Wu Qingbin, Yuan Xiaochen, Bai Jing, Han Ruiqin, Li Zhigang, Zhang Honggang, Xiu Ruijuan
Key Laboratory for Microcirculation, Ministry of Health, Institute of Microcirculation, Chinese Academy Medical Sciences and Pecking Union Medical College, Beijing, China.
Department of Pharmacy, the Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Aging (Albany NY). 2019 Aug 29;11(16):6120-6133. doi: 10.18632/aging.102171.
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 , 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.
微小RNA（miRNA）已成为阿尔茨海默病（AD）病理学中的关键调节因子。MiR-181a与海马记忆形成相关，且在轻度认知障碍（MCI）患者中异常表达，然而，其在AD中的作用及潜在机制却知之甚少。在此，我们报告称，在APP/PS1小鼠中，miR-181a表达下降，与淀粉样β蛋白（Aβ）水平升高同步，这表明miR-181a水平与AD发展呈负相关。此外，通过海马内注射慢病毒过表达miR-181a可改善APP/PS1小鼠的认知缺陷和淀粉样斑块沉积，表明miR-181a对AD进展具有有益作用。此外，miR-181a可减缓APP/PS1小鼠中周细胞的丢失和血脑屏障的破坏。此外，miR-181a可防止Aβ积累诱导的周细胞凋亡，这归因于miR-181a对FOXO1的负调控，因为恢复FOXO1可消除miR-181a对周细胞凋亡的保护作用。总之，这些结果可能确定miR-181a为AD病理学的一种新型调节因子，也暗示miR-181a对血脑屏障周细胞的保护作用可能是其对APP/PS1小鼠产生改善作用的基础。
