Zonation-dependent single-endothelial cell transcriptomic changes in the aged brain
Publication in refereed journal

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摘要With advances in single-cell genomics, molecular signatures of cells comprising the brain vasculature are revealed in unprecedented detail1,2, yet the ageing-associated cell subtype transcriptomic changes which may contribute to neurovascular dysfunction in neurodegenerative diseases3–7 remain elusive. Here, we performed single-cell transcriptomic profiling of brain endothelial cells (EC) in young adult and aged mice to characterize their ageing-associated genome-wide expression changes. We identified zonation-dependent transcriptomic changes in aged brain EC subtypes, with capillary ECs exhibiting the most transcriptomic alterations. Pathway enrichment analysis revealed altered immune/cytokine signaling in ECs of all vascular segments, while functional changes impacting the blood-brain barrier (BBB) and glucose/energy metabolism were most prominently implicated in ECs of the capillary bed – the primary site where ECs and other neurovascular unit (NVU) cell types closely interact and coordinate to regulate BBB and cerebral blood flow in health and diseased conditions8–17. Furthermore, an overrepresentation of Alzheimer’s disease (AD)-associated genes identified from GWAS studies was evident among the human orthologs of differentially expressed genes of aged capillary ECs but not other EC subtypes. Importantly, for numerous EC-enriched differentially expressed genes with important functional roles at the BBB and/or association with AD, we found concordant expression changes in human aged or AD brains. Finally, we demonstrated that treatment with exenatide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, strongly reverses transcriptomic changes in ECs and largely reduces BBB leakage in the aged brain. Thus, our study provides insights into detailed transcriptomic alterations underlying brain EC ageing that are complex with subtype specificity yet amenable to pharmacological interventions.
著者Lei Zhao, Zhongqi Li, Joaquim S. L. Vong, Xinyi Chen, Hei-Ming Lai, Leo Y. C. Yan, Junzhe Huang, Samuel K. H. Sy, Xiaoyu Tian, Yu Huang, Ho Yin Edwin Chan, Hon-Cheong So, Wai-Lung Ng, Yamei Tang, Wei-Jye Lin, Vincent C.T. Mok, Ho Ko
期刊名稱bioRxiv
出版年份2019
月份10
日期11
文章號碼800318
電子國際標準期刊號2379-3708
語言英式英語

上次更新時間 2020-03-08 於 01:46