Research Paper Volume 11, Issue 16 pp 6120—6133

MicroRNA-181a protects against pericyte apoptosis via directly targeting FOXO1: implication for ameliorated cognitive deficits in APP/PS1 mice

Qingbin Wu 1, *, , Xiaochen Yuan 1, *, , Jing Bai 2, *, , Ruiqin Han 3, , Zhigang Li 4, , Honggang Zhang 1, , Ruijuan Xiu 1, ,

  • 1 Key Laboratory for Microcirculation, Ministry of Health, Institute of Microcirculation, Chinese Academy Medical Sciences and Pecking Union Medical College, Beijing, China
  • 2 Department of Pharmacy, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China
  • 3 Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, China
  • 4 School of Acupuncture, Moxibustion and Tuina, Beijing University of Chinese Medicine, Beijing, China
* Equal contribution

received: May 22, 2019 ; accepted: August 5, 2019 ; published: August 29, 2019 ;

https://doi.org/10.18632/aging.102171
How to Cite

Copyright © 2019 Wu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

MicroRNAs (miRNAs) have emerged as critical regulators in the pathology of Alzheimer’s disease (AD). MiR-181a is associated with hippocampal memory formation and aberrantly expressed in patients with mild cognitive impairment (MCI), however, little is known about its role and underlying mechanism involved in AD. Here, we report that miR-181a expression declines in APP/PS1 mice, synchronous with the increase in amyloid β (Aβ) level, which suggests a reverse correlation between miR-181a level and AD development. Additionally, lentiviral overexpression of miR-181a via intrahippocampal injection ameliorates cognitive deficits and amyloid plaque deposition in APP/PS1 mice, indicating a beneficial role of miR-181a against AD progression. Moreover, miR-181a decelerates pericyte loss and blood-brain barrier breakdown in APP/PS1 mice. Furthermore, miR-181a protects against Aβ accumulation-induced pericyte apoptosis in vitro, which is attributed to the negative regulation of FOXO1 by miR-181a, since FOXO1 restoration abolishes miR-181a protective role against pericyte apoptosis. Altogether, these results may identify miR-181a as a novel regulator of AD pathology, and also implicate that the protection of miR-181a in blood-brain barrier pericytes may underlie its ameliorating effect on APP/PS1 mice.

Abbreviations

CNS: central nervous system; BBB: blood-brain barrier; NVU: neurovascular unit; AD: Alzheimer’s disease; Aβ: amyloid β-peptide; MCI: mild cognitive impairment; ELISA: enzyme-linked immunosorbent assay.