Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain

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

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

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.

Original languageEnglish
Article number4413
JournalNature Communications
Volume11
Issue number1
DOIs
StatePublished - 1 Dec 2020
Externally publishedYes

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