小胶质细胞
生物
星形胶质细胞
炎症
转录组
阿尔茨海默病
特雷姆2
蛋白质稳态
病理
老年斑
电池类型
神经胶质
β淀粉样蛋白
基因表达
细胞生物学
神经科学
免疫学
细胞
中枢神经系统
基因
医学
疾病
遗传学
生物化学
肽
作者
Amy M. Smith,Karen Davey,Stergios Tsartsalis,Combiz Khozoie,Nurun Fancy,See Swee Tang,Eirini Liaptsi,Maria Weinert,A. McGarry,Robert C. J. Muirhead,Steve Gentleman,David R. Owen,Paul M. Matthews
标识
DOI:10.1007/s00401-021-02372-6
摘要
To better define roles that astrocytes and microglia play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.
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