Division of Neurology, Department of Medicine and Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong.
Nat Commun. 2020 Sep 4;11(1):4413. doi: 10.1038/s41467-020-18249-3.
The molecular signatures of cells in the brain have been revealed in unprecedented detail, yet the ageing-associated genome-wide expression changes that may contribute to neurovascular dysfunction in neurodegenerative diseases remain elusive. Here, we report zonation-dependent transcriptomic changes in aged mouse brain endothelial cells (ECs), which prominently implicate altered immune/cytokine signaling in ECs of all vascular segments, and functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism especially in capillary ECs (capECs). An overrepresentation of Alzheimer disease (AD) GWAS genes is evident among the human orthologs of the differentially expressed genes of aged capECs, while comparative analysis revealed a subset of concordantly downregulated, functionally important genes in human AD brains. Treatment with exenatide, a glucagon-like peptide-1 receptor agonist, strongly reverses aged mouse brain EC transcriptomic changes and BBB leakage, with associated attenuation of microglial priming. We thus revealed transcriptomic alterations underlying brain EC ageing that are complex yet pharmacologically reversible.
大脑细胞的分子特征以前所未有的细节被揭示出来，但仍难以确定可能导致神经退行性疾病中神经血管功能障碍的与衰老相关的全基因组表达变化。在这里，我们报告了年老小鼠脑内皮细胞（EC）中与区域相关的转录组变化，这些变化突出表明所有血管段的 EC 中免疫/细胞因子信号发生改变，并且影响血脑屏障（BBB）和葡萄糖/能量代谢的功能变化，尤其是在毛细血管 EC（capEC）中。在差异表达的年老 capEC 基因的人类直系同源物中，阿尔茨海默病（AD）GWAS 基因明显过表达，而比较分析显示在人类 AD 大脑中存在一组下调的、功能重要的基因。用胰高血糖素样肽-1 受体激动剂 exenatide 治疗可强烈逆转年老小鼠脑 EC 的转录组变化和 BBB 渗漏，并伴有小胶质细胞的启动减弱。因此，我们揭示了脑 EC 衰老的潜在转录组改变，其复杂但具有药理学可逆转性。
