School of Public Health, Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, China.
Brain Pathol. 2019 Jul;29(4):558-573. doi: 10.1111/bpa.12698. Epub 2019 Jan 22.
The oxysterol 27-hydroxycholesterol (27-OHC) has been considered to play a key role in the pathogenesis of Alzheimer's disease (AD). Because β-amyloid peptide (Aβ) is the pathological hallmark of AD, the aim of this study is to verify whether 27-OHC could lead to cognitive impairment through modulating Aβ accumulation and deposition. Regulation of Aβ metabolism was explored as the pathogenic mechanism of 27-OHC. Furthermore, microRNAs (miRNAs) and their relations with 27-OHC were also detected. In present study, matched case-control study and APP/PS1 transgenic mice research were conducted. The results showed that the 27-OHC and Aβ in plasma were increased in mild cognitive impairment patients, and a slight correlation was found between 27-OHC and Aβ1-40. This relationship was also proved by the research of APP/PS1 mice. More severe learning and memory impairment and higher Aβ1-40 expression in brain and plasma were detected in the APP/PS1 mice of 27-OHC treatment group. In addition, increased amyloid plaques were also found in the hippocampus of 27-OHC-treated mice. In order to find out the mechanism of 27-OHC on regulating Aβ metabolism, the factors of Aβ production (APP, BACE1 and ADAM10), transport (LRP1 and RAGE) and elimination (NEP and IDE) were tested respectively. The gene and protein expressions of APP, BACE1 and RAGE were increased while LRP1 and IDE were decreased in the brain of 27-OHC-treated mice. At last, down-regulated expression of miRNA let-7g-5p was found after 27-OHC treatment. In conclusion, these findings suggested that excessive 27-OHC could enhance the accumulation and deposition of Aβ both in brain and blood, resulting in a severe impairment of cognition, especially in the modulation of Aβ1-40. The mechanism might be associated with the regulation of Aβ metabolism, and miRNA let-7g-5p was likely to play a vital role in this pathological process induced by 27-OHC.
氧化固醇 27-羟胆固醇（27-OHC）被认为在阿尔茨海默病（AD）的发病机制中起关键作用。由于β-淀粉样肽（Aβ）是 AD 的病理标志，因此本研究旨在验证 27-OHC 是否可以通过调节 Aβ 积累和沉积导致认知障碍。探索 Aβ代谢的调节作为 27-OHC 的发病机制。此外，还检测了 microRNAs（miRNAs）及其与 27-OHC 的关系。本研究进行了匹配的病例对照研究和 APP/PS1 转基因小鼠研究。结果表明，轻度认知障碍患者血浆中的 27-OHC 和 Aβ增加，并且 27-OHC 与 Aβ1-40 之间存在轻微相关性。APP/PS1 小鼠的研究也证明了这种关系。在 27-OHC 处理组的 APP/PS1 小鼠中，发现更严重的学习和记忆障碍以及大脑和血浆中更高的 Aβ1-40 表达。此外，在 27-OHC 处理的小鼠海马中也发现了更多的淀粉样斑块。为了找出 27-OHC 调节 Aβ 代谢的机制，分别检测了 Aβ 产生（APP、BACE1 和 ADAM10）、转运（LRP1 和 RAGE）和消除（NEP 和 IDE）的因素。在 27-OHC 处理的小鼠大脑中，APP、BACE1 和 RAGE 的基因和蛋白表达增加，而 LRP1 和 IDE 减少。最后，发现 27-OHC 处理后 let-7g-5p 的 miRNA 表达下调。总之，这些发现表明，过多的 27-OHC 可增强 Aβ 在大脑和血液中的积累和沉积，导致认知严重障碍，特别是在 Aβ1-40 的调节方面。该机制可能与 Aβ 代谢的调节有关，miRNA let-7g-5p 可能在 27-OHC 诱导的这种病理过程中发挥重要作用。
