@article{94ec708cda15414fb5fa1a54f3a293a8,
title = "Pharmacologically reversible zonation-dependent endothelial cell transcriptomic changes with neurodegenerative disease associations in the aged brain",
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.",
author = "Lei Zhao and Zhongqi Li and Vong, {Joaquim S.L.} and Xinyi Chen and Lai, {Hei Ming} and Yan, {Leo Y.C.} and Junzhe Huang and Sy, {Samuel K.H.} and Xiaoyu Tian and Yu Huang and Chan, {Ho Yin Edwin} and So, {Hon Cheong} and Ng, {Wai Lung} and Yamei Tang and Lin, {Wei Jye} and Mok, {Vincent C.T.} and Ho Ko",
note = "Funding Information: We thank members of the Ko laboratory for helpful discussions; Rossa Chiu and Dennis Lo for the generous support and access to sequencing facilities, David Attwell for insightful advice on an earlier version of the manuscript, and William Wu for helpful discussions and access to confocal microscopy; Becky Yung, Anki Miu, Rebecca Chau, Pauline Kwan, and Rachel Hui for providing administrative support to the project. This work was in part funded by the National Key Research and Development Program of China (2016YFC1300600) (V.C.T.M.); a Faculty Innovation Award (FIA2017/B/01) from the Faculty of Medicine, the Chinese University of Hong Kong (CUHK), and a Croucher Innovation Award from the Croucher Foundation (H.K.); the Gerald Choa Neuroscience Center, Margaret K. L. Cheung Research Centre for Parkinsonism Management, Faculty of Medicine, CUHK (V.C.T.M. and H.K.); the Collaborative Research Fund (C6027-19GF) and the Area of Excellence Scheme (AoE/M-604/16) of the University Grants Committee, Hong Kong (H.K.). Publisher Copyright: {\textcopyright} 2020, The Author(s).",
year = "2020",
month = dec,
day = "1",
doi = "10.1038/s41467-020-18249-3",
language = "English",
volume = "11",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",
}