The First Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, 161000, PR China.
The First Department of Neurology, The Second Affiliated Hospital of Qiqihar Medical University, Qiqihar, 161000, PR China.
Neurosci Lett. 2021 Jul 27;758:135674. doi: 10.1016/j.neulet.2021.135674. Epub 2021 Jan 30.
Alzheimer's disease (AD) is a neurodegenerative condition leading to severe disability from progressive impairments in cognitive functions including memory and learning. Non-coding microRNAs (miRNAs or miRs) have been linked to the pathogenesis of AD. The present study aimed to investigate the clinical significance and biological function of miR-140 in AD. First, we examined the expression of miR-140 and PINK1 in brain tissues of the established AD model rats and neurons cultured with Aβ-derived diffusible ligands (AβDDLs). We identified an interaction between miR-140 and PINK1, and measured spatial learning and memory abilities of the model rats using the Morris water maze (MWM) test. After ectopic expression and depletion experiments in neurons and AD rats, we measured the levels of reactive oxygen species (ROS), and mitochondrial membrane potential (MMP), along with mTOR expression and phosphorylation, and autophagy-related factors. Results showed up-regulation of miR-140 and down-regulation of PINK1 in AD model rats and neurons. PINK1 was verified to be a direct target of miR-140, and silencing of miR-140 suppressed mitochondrial dysfunction, and enhanced autophagy in AD model rats and neurons, as supported by decreased levels of mTOR expression and phosphorylation, β-amyloid p-Tau (Ser396), p-Tau (Thr231), Tau and ROS, and increased MMP levels and expression of Beclin 1 expression and LC3-II/LC3-I. Collectively, functional suppression of miR-140 enhanced autophagy and prevented mitochondrial dysfunction by upregulating PINK1, ultimately suggesting a novel therapeutic target for AD.
阿尔茨海默病（AD）是一种神经退行性疾病，导致认知功能（包括记忆和学习）进行性受损，严重致残。非编码 microRNAs（miRNAs 或 miRs）与 AD 的发病机制有关。本研究旨在探讨 miR-140 在 AD 中的临床意义和生物学功能。首先，我们检测了建立的 AD 模型大鼠脑组织和 Aβ 衍生可扩散配体（AβDDLs）培养的神经元中 miR-140 和 PINK1 的表达。我们鉴定了 miR-140 和 PINK1 之间的相互作用，并使用 Morris 水迷宫（MWM）测试测量了模型大鼠的空间学习和记忆能力。在神经元和 AD 大鼠中外源表达和耗竭实验后，我们测量了活性氧（ROS）和线粒体膜电位（MMP）水平，以及 mTOR 表达和磷酸化水平以及自噬相关因子。结果显示，AD 模型大鼠和神经元中 miR-140 上调，PINK1 下调。PINK1 被验证为 miR-140 的直接靶标，沉默 miR-140 可抑制线粒体功能障碍，并增强 AD 模型大鼠和神经元中的自噬，这得到了 mTOR 表达和磷酸化、β-淀粉样蛋白 p-Tau（Ser396）、p-Tau（Thr231）、Tau 和 ROS 水平降低以及 MMP 水平和 Beclin 1 表达以及 LC3-II/LC3-I 表达增加的支持。总之，miR-140 的功能抑制通过上调 PINK1 增强了自噬并防止了线粒体功能障碍，最终为 AD 提供了一个新的治疗靶点。
