Mitochondrial pore and synaptic stress in Alzheimer's disease

项目主任/首席调查员：杜恒 项目说明/摘要 线粒体功能障碍和突触丢失是阿尔茨海默病的早期病理特征。 最近的研究表明，AD中线粒体的改变是A？介导的突触病理的基础 结果表明：1)AD患者线粒体功能障碍与突触丢失显著相关； 2)线粒体的保护作用减弱了Aβ诱导的突触变化。然而，它的作用机制 A？诱导的线粒体功能障碍和随之而来的突触损伤还没有完全描述出来。值得注意的是， 神经元中的线粒体在性质上是不同的。神经元线粒体的亚群，位于 突触或即突触线粒体在维持突触活动/功能方面发挥着关键作用，因为它们 物理上接近突触。因此，为了阐明突触增强的机制 线粒体功能障碍对加深对大鼠脑内突触病理的认识具有重要意义 阿尔茨海默病的发病机制在初步研究中，我们已经证明了突触线粒体经历了 亲环素D(CypD)介导的线粒体通透性转换孔(MPTP)倾向增加 在A？环境中，转基因AD小鼠过表达A？伴随着这些变化，一种受侮辱的突触 线粒体出现呼吸缺陷。此外，A？治疗导致轴突减少 培养的海马神经元线粒体密度和突触丢失。相比之下，这些 对突触线粒体和突触改变的有害影响显著减弱 因此，我提出了一个假说，认为cypD是由cypD介导的 MPTP是A？诱导突触线粒体功能障碍和突触的潜在机制 改装。为了解决这个概念，我将利用AD小鼠模型(APP小鼠)和一种新的遗传学 操纵转基因小鼠模型(遗传性cypD缺陷APP小鼠)以及cypD缺陷 海马神经元培养，用于本申请中提出的研究。本项目包含三个目标：1)。至 检测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对环境中突触(轴突)线粒体动力学和运动性的影响； 3)确定cypD介导的突触线粒体功能障碍是否参与A？诱导的突触 应用程序鼠标的变化。在这个项目完成后，我将确定cypD介导的参与 MPTP在Aβ诱导的突触线粒体功能障碍中的作用及cypD介导的MPTP对突触的影响 APP/A中线粒体动力学、运动性、突触功能及动物学习记忆能力的变化 过度表达老鼠。这项研究的发现将对新技术的发展产生积极的影响 AD治疗的治疗方法。这个项目也将成为我科学生涯的坚实基础 结合突触线粒体，确立有别于导师的研究方向 阿尔茨海默病的功能障碍和突触改变。 PHS 398/2590(06/09版)页面续格式页面

Program Director/Principal Investigator: Du, Heng Project Description/Abstract Mitochondrial dysfunction and synaptic loss are early pathological features of Alzheimer's disease. Recent studies indicate that mitochondrial alterations in AD underlie A¿-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 A¿-induced synaptic changes. However, the mechanisms of A¿-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 A¿-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 A¿ milieu, transgenic AD mice overexpressing A¿. Along with these changes, A¿-insulted synaptic mitochondria underwent respiration defects. In addition, A¿ 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 A¿-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 A¿ milieus; and 3) to determine whether cypD-mediated synaptic mitochondrial dysfunction contributes to A¿-induced synaptic alterations in APP mice. Upon the completion of this project, I will determine the involvement of cypD mediated mPTP in A¿ 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/A¿ 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. PHS 398/2590 (Rev. 06/09) Page Continuation Format Page