Role of Cyclophilin D in Abeta- induced synaptic injury

描述（由申请人提供）：线粒体功能障碍和突触损伤是阿尔茨海默病（AD）的早期特征。淀粉样蛋白-肽(A)对线粒体和突触功能有有害影响，有助于AD患者能量衰竭、呼吸链损伤、活性氧（ROS）产生增加、线粒体结构损伤和突触丧失。线粒体膜通透性过渡孔（mPTP）是细胞坏死和凋亡的关键调控因子。亲环蛋白D （CypD）是一种肽基脯氨酸异构酶F，存在于线粒体中，在打开线粒体膜通透性过渡孔（mPTP）导致细胞死亡中起核心作用。我们已经证明cypd介导的mPTP增强了A¿诱导的AD小鼠线粒体功能障碍和认知功能下降。然而，cypd介导的突触线粒体和认知异常在A¿和氧化应激环境下的机制尚未完全阐明。我们的初步研究表明CypD参与了A¿诱导的线粒体分布、功能、突触丧失和PKA/CREB信号转导途径的改变，我们假设CypD/A¿介导的mPTP干扰了突触线粒体运输、线粒体动力学和线粒体功能，从而导致突触功能障碍以及突触结构和传递的改变。这可能是行为和电生理功能受损的原因。本提案的目标是获得CypD在A¿诱导的突触和神经元应激中的作用的新见解，重点关注突触线粒体特性，氧化应激，突触和树突棘改变，突触前和突触后功能，突触传递，cAMP/PKA/CREB相关信号转导和神经元功能，利用一种新的转基因小鼠模型和神经元培养（增加神经元CypD的表达），以及Tg - mAPP小鼠CypD基因缺乏)。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction and synaptic damage are early features of Alzheimer's disease (AD). Amyloid-¿ peptide (A¿) has deleterious effects on mitochondrial and synaptic function and contributes to energy failure, respiratory chain impairment, increased production of reactive oxygen species (ROS), mitochondrial structure damage, and synaptic loss in AD. Mitochondrial membrane permeability transition pore (mPTP) is a key regulator for both necrotic and apoptotic cell death. Cyclophilin D (CypD), a peptidylprolyl isomerase F, resides in the mitochondria and plays a central role in opening the mitochondrial membrane permeability transition pore (mPTP) leading to cell death. We have demonstrated that CypD-mediated mPTP potentiates A¿-induced mitochondrial malfunction and a decline in cognitive function in the AD mice. However, the mechanisms underlying CypD-mediated synaptic mitochondrial and cognitive abnormalities in an A¿ and oxidative stress milieu have not been fully elucidated. Based on our preliminary studies showing the involvement of CypD in A¿-induced changes in mitochondrial distribution, function, synaptic loss, and PKA/CREB signal transduction pathway, we hypothesize that the CypD/A¿-mediated mPTP interferes with synaptic mitochondrial trafficking, mitochondria dynamics and mitochondrial function, consequently, causing synaptic dysfunction and alternations in synaptic structure and transmission, which is likely to underlie impaired behavioral and electrophysiologic function. The goal of this proposal is to gain new insight into the role of CypD in A¿ -induced synaptic and neuronal stress, focusing on synaptic mitochondrial properties, oxidative stress, synapse and dendritic spine alternations, pre- and post-synaptic function, synaptic transmission, cAMP/PKA/CREB- associated signal transduction and neuronal function, utilizing a novel genetically manipulated transgenic mouse model and neuron culture (increased expression of neuronal CypD, and genetic deficiency of CypD in Tg mAPP mice). PUBLIC HEALTH RELEVANCE: The goal of this proposal is to gain new insight into the role of CypD in A¿ -induced synaptic and neuronal stress, focusing on synaptic mitochondrial properties, oxidative stress, synapse and dendritic spine alternations, pre- and post-synaptic function, synaptic transmission, cAMP/PKA/CREB-associated signal transduction and neuronal function, utilizing a novel genetically manipulated transgenic mouse model and neuron culture (increased expression of neuronal CypD, and genetic deficiency of CypD in Tg mAPP mice).