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 () and Ho Ko ()
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Lei Zhao: The Chinese University of Hong Kong
Zhongqi Li: The Chinese University of Hong Kong
Joaquim S. L. Vong: The Chinese University of Hong Kong
Xinyi Chen: The Chinese University of Hong Kong
Hei-Ming Lai: The Chinese University of Hong Kong
Leo Y. C. Yan: The Chinese University of Hong Kong
Junzhe Huang: The Chinese University of Hong Kong
Samuel K. H. Sy: The Chinese University of Hong Kong
Xiaoyu Tian: The Chinese University of Hong Kong
Yu Huang: The Chinese University of Hong Kong
Ho Yin Edwin Chan: The Chinese University of Hong Kong
Hon-Cheong So: The Chinese University of Hong Kong
Wai-Lung Ng: The Chinese University of Hong Kong
Yamei Tang: Sun Yat-Sen University
Wei-Jye Lin: Sun Yat-Sen University
Vincent C. T. Mok: The Chinese University of Hong Kong
Ho Ko: The Chinese University of Hong Kong

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18249-3

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