicate that the Cx43–ACKR3 axis plays a pivotal role in exacerbating neuroinflammatory responses and enhancing neuronal apoptosis, which are key contributors to the pathology of SAH. The data reveal that disrupting this axis could serve as a therapeutic target, suggesting potential interventions to mitigate neuroinflammation, restore astrocytic functionality, and ultimately protect against neuronal damage. This study contributes to the understanding of glial cell dynamics in SAH and opens avenues for novel therapeutic approaches to treat this severe condition.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 8","pages":"1565-1588"},"PeriodicalIF":5.4,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778546","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":"The Alzheimer's Disease Gene SORL1 Regulates Lysosome Function in Human Microglia","authors":"Swati Mishra,&nbsp;Nader Morshed,&nbsp;Sonia Beant Sidhu,&nbsp;Chizuru Kinoshita,&nbsp;Beth Stevens,&nbsp;Suman Jayadev,&nbsp;Jessica E. Young","doi":"10.1002/glia.70009","DOIUrl":"10.1002/glia.70009","url":null,"abstract":"<p>The <i>SORL1</i> gene encodes the sortilin-related receptor protein SORLA, a sorting receptor that regulates endo-lysosomal trafficking of various substrates. Loss of function variants in <i>SORL1</i> are causative for Alzheimer's disease (<span>AD</span>) and decreased expression of SORLA has been repeatedly observed in human <span>AD</span> brains. <i>SORL1</i> is highly expressed in the central nervous system, including in microglia, the tissue-resident immune cells of the brain. Loss of SORLA leads to enlarged lysosomes in hiPSC-derived microglia-like cells (hMGLs). However, how SORLA deficiency contributes to lysosomal dysfunction in microglia and how this contributes to <span>AD</span> pathogenesis is not known. In this study, we show that loss of SORLA results in decreased lysosomal degradation and lysosomal enzyme activity due to altered trafficking of lysosomal enzymes in hMGLs. Phagocytic uptake of fibrillar amyloid beta 1–42 and synaptosomes is increased in SORLA-deficient hMGLs, but due to reduced lysosomal degradation, these substrates aberrantly accumulate in lysosomes. An alternative mechanism of lysosome clearance, lysosomal exocytosis, is also impaired in <i>SORL1</i>-deficient microglia, which may contribute to an altered immune response. Overall, these data suggest that SORLA has an important role in the proper trafficking of lysosomal hydrolases in hMGLs, which is critical for microglial function. This further substantiates the microglial endo-lysosomal network as a potential novel pathway through which <i>SORL1</i> may increase <span>AD</span> risk and contribute to the development of <span>AD</span>. Additionally, our findings may inform the development of novel lysosome and microglia-associated drug targets for <span>AD</span>.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 7","pages":"1329-1348"},"PeriodicalIF":5.4,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778554","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":"Multi-Omic Analysis Reveals Astrocytic Annexin-A2 as Critical for Network-Level Circadian Timekeeping in the Suprachiasmatic Nucleus","authors":"Andrew P. Patton,&nbsp;Toke P. Krogager,&nbsp;Elizabeth S. Maywood,&nbsp;Nicola J. Smyllie,&nbsp;Emma L. Morris,&nbsp;Mark Skehel,&nbsp;Michael H. Hastings","doi":"10.1002/glia.70018","DOIUrl":"10.1002/glia.70018","url":null,"abstract":"<p>The mammalian suprachiasmatic nucleus (SCN) orchestrates daily (circadian) rhythms of physiology and behavior by broadcasting timing cues generated autonomously by its mutually reinforcing network of ~10,000 neurons and ~3000 astrocytes. Although astrocytic control of extracellular glutamate and GABA has been implicated in driving circadian oscillations in SCN gene expression and neuronal activity, the full scale of the network-level signaling mechanisms is unknown. To understand better how this astrocyte-neuron network operates, we adopted a multi-omics approach, first using SILAC-based mass spectrometry to generate an SCN proteome where ~7% of identified proteins were circadian. This circadian proteome was analyzed bioinformatically alongside existing single-cell RNAseq transcriptomic data to identify the cell-types and processes to which they contribute. This highlighted “S100 protein binding,” tracked to astrocytes, and revealed annexin-A2 (Anxa2) as an astrocyte-enriched circadian protein for further investigation. We show that Anxa2 and its partner S100a10 are co-expressed and enriched in SCN astrocytes. We also show that pharmacological disruption of their association acutely and reversibly dysregulated the circadian cycle of astrocytic calcium levels and progressively compromised SCN neuronal oscillations. Anxa2 and S100a10 interaction therefore constitutes an astrocytic cellular signaling axis that regulates circadian neuronal excitability and ultimately SCN network coherence necessary for circadian timekeeping.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 7","pages":"1483-1501"},"PeriodicalIF":5.4,"publicationDate":"2025-04-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143762472","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":"Targeting Connexin 43 in Retinal Astrocytes Promotes Neuronal Survival in Glaucomatous Injury","authors":"Khulan Batsuuri,&nbsp;Abduqodir H. Toychiev,&nbsp;Suresh Viswanathan,&nbsp;Stefanie G. Wohl,&nbsp;Miduturu Srinivas","doi":"10.1002/glia.70013","DOIUrl":"10.1002/glia.70013","url":null,"abstract":"<p>Astrocytes in the retina and optic nerve head play an important role in the pathogenesis of glaucoma. Astrocytes extensively express connexin 43 (Cx43), a protein that forms gap junction (GJ) channels and transmembrane unopposed hemichannels. While it is well documented that Cx43 expression is augmented in retinal injuries, the role of astrocytic Cx43 channels in glaucomatous injury is not fully understood. Here, we used a mouse model of ocular hypertension caused by intracameral microbead injections and a more severe model, optic nerve crush (ONC) injury, and assessed changes in Cx43 expression and GJ channel function. The effect of astrocyte-specific deletion of Cx43 (Cx43KO) on retinal ganglion cell (RGC) loss and visual function was also assessed. We show that the Cx43 expression is increased in retinal astrocytes at early time points and remained elevated even after sustained elevation of intraocular pressure (IOP) (~8 weeks), which paralleled an increase in astrocytic GJ coupling. Deletion of astrocytic Cx43 markedly improved the survival of RGCs by ~93% and preserved visual function as assessed by ERG and reduced numbers of activated microglial/macrophages in the glaucomatous retina. Cx43 expression was also substantially increased after ONC injury, and the absence of Cx43 in this model increased RGC survival by ~48%. These results reveal a deleterious role for Cx43 in glaucoma progression. Intravitreal injections of Gap19, a peptide that reportedly inhibits Cx43 hemichannels but not GJ channels, markedly increased RGC survival and visual function. Further studies are required to assess whether targeting Cx43 hemichannels might be useful for glaucoma treatment.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 7","pages":"1398-1419"},"PeriodicalIF":5.4,"publicationDate":"2025-03-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143741799","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":"The Histone Methyltransferases EHMT1 and EHMT2 Repress the Expression of Genes Related to Excitability and Cell Death in Oligodendrocyte Progenitors","authors":"Mathilde Pruvost,&nbsp;Hye-Jin Park,&nbsp;Chloé Habermacher,&nbsp;Meng Li,&nbsp;Maria Cecilia Angulo,&nbsp;Jia Liu,&nbsp;Patrizia Casaccia","doi":"10.1002/glia.70014","DOIUrl":"10.1002/glia.70014","url":null,"abstract":"<div>\u0000 \u0000 <p>Oligodendrocyte progenitor cells (OPCs) represent a population of electrically active and dividing cells, which are capable of responding to neuronal activity by proliferating and differentiating. Here, we report that the repressive euchromatic H3K9me2 histone mark, deposited by the histone methyltransferases EHMT1 and EHMT2 enzymes, increases in proliferating OPCs in mice following optogenetic stimulation of neuronal activity. Using primary cultured OPCs with genetic deletion of <i>Ehmt1</i> and <i>Ehmt2</i>, and pharmacological inhibition of EHMT enzymatic activity, we reveal the importance of these enzymes in repressing the expression of genes regulating cell death and electrical properties in proliferating OPCs. Consistent with these findings, we detect higher levels of cholinergic muscarinic receptors, fewer numbers of oligodendrocyte lineage cells, and lower levels of the myelin basic protein (MBP) in mice with lineage-specific ablation of <i>Ehmt1</i> and <i>Ehmt2</i>. Together these data suggest that the repressive H3K9me2 histone mark, whose levels increase in proliferating OPCs after neuronal stimulation, is an important modulator of cell death and proteins regulating the electrical properties of OPCs.</p>\u0000 </div>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 7","pages":"1420-1436"},"PeriodicalIF":5.4,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707921","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":"Hippocampal Astrocyte Morphology Follows an Unexpected Trajectory With Age in a Transgenic Rodent Model of Tauopathy","authors":"Emma Augustin,&nbsp;Tatiana Vinasco-Sandoval,&nbsp;Miriam Riquelme-Perez,&nbsp;Damien Plassard,&nbsp;Mylène Gaudin,&nbsp;Gwenaëlle Aurégan,&nbsp;Julien Mitja,&nbsp;Sueva Bernier,&nbsp;Charlène Joséphine,&nbsp;Fanny Petit,&nbsp;Caroline Jan,&nbsp;Anne-Sophie Hérard,&nbsp;Marie-Claude Gaillard,&nbsp;Agathe Launay,&nbsp;Emilie Faivre,&nbsp;Luc Buée,&nbsp;Anne-Laurence Boutillier,&nbsp;David Blum,&nbsp;Alexis-Pierre Bemelmans,&nbsp;Gilles Bonvento,&nbsp;Karine Cambon","doi":"10.1002/glia.70019","DOIUrl":"10.1002/glia.70019","url":null,"abstract":"<p>Individual protoplasmic astrocytes have very complex and diverse spongiform shapes. The morphological diversity of astrocytes is determined by the structural and functional interactions of the astrocyte with its microenvironment. When faced with pathological conditions, astrocytes reorganize their morphology. Yet, little is known about the astrocytic response in pure tauopathies and its evolution over time. Here, we aimed to investigate the consequences of a primary neuronal tau pathology on astrocyte fine morphology at three stages of the disease using the transgenic Thy-Tau22 mouse model. We first showed that hippocampal astrocytes in Thy-Tau22 mice progressively accumulate hyperphosphorylated tau with age. We then developed a pipeline of analyses, including 3D reconstruction of hippocampal tdTomato-labeled astrocytes via a PHP.eB adeno-associated virus, confocal microscopy, Imaris software morphometric analysis, and an advanced statistical analysis. During normal aging, the complexity of astrocyte morphology peaked at adulthood, then declined. In contrast, in Thy-Tau22 mice, tauopathy was associated with a simpler initial morphology, followed by the appearance of a cluster of complex cells at the most advanced stage. Using principal component analysis and hierarchical clustering based on 10 morphological features, we were able to identify different astrocyte morphotypes whose relative proportion varies differently with age between WT and Thy-Tau22 mice. Interestingly, we revealed that a fraction of astrocytes with a complex morphology re-emerges late in tauopathy-affected animals. Our data highlight the concept of significant and reversible structural plasticity of astrocytes when faced with chronic pathological conditions.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"73 7","pages":"1502-1519"},"PeriodicalIF":5.4,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.70019","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143676660","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}