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海马神经元敲低MCU改善阿尔茨海默病小鼠学习记忆功能障碍

蔡红艳^1,2,3,*, 乔晶¹, 陈思茹¹, 樊卫平¹

¹山西医科大学微生物学与免疫学教研室，太原 030001；²山西医科大学细胞生理学教育部重点实验室，太原 030001；³山西医科大学细胞生理学山西省重点实验室，太原 030001

摘要

阿尔茨海默病(Alzheimer’s disease, AD)是一种严重威胁老年人健康的神经退行性疾病，目前为止仍然缺乏有效的治疗方法。最新研究表明，线粒体功能紊乱是AD发展的直接原因。线粒体钙离子单向转运体(mitochondrial calcium uniporter, MCU)位于线粒体内膜，是线粒体Ca2+摄取的主要通道。MCU表达异常可引起线粒体钙稳态失衡，最终导致线粒体功能紊乱。本研究旨在明确敲低MCU对AD海马神经元和模型小鼠学习记忆功能的影响。以慢病毒和腺相关病毒为载体转染shRNA，分别干扰海马神经元(HT22细胞)和淀粉样前体蛋白(amyloid precursor protein, APP)/早老素1 (presenilin 1, PS1)/tau AD转基因小鼠海马MCU表达，用MTS法检测HT22细胞活性，用Y迷宫和Morris水迷宫实验检测APP/PS1/tau转基因小鼠学习记忆功能障碍的变化。结果显示，MCU低表达可以逆转β淀粉样蛋白1-42 (amyloid beta protein 1-42, Aβ1-42)或冈田酸(okadaic acid, OA)诱导的海马神经元活性下降；海马神经元敲低MCU能够提高APP/PS1/tau小鼠的自发交替正确率(反映空间工作记忆)，缩短逃避潜伏期，增加目标象限游泳时间百分比和穿台次数(反映空间参考记忆)。以上结果提示，海马神经元敲低MCU具有抗AD作用，有望成为AD防治的一种新策略。

关键词： 阿尔茨海默病; 线粒体功能紊乱; 线粒体钙稳态失衡; 线粒体钙离子单向转运体; 学习记忆功能障碍

Mitochondrial calcium uniporter knockdown in hippocampal neurons improved the learning and memory dysfunction of Alzheimer’s disease mice

CAI Hong-Yan^1,2,3,*, QIAO Jing¹, CHEN Si-Ru¹, FAN Wei-Ping¹

¹Department of Microbiology and Immunology, Shanxi Medical University, Taiyuan 030001, China；²Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China；³Key Laboratory of Cellular Physiology of Shanxi Province, Shanxi Medical University, Taiyuan 030001, China

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder, which seriously affects health of the elderly, and is still irreversible up to now. Recent studies have indicated that mitochondrial dysfunction is a direct reason to promote the development of AD. Mitochondrial calcium uniporter (MCU), located in the inner membrane of mitochondria, is a key channel of mitochondrial Ca2+ uptake. Abnormal MCU expression results in imbalance of mitochondrial calcium homeostasis, ultimately leading to mitochondrial dysfunction. The purpose of this study was to determine the effects of MCU knockdown on AD hippocampal neurons and learning and memory function of AD model mice. Lentivirus and adeno-associated virus were used as vectors to transfect shRNA into hippocampal neurons (HT22 cells) and hippocampi of amyloid precursor protein (APP)/presenilin 1 (PS1)/tau AD transgenic mice, respectively, in order to interfere with MCU expression. The cellular activity of HT22 cells was detected by MTS method, and the changes of learning and memory dysfunction in APP/PS1/tau AD transgenic mice were tested by Y maze and Morris water maze. The results showed that MCU knockdown reversed the cellular activity of HT22 cells decreased by amyloid beta protein 1-42 (Aβ1-42) or okadaic acid (OA). Knockdown of MCU in hippocampal neurons improved spontaneous alternation (spatial working memory), decreased escape latency, and increased time in target quadrant and number of platform crossing (spatial reference memory) of the APP/PS1/tau mice. This study suggests that MCU knockdown in hippocampal neurons has anti-AD effect, and it is expected to be a new strategy for prevention and treatment of AD.

Key words: Alzheimer’s disease; mitochondrial dysfunction; imbalance of mitochondrial calcium homeostasis; mitochondrial calcium uniporter; learning and memory dysfunction

收稿日期：　　录用日期：

通讯作者：蔡红艳　　E-mail: yancai1@163.com

DOI: 10.13294/j.aps.2022.0081

引用本文：

蔡红艳, 乔晶, 陈思茹, 樊卫平. 海马神经元敲低MCU改善阿尔茨海默病小鼠学习记忆功能障碍[J]. 生理学报 2022; 74 (5): 715-725.

CAI Hong-Yan, QIAO Jing, CHEN Si-Ru, FAN Wei-Ping. Mitochondrial calcium uniporter knockdown in hippocampal neurons improved the learning and memory dysfunction of Alzheimer’s disease mice. Acta Physiol Sin 2022; 74 (5): 715-725 (in Chinese with English abstract).