Glia最新文献

{"title":"ApoE4 expression disrupts tau uptake, trafficking, and clearance in astrocytes","authors":"Maxwell Eisenbaum,&nbsp;Andrew Pearson,&nbsp;Camila Ortiz,&nbsp;Michael Mullan,&nbsp;Fiona Crawford,&nbsp;Joseph Ojo,&nbsp;Corbin Bachmeier","doi":"10.1002/glia.24469","DOIUrl":"10.1002/glia.24469","url":null,"abstract":"<p>Tauopathies are a collection of neurodegenerative diseases characterized by the accumulation of pathogenic aggregates of the microtubule-associated protein tau. Despite the prevalence and diversity of tau astrogliopathy in tauopathies, the interactions between astrocytes and tau in the brain, and the influence of neurodegenerative genetic risk factors like the apolipoprotein E4 (apoE4) isoform, are largely unknown. Here, we leveraged primary and immortalized astrocytes expressing humanized apoE isoforms to characterize the mechanisms by which astrocytes interact with and eliminate extracellular tau, and the influence of apoE genotype on these processes. Our work indicates that astrocytes rapidly internalize, process, and release tau via an exosomal secretory mechanism under physiological conditions. However, we found that apoE4 disrupted these processes in comparison to apoE3, resulting in an astrocytic phenotype prone to intracellular tau accumulation. Furthermore, exposure to repetitive mild traumatic brain injuries exacerbated the apoE4-induced impairments in tau processing and elimination by astrocytes in apoE4 targeted-replacement mice. The diminished ability of apoE4 astrocytes to eliminate extracellular tau can lead to an accumulation of pathogenic tau, which induces mitochondrial dysfunction, as demonstrated by our studies. In total, our findings suggest that the apoE4 isoform lowers the threshold of astrocytic resilience to pathogenic tau, rendering them susceptible to bioenergetic deficits in the early stages of neurodegenerative diseases such as traumatic brain injury, potentially contributing to neurological decline.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"184-205"},"PeriodicalIF":6.2,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10153964","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":"Inhibiting astrocyte connexin-43 hemichannels blocks radiation-induced vesicular VEGF-A release and blood–brain barrier dysfunction","authors":"Steffi Schumacher,&nbsp;Hanane Tahiri,&nbsp;Pascal Ezan,&nbsp;Nathalie Rouach,&nbsp;Katja Witschas,&nbsp;Luc Leybaert","doi":"10.1002/glia.24460","DOIUrl":"10.1002/glia.24460","url":null,"abstract":"<p>Therapeutic brain irradiation with ionizing radiation exerts multiple side effects including barrier leakage that disturbs glial-neuronal functioning and may affect cognition. Astrocytes contribute to barrier leakage by endfeet release of various vasoactive substances acting on capillary endothelial cells forming the barrier. Here, we investigated X-ray effects on astrocytic vesicular transport in mice and determined whether interfering with astrocyte connexins affects radiation-induced barrier leakage. We found that astrocytic VEGF-A-loaded VAMP3 vesicles drastically reorganize starting from 6 h post-irradiation and move in a calcium- and Cx43-dependent manner towards endfeet where VEGF-A is released, provoking barrier leakage. Vesicular transport activation, VEGF-A release and leakage 24 h post-irradiation were all potently inhibited by astrocytic Cx43 KO, Cx43S255/262/279/282A (MK4) mutant mice and TATGap19 inhibition of Cx43 hemichannel opening. Astrocyte VEGF release is a major player in complications of brain irradiation, which can be mitigated by anti-VEGF treatments. Targeting Cx43 hemichannels allows to prevent astrocyte VEGF release at an early stage after brain irradiation.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"34-50"},"PeriodicalIF":6.2,"publicationDate":"2023-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10534275","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":"Astrocytic FoxO1 in the hypothalamus regulates metabolic homeostasis by coordinating neuropeptide Y neuron activity","authors":"Khanh Van Doan,&nbsp;Le Trung Tran,&nbsp;Dong Joo Yang,&nbsp;Thu Thi Anh Ha,&nbsp;Thi Dang Mai,&nbsp;Seul Ki Kim,&nbsp;Ronald A. DePinho,&nbsp;Dong-Min Shin,&nbsp;Yun-Hee Choi,&nbsp;Ki Woo Kim","doi":"10.1002/glia.24448","DOIUrl":"10.1002/glia.24448","url":null,"abstract":"<p>The forkhead box transcription factor O1 (FoxO1) is expressed ubiquitously throughout the central nervous system, including in astrocytes, the most prevalent glial cell type in the brain. While the role of FoxO1 in hypothalamic neurons in controlling food intake and energy balance is well-established, the contribution of astrocytic FoxO1 in regulating energy homeostasis has not yet been determined. In the current study, we demonstrate the essential role of hypothalamic astrocytic FoxO1 in maintaining normal neuronal activity in the hypothalamus and whole-body glucose metabolism. Inhibition of FoxO1 function in hypothalamic astrocytes shifts the cellular metabolism from glycolysis to oxidative phosphorylation, enhancing astrocyte ATP production and release meanwhile decreasing astrocytic export of lactate. As a result, specific deletion of astrocytic FoxO1, particularly in the hypothalamus, causes a hyperactivation of hypothalamic neuropeptide Y neurons, which leads to an increase in acute feeding and impaired glucose regulation and ultimately results in diet-induced obesity and systemic glucose dyshomeostasis.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"71 12","pages":"2735-2752"},"PeriodicalIF":6.2,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24448","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10120343","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":"How brain ‘cleaners’ fail: Mechanisms and therapeutic value of microglial phagocytosis in Alzheimer's disease","authors":"Junjun Ni,&nbsp;Zhen Xie,&nbsp;Zhenzhen Quan,&nbsp;Jie Meng,&nbsp;Hong Qing","doi":"10.1002/glia.24465","DOIUrl":"10.1002/glia.24465","url":null,"abstract":"<p>Microglia are the resident phagocytes of the brain, where they primarily function in the clearance of dead cells and the removal of un- or misfolded proteins. The impaired activity of receptors or proteins involved in phagocytosis can result in enhanced inflammation and neurodegeneration. RNA-seq and genome-wide association studies have linked multiple phagocytosis-related genes to neurodegenerative diseases, while the knockout of such genes has been demonstrated to exert protective effects against neurodegeneration in animal models. The failure of microglial phagocytosis influences AD-linked pathologies, including amyloid β accumulation, tau propagation, neuroinflammation, and infection. However, a precise understanding of microglia-mediated phagocytosis in Alzheimer's disease (AD) is still lacking. In this review, we summarize current knowledge of the molecular mechanisms involved in microglial phagocytosis in AD across a wide range of pre-clinical, <i>post-mortem</i>, ex vivo, and clinical studies and review the current limitations regarding the detection of microglia phagocytosis in AD. Finally, we discuss the rationale of targeting microglial phagocytosis as a therapeutic strategy for preventing AD or slowing its progression.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 2","pages":"227-244"},"PeriodicalIF":6.2,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10122636","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":"Expression of functionally distinct ecto-5′-nucleotidase/CD73 glycovariants in reactive astrocytes in experimental autoimmune encephalomyelitis and neuroinflammatory conditions in vitro","authors":"Marija Adzic Bukvic,&nbsp;Danijela Laketa,&nbsp;Milorad Dragic,&nbsp;Irena Lavrnja,&nbsp;Nadezda Nedeljkovic","doi":"10.1002/glia.24459","DOIUrl":"10.1002/glia.24459","url":null,"abstract":"<p>Ecto-5′-nucleotidase/CD73 (eN/CD73) is a membrane-bound enzyme involved in extracellular production of adenosine and a cell adhesion molecule involved in cell–cell interactions. In neuroinflammatory conditions such as experimental autoimmune encephalomyelitis (EAE), reactive astrocytes occupying active demyelination areas significantly upregulate eN/CD73 and express additional eN/CD73 variants. The present study investigated whether the different eN/CD73 variants represent distinct glycoforms and the functional consequences of their expression in neuroinflammatory states. The study was performed in animals at different stages of EAE and in primary astrocyte cultures treated with a range of inflammatory cytokines. Upregulation at the mRNA, protein, and functional levels, as well as the appearance of multiple eN/CD73 glycovariants were detected in the inflamed spinal cord tissue. At the peak of the disease, eN/CD73 exhibited higher AMP turnover and lower enzyme-substrate affinity than the control group, which was attributed to altered glycosylation under neuroinflammatory conditions. A subsequent in vitro study showed that primary astrocytes upregulated eN/CD73 and expressed the multiple glycovariants upon stimulation with TNFα, IL-1β, IL-6, and ATP, with the effect occurring at least in part via induction of JAK/STAT3 signaling. Experimental removal of glycan moieties from membrane glycoproteins by PNGaseF decreased eN/CD73 activity but had no effect on the enzyme's involvement in astrocyte migration. Our results suggest that neuroinflammatory states are associated with the appearance of functionally distinct eN/CD73 glycovariants, which may play a role in the development of the reactive astrocyte phenotype.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"19-33"},"PeriodicalIF":6.2,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10104294","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":"TREM2 promotes glioma progression and angiogenesis mediated by microglia/brain macrophages","authors":"Xuezhen Chen,&nbsp;Yue Zhao,&nbsp;Yimin Huang,&nbsp;Kaichuan Zhu,&nbsp;Fan Zeng,&nbsp;Junyi Zhao,&nbsp;Huaqiu Zhang,&nbsp;Xinzhou Zhu,&nbsp;Helmut Kettenmann,&nbsp;Xianyuan Xiang","doi":"10.1002/glia.24456","DOIUrl":"https://doi.org/10.1002/glia.24456","url":null,"abstract":"<p>Triggering receptor expressed on myeloid cell 2 (TREM2), a myeloid cell-specific signaling molecule, controls essential functions of microglia and impacts on the pathogenesis of Alzheimer's disease and other neurodegenerative disorders. TREM2 is also highly expressed in tumor-associated macrophages in different types of cancer. Here, we studied whether TREM2 influences glioma progression. We found a gender-dependent effect of glioma growth in wild-type (WT) animals injected with GL261-EGFP glioma cells. Most importantly, TREM2 promotes glioma progression in male but not female animals. The accumulation of glioma-associated microglia/macrophages (GAMs) and CD31⁺ blood vessel density is reduced in male TREM2-deficient mice. A transcriptomic analysis of glioma tissue revealed that TREM2 deficiency suppresses immune-related genes. In an organotypic slice model devoid of functional vascularization and immune components from periphery, the tumor size was not affected by TREM2-deficiency. In human resection samples from glioblastoma, TREM2 is upregulated in GAMs. Based on the Cancer Genome Atlas Program (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases, the TREM2 expression levels were negatively correlated with survival. Thus, the TREM2-dependent crosstalk between GAMs and the vasculature formation promotes glioma growth.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"71 11","pages":"2679-2695"},"PeriodicalIF":6.2,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24456","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"5889552","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":"An 840 kb distant upstream enhancer is a crucial regulator of catecholamine-dependent expression of the Bdnf gene in astrocytes","authors":"Annela Avarlaid,&nbsp;Eli-Eelika Esvald,&nbsp;Indrek Koppel,&nbsp;Annabel Parkman,&nbsp;Anna Zhuravskaya,&nbsp;Eugene V. Makeyev,&nbsp;Jürgen Tuvikene,&nbsp;Tõnis Timmusk","doi":"10.1002/glia.24463","DOIUrl":"10.1002/glia.24463","url":null,"abstract":"<p>Brain-derived neurotrophic factor (BDNF) plays a fundamental role in the developing and adult nervous system, contributing to neuronal survival, differentiation, and synaptic plasticity. Dysregulation of BDNF synthesis, secretion or signaling has been associated with many neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Although the transcriptional regulation of the <i>Bdnf</i> gene has been extensively studied in neurons, less is known about the regulation and function of BDNF in non-neuronal cells. The most abundant type of non-neuronal cells in the brain, astrocytes, express BDNF in response to catecholamines. However, genetic elements responsible for this regulation have not been identified. Here, we investigated four potential <i>Bdnf</i> enhancer regions and based on reporter gene assays, CRISPR/Cas9 engineering and CAPTURE-3C-sequencing we conclude that a region 840 kb upstream of the <i>Bdnf</i> gene regulates catecholamine-dependent expression of <i>Bdnf</i> in rodent astrocytes. We also provide evidence that this regulation is mediated by CREB and AP1 family transcription factors. This is the first report of an enhancer coordinating the transcription of <i>Bdnf</i> gene in non-neuronal cells.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"90-110"},"PeriodicalIF":6.2,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24463","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10448787","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":"Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS","authors":"Tal Ganz,&nbsp;Omri Zveik,&nbsp;Nina Fainstein,&nbsp;Marva Lachish,&nbsp;Ariel Rechtman,&nbsp;Lihi Sofer,&nbsp;Livnat Brill,&nbsp;Tamir Ben-Hur,&nbsp;Adi Vaknin-Dembinsky","doi":"10.1002/glia.24453","DOIUrl":"10.1002/glia.24453","url":null,"abstract":"<p>Remyelination failure is considered a major obstacle in treating chronic-progressive multiple sclerosis (MS). Studies have shown blockage in the differentiation of resident oligodendrocyte progenitor cells (OPC) into myelin-forming cells, suggesting that pushing OPC into a differentiation program might be sufficient to overcome remyelination failure. Others stressed the need for a permissive environment to allow proper activation, migration, and differentiation of OPC. PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models. We examined PD0325901 effects in the chronically inflamed central nervous system. Treatment with PD0325901 induced OPC differentiation into mature oligodendrocytes with high morphological complexity. However, treatment of Biozzi mice with chronic-progressive experimental autoimmune encephalomyelitis with PD0325901 showed no clinical improvement in comparison to the control group, no reduction in demyelination, nor induction of OPC migration into foci of demyelination. PD0325901 induced a direct general immunosuppressive effect on various cell populations, leading to a diminished phagocytic capability of microglia and less activation of lymph-node cells. It also significantly impaired the immune-modulatory functions of OPC. Our findings suggest OPC regenerative function depends on a permissive environment, which may include pro-regenerative inflammatory elements. Furthermore, they indicate that maintaining a delicate balance between the pro-myelinating and immune functions of OPC is of importance. Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"71 12","pages":"2815-2831"},"PeriodicalIF":6.2,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24453","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10080039","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":"Pathological Bergmann glia alterations and disrupted calcium dynamics in ataxic Canavan disease mice","authors":"Vanessa L. Hull,&nbsp;Yan Wang,&nbsp;Travis Burns,&nbsp;Sarah Sternbach,&nbsp;Shuaishuai Gong,&nbsp;Jennifer McDonough,&nbsp;Fuzheng Guo,&nbsp;Laura N. Borodinsky,&nbsp;David Pleasure","doi":"10.1002/glia.24454","DOIUrl":"10.1002/glia.24454","url":null,"abstract":"<p>Canavan disease (CD) is a recessively inherited pediatric leukodystrophy resulting from inactivating mutations to the oligodendroglial enzyme aspartoacylase (ASPA). ASPA is responsible for hydrolyzing the amino acid derivative <i>N</i>-acetyl-L-aspartate (NAA), and without it, brain NAA concentrations increase by 50% or more. Infants and children with CD present with progressive cognitive and motor delays, cytotoxic edema, astroglial vacuolation, and prominent spongiform brain degeneration. ASPA-deficient CD mice (<i>Aspa</i>^nur7/nur7) present similarly with elevated NAA, widespread astroglial dysfunction, ataxia, and Purkinje cell (PC) dendritic atrophy. Bergmann glia (BG), radial astrocytes essential for cerebellar development, are intimately intertwined with PCs, where they regulate synapse stability, functionality, and plasticity. BG damage is common to many neurodegenerative conditions and frequently associated with PC dysfunction and ataxia. Here, we report that, in CD mice, BG exhibit significant morphological alterations, decreased structural associations with PCs, loss of synaptic support proteins, and altered calcium dynamics. We also find that BG dysfunction predates cerebellar vacuolation and PC damage in CD mice. Previously, we developed an antisense oligonucleotide (ASO) therapy targeting Nat8l (<i>N</i>-acetyltransferase-8-like, “Nat8l ASO”) that inhibits the production of NAA and reverses ataxia and PC atrophy in CD mice. Here, we show that Nat8l ASO administration in adult CD mice also leads to BG repair. Furthermore, blocking astroglial uptake of NAA is neuroprotective in astroglia-neuron cocultures exposed to elevated NAA. Our findings suggest that restoration of BG structural and functional integrity could be a mechanism for PC regeneration and improved motor function.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"71 12","pages":"2832-2849"},"PeriodicalIF":6.2,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/glia.24454","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10158633","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":"Endothelial senescence alleviates cognitive impairment in a mouse model of Alzheimer's disease","authors":"Sayo Horibe,&nbsp;Takuo Emoto,&nbsp;Taiji Mizoguchi,&nbsp;Toru Tanaka,&nbsp;Shoji Kawauchi,&nbsp;Naoto Sasaki,&nbsp;Tomoya Yamashita,&nbsp;Koji Ikeda,&nbsp;Noriaki Emoto,&nbsp;Ken-ichi Hirata,&nbsp;Yoshiyuki Rikitake","doi":"10.1002/glia.24461","DOIUrl":"10.1002/glia.24461","url":null,"abstract":"<p>Alzheimer's disease (AD) is among the most prevalent age-related neurodegenerative diseases. Endothelial cell (EC) senescence was discovered in the AD brain, but its function in AD pathogenesis was unidentified. Here we created an AD mouse model with EC senescence (APP/PS1;TERF2DN mice) by intercrossing APP/PS1 mice with Tie2 promoter-driven dominant negative telomeric repeat-binding factor 2 transgenic mice (TERF2DN-Tg mice). We evaluated cognitive functions and AD brain pathology in APP/PS1;TERF2DN mice. Surprisingly, compared with the control APP/PS1 mice, APP/PS1;TERF2DN mice demonstrated the attenuation of cognitive impairment and amyloid-β (Aβ) pathology, accompanied by the compaction of Aβ plaques with increased microglial coverage and reduced neurite dystrophy. Moreover, we evaluated whether EC senescence could affect microglial morphology and phagocytosis of Aβ. Compared with wild-type mice, microglia in TERF2DN-Tg mice display increased numbers of endpoints (a morphometric parameter to quantify the number of processes) and Aβ phagocytosis and related gene expression. Single-cell RNA-sequencing analysis showed that compared with APP/PS1 mouse microglia, APP/PS1;TERF2DN mouse microglia displayed a modest decline in disease-associated microglia, accompanied by an altered direction of biological process branching from antigen synthesis and arrangement to ribonucleoprotein complex biogenesis. Our outcomes indicate that EC senescence alters microglia toward a protective phenotype with a rise in phagocytic and barrier roles, and may offer a clue to create a novel preventive/therapeutic method to treat AD.</p>","PeriodicalId":174,"journal":{"name":"Glia","volume":"72 1","pages":"51-68"},"PeriodicalIF":6.2,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10407831","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}