Mitochondrial pore and synaptic stress in Alzheimer's disease

描述（由申请人提供）：线粒体功能障碍和突触丧失是阿尔茨海默病的早期病理特征。近年来的研究表明，线粒体改变是阿尔茨海默病中β介导的突触病理的基础，研究结果表明：1)阿尔茨海默病中线粒体功能障碍与突触丧失有显著相关性；2)线粒体的保护减弱了β诱导的突触变化。然而，Abeta诱导的线粒体功能障碍和随之而来的突触损伤的机制尚未完全描述。值得注意的是，神经元中的线粒体在其性质上是异质的。位于突触的神经元线粒体亚群或称为突触线粒体，由于它们与突触的物理接近，在维持突触活动/功能中起关键作用。因此，阐明β增强突触线粒体功能障碍的机制对加深我们对突触病理在AD发病机制中的认识具有重要意义。在初步研究中，我们已经证明，在Abeta环境中，突触线粒体对亲环蛋白D （cypD）介导的线粒体通透性过渡孔（mPTP）的倾向增加，转基因AD小鼠过度表达Abeta。在这些变化的同时，受β损伤的突触线粒体也出现了呼吸缺陷。此外，Abeta治疗导致培养海马神经元轴突线粒体密度降低和突触缺失。相反，这些对突触线粒体和突触改变的有害影响通过cypD的基因缺失而被阻断，从而显著减弱。因此，我提出了一个假设，cypd介导的mPTP是abeta诱导的突触线粒体功能障碍和突触改变的潜在机制。为了解决这一概念，我将利用AD小鼠模型（APP小鼠）和一种新的转基因小鼠模型（遗传cypd缺陷的APP小鼠）以及cypd缺陷的海马神经元培养来进行本应用中提出的研究。本项目有三个目的：1)确定cypd介导的mPTP对APP小鼠突触线粒体功能的影响；2)确定cypd介导的mPTP对突触（轴突）线粒体动力学和运动的影响；3)确定cypd介导的突触线粒体功能障碍是否有助于APP小鼠β诱导的突触改变。在这个项目完成后，我将确定cypD介导的mPTP在Abeta诱导的突触线粒体功能障碍中的作用，以及cypD介导的mPTP对APP/ Abeta过表达小鼠突触线粒体动力学和运动性、突触功能和动物学习/记忆能力的影响。本研究的发现将对阿尔茨海默病治疗新方法的发展产生积极影响。这个项目也将为我的科学生涯奠定坚实的基础，通过结合突触线粒体功能障碍和突触改变在AD中建立一个不同于导师的研究方向。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction and synaptic loss are early pathological features of Alzheimer's disease. Recent studies indicate that mitochondrial alterations in AD underlie Abeta-mediated synaptic pathology as evidenced by the observations: 1) significant correlation of mitochondrial dysfunction with synaptic loss in AD; and 2) the protection of mitochondria attenuates Abeta -induced synaptic changes. However, the mechanisms of Abeta -induced mitochondrial dysfunction and the consequent synaptic damages have not fully delineated. Notably, mitochondria in neurons are heterogeneous in their properties. A sub-group of neuronal mitochondria locating at synapses or namely synaptic mitochondria play a pivotal role in maintaining synaptic activity/function due to their physical proximity to synapses. Thus, to elucidate the mechanisms underlying Abeta -potentiated synaptic mitochondrial dysfunction is of great significance to deepen our understanding of the synaptic pathology in the pathogenesis of the AD. In the preliminary studies, we have demonstrated that synaptic mitochondria undergo increased propensity towards cyclophilin D (cypD)-mediated mitochondrial permeability transition pore (mPTP) in the Abeta milieu, transgenic AD mice overexpressing Abeta. Along with these changes, Abeta -insulted synaptic mitochondria underwent respiration defects. In addition, Abeta treatment resulted in decreased axonal mitochondrial density and the loss of synapses in cultured hippocampal neurons. As a contrast, these detrimental effects on synaptic mitochondrial and synaptic alterations were significantly attenuated by the blockade of cypD through genetic depletion of cypD. Thus, I have formulated a hypothesis that cypD-mediated mPTP is a potential mechanism underlying Abeta-induced synaptic mitochondrial dysfunction and synaptic alterations. To address this concept, I will utilize an AD mouse model (APP mice) and a novel genetically manipulated transgenic mouse model (genetic cypD-deficient APP mice) as well as cypD-deficiency hippocampal neuron cultures for the studies proposed in this application. This project contains three aims: 1). to determine the impact of cypD-mediated mPTP on synaptic mitochondrial function in APP mice; 2) to determine the impact of cypD-mediated mPTP on synaptic (axonal) mitochondrial dynamics and motility in Abeta milieus; and 3) to determine whether cypD-mediated synaptic mitochondrial dysfunction contributes to Abeta -induced synaptic alterations in APP mice. Upon the completion of this project, I will determine the involvement of cypD mediated mPTP in Abeta induced synaptic mitochondrial dysfunction, and the impact of cypD mediated mPTP on synaptic mitochondrial dynamics and motility, and synaptic function as well as animal learning/memory ability in APP/ Abeta overexpressing mice. Finding derived from this study will have positive impact on the development of new therapeutic approaches for AD treatment. This project will also serve as a firm foundation of my scientific career to establish a research direction distinct from my mentors' by the combination of synaptic mitochondrial dysfunction and synaptic alterations in AD.