Dimitra Sokolova, Shari Addington Ghansah, Francesca Puletti, Tatiana Georgiades, Sebastiaan De Schepper, Yongjing Zheng, Gerard Crowley, Ling Wu, Javier Rueda-Carrasco, Angeliki Koutsiouroumpa, Philip Muckett, Oliver J Freeman, Baljit S Khakh, Soyon Hong
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These astrocytes are distinguished by their peri-synaptic processes which are 'bulbous' in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated <i>in vitro</i> and <i>in vivo</i> approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down <i>Mfge8</i> specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.</p>","PeriodicalId":519960,"journal":{"name":"bioRxiv : the preprint server for biology","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11383703/pdf/","citationCount":"0","resultStr":"{\"title\":\"Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models.\",\"authors\":\"Dimitra Sokolova, Shari Addington Ghansah, Francesca Puletti, Tatiana Georgiades, Sebastiaan De Schepper, Yongjing Zheng, Gerard Crowley, Ling Wu, Javier Rueda-Carrasco, Angeliki Koutsiouroumpa, Philip Muckett, Oliver J Freeman, Baljit S Khakh, Soyon Hong\",\"doi\":\"10.1101/2024.08.31.606944\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Region-specific synapse loss is an early pathological hallmark in Alzheimer's disease (AD). 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引用次数: 0
摘要
区域特异性突触丢失是阿尔茨海默病(AD)的早期病理特征。小鼠和人类的最新数据显示,小胶质细胞是大脑驻留的巨噬细胞,是突触丢失的细胞介质;然而,小胶质细胞吞噬突触的上游调节因子仍然难以捉摸。在这里,我们报告了一个独特的星形胶质细胞亚群,它们是维持突触稳态所必需的胶质细胞,在突触丢失开始时以区域特异性的方式随年龄和淀粉样变性而出现。这些星形胶质细胞的特征是突触周围过程的形态呈 "球状",含有积聚的 p62 免疫反应体,并具有缩小的领地域,导致星形胶质细胞-突触覆盖率下降。利用体外和体内综合方法,我们发现星形胶质细胞上调并分泌吞噬调节因子--乳脂球-EGF因子8(MFG-E8),这对于促进小胶质细胞-突触在其局部环境中的吞噬是充分和必要的。最后,我们发现,在两个独立的淀粉样变性小鼠 AD 模型中,利用病毒 CRISPR-saCas9 系统特异性地敲除星形胶质细胞中的 Mfge8 可防止小胶质细胞吞噬突触并改善突触丢失。总之,我们的研究结果突显了在淀粉样蛋白模型中,星形胶质细胞与小胶质细胞在决定突触命运方面的相互影响,并将星形胶质细胞的 MFGE8 定义为在 AD 最早期阶段改善突触丢失的潜在靶点。
Region-specific synapse loss is an early pathological hallmark in Alzheimer's disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are 'bulbous' in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated in vitro and in vivo approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down Mfge8 specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.