Issue Archive

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

Received: 　　Accepted:

Corresponding author: 蔡红艳　　E-mail: yancai1@163.com

DOI: 10.13294/j.aps.2022.0081

Citing This Article：

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).