线粒体动力学失衡介导海马神经元损伤是阿尔兹海默病（AD）的重要病理机制。及时恢复线粒体动力学稳态，能够减轻甚至逆转神经元损伤。然而AD中线粒体动力学失衡的调控机制迄今不明。线粒体运输系统调控线粒体的运动分布，Miro/Milton复合体是其中的重要组分。项目前期研究首次发现：Rho GTP酶的活化因子早老素2（PS2）能够结合并激活Miro/Milton复合体；AD模型中PS2的突变或缺失诱导线粒体运动分布异常及神经元损伤。以上结果提示：PS2做为线粒体动力学失衡的调控蛋白介导AD神经元损伤。本项目拟通过体内体外研究阐明：PS2突变及缺失通过抑制Miro/Milton复合体活性，介导线粒体动力学失衡，导致AD神经元损伤。试图以线粒体动力学失衡介导神经元损伤为切入点，探索PS2的致病机制；为延缓甚至逆转AD病程进展提供方向。

Damage of hippocampal neurons by dysfunction of mitochondrial dynamics is the major pathological mechanism of Alzheimer's disease (AD). Improvement of mitochondrial dynamics imbalance in time should alleviate or reverse damage of hippocampal neurons. However, the mechanism of dysfunction of mitochondrial dynamics in PD is still unknown. Mitochondrial transportation system regulates the movement and distribution of Mitochondria. Miro/Milton complex is the major part of mitochondrial transportation system. Our previous study for the first time demonstrated that Presenilin2 (PS2), Rho GTP activating factor, interacts with and activates Miro/Milton complex. Furthermore, ectopic expression of PS2-siRNA or PS2-D439A induced abnormal distribution of mitochondria and neuron gamage in AD models. Our findings indicated that PS2, as a regulator of mitochondrial dynamics, induces hippocampal neurons damage in AD. In this research, we plan to demonstrate the mutation or deletion of PS2 inducing dysfunction of mitochondrial dynamics via inactiving Miro/Milton complex in AD. Moreover, we try to find the specific pathogenic mechanism of PS2 by starting at dysfunction of mitochondrial dynamics, and give new insight into inhibiting or reversing the progression of AD.