Structural and Functional Properties of cyclophilin D and Abeta interaction.

描述(申请人提供)：线粒体功能障碍是阿尔茨海默病(AD)的早期特征。淀粉样蛋白-？多肽(A？)对线粒体功能有不良影响，并导致AD时呼吸链受损、能量衰竭、活性氧(ROS)生成和神经元凋亡。最近的研究强调了线粒体A？在阿尔茨海默病的发病机制中。亲环素D(CypD)是线粒体膜通透性转换(MPT)过程中与线粒体膜结合的一种多肽基脯氨酰异构酶F，位于线粒体基质中。CypD在打开线粒体膜通透性转换孔(MPTP)导致细胞死亡中起核心作用。阿尔茨海默病病区神经元CypD水平显著升高。我们已经证明了CypD-A的存在？AD脑和TG Mapp小鼠大脑皮质线粒体中的复合体以及重组CypD蛋白与A？表面等离子体共振(SPR)。CypD缺乏(缺乏A？结合伴侣)对A？介导的线粒体和突触功能障碍具有保护作用。此外，我们的初步研究表明，CypD的表达增加(增强CypD-A？相互作用)加剧了线粒体和神经元的扰动，并提早出现空间学习/记忆障碍。这些研究使我们假设CypD是一个关键的线粒体靶点，增强了A？介导的线粒体和神经元功能障碍。封锁CypD-A？相互作用将减弱A？诱导的线粒体和神经元的扰动。本项目的目的是阐明CypD-A？使用晶体(Aim 1)和核磁共振(Aim 2)结构分析相互作用，并分析CypD与A？导致线粒体和神经元功能障碍(目标3)。本文的研究在三个方面具有重要意义和创新性。首先，预期结果将揭示带A的CypD的结构细节？在原子分辨率下，这是从未报道过的。第二，CypD-A的后果是什么？A？介导的线粒体和神经元功能障碍的相互作用将在结构和功能分析的基础上阐明。第三，这一建议的结果将通过建立预防和治疗干预的新目标，对AD领域产生深远影响。 公共卫生相关性：该项目的目标是阐明CypD-A的基础？使用晶体和核磁共振结构分析相互作用，并分析线粒体途径的关键方面，通过哪些CypD与A？导致线粒体和神经元损伤。这一提议的结果将通过建立预防和治疗干预的新目标，对AD领域产生深远的影响。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Amyloid-? peptide (A?) has deleterious effects on mitochondrial function and contributes to respiratory chain impairment, energy failure, generation of reactive oxygen species (ROS), and neuronal apoptosis in AD. Recent studies have highlighted the pivotal role of mitochondrial A? in Alzheimer's disease pathogenesis. Cyclophilin D (CypD), a peptidylprolyl isomerase F, resides in the mitochondrial matrix and associates with the inner mitochondrial membrane during the mitochondrial membrane permeability transition (mPT). CypD plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death. The level of CypD was significantly elevated in neurons in AD-affected regions. We have demonstrated the presence of CypD-A? complex in the cortical mitochondria of AD brain and Tg mAPP mice, and the binding of recombinant CypD protein to A? with surface plasmon resonance (SPR). CypD deficiency (lacking A? binding partner) protected against A? -mediated mitochondrial and synaptic dysfunction. Further, our pilot studies showed that increased expression of CypD (enhancing CypD- A? interaction) exacerbated mitochondrial and neuronal perturbation as well as early onset of deficits in spatial learning/memory. These studies lead us to hypothesize that CypD is a critical mitochondrial target potentiating A?-mediated mitochondrial and neuronal dysfunction. Blockade of the CypD-A? interaction will attenuate A?-induced mitochondrial and neuronal perturbation. The goal of this project is to elucidate the basis of CypD-A? interaction using crystal (Aim 1) and NMR (Aim 2) structural analyses, and to analyze critical aspects of the intracellular pathway through which engagement of CypD with A? induces mitochondrial and neuronal dysfunction (Aim 3). The proposed research is highly significant and innovative on three points. First, the expected outcomes will reveal the structural details of CypD with A? at atomic resolution, which has never been reported. Second, the consequence of CypD-A? interaction in A?-mediated mitochondrial and neuronal dysfunction will be elucidated based on structural and functional analysis. Third, the results of this proposal will have a profound impact on the AD field by establishing a new target for preventive and therapeutic intervention. PUBLIC HEALTH RELEVANCE: The goal of this project is to elucidate the basis of CypD-A? interaction using crystal and NMR structural analyses, and to analyze critical aspects of the mitochondrial pathway through which engagement of CypD with A? induces mitochondrial and neuronal damages. The results of this proposal will have a profound impact on the AD field by establishing a new target for preventive and therapeutic intervention.