Abstract：
Alzheimer\'s disease (AD) is a progressive and degenerative disorder accompanied by emotional disturbance, especially anxiety and depression. More and more evidence shows that the imbalance of mitochondrial Ca2+ (mCa2+) homeostasis has a close connection with the pathogenesis of anxiety and depression. The Mitochondrial Calcium Uniporter (MCU), a key channel of mCa2+ uptake, induces the imbalance of mCa2+ homeostasis and may be a therapeutic target for anxiety and depression of AD. In the present study, we revealed for the first time that MCU knockdown in hippocampal neurons alleviated anxious and depressive behaviors of APP/PS1/tau mice through elevated plus-maze (EPM), elevated zero maze (EZM), sucrose preference test (SPT) and tail suspension test (TST). Western blot analysis results demonstrated that MCU knockdown in hippocampal neurons increased levels of glutamate decarboxylase 67 (GAD67), vesicular GABA transporter (vGAT) and GABAA receptor α1 (GABRA1) and activated the PKA-CREB-BDNF signaling pathway. This study indicates that MCU inhibition has the potential to be developed as a novel therapy for anxiety and depression in AD.
摘要：
阿尔茨海默病(Alzheimer\'sdisease,AD)是一种伴随情绪障碍的进行性退行性疾病,尤其是焦虑和抑郁.越来越多的证据表明,线粒体Ca2+(mCa2+)稳态失衡与焦虑抑郁的发病机制密切相关。线粒体钙离子转运蛋白（MCU），mCa2+吸收的关键通道，诱导mCa2+稳态失衡，可能是AD焦虑和抑郁的治疗靶点。在本研究中,我们首次揭示了海马神经元中的MCU敲除通过升高的迷宫（EPM）减轻了APP/PS1/tau小鼠的焦虑和抑郁行为，高架零迷宫（EZM），蔗糖偏好试验(SPT)和尾悬试验(TST)。Westernblot分析结果表明，MCU敲低海马神经元谷氨酸脱羧酶67（GAD67）水平升高，囊泡GABA转运体(vGAT)和GABAA受体α1(GABRA1)并激活PKA-CREB-BDNF信号通路。这项研究表明，MCU抑制有可能被开发为AD中焦虑和抑郁的新疗法。
