Pharmacologically Reversible Zonation-dependent Endothelial Cell Transcriptomic Changes with Neurodegenerative Disease Associations in the Aged Brain

Overview

Journal Nat Commun

Specialty Biology

Date 2020 Sep 5

PMID 32887883

Citations 54

Authors

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

Affiliations

Soon will be listed here.

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.

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