ABeta degrading enzyme and mitochondrial function

描述（由申请人提供）：线粒体功能障碍是阿尔茨海默病（AD）影响大脑的早期特征之一。最近的研究强调了线粒体A¿在AD发病机制中的作用。A¿在阿尔茨海默病大脑和转基因突变淀粉样前体蛋白（mAPP）小鼠的线粒体中逐渐积累，这与阿尔茨海默病的线粒体和神经元功能障碍有关。因此，线粒体中A¿的积累可能是导致线粒体和神经元扰动的初始病理事件。线粒体肽体是一种新型的线粒体肽酶，负责降解线粒体中的前序列和其他短的非结构化肽。人类PreP的同源物hPreP位于脑线粒体中，能够在体外降解A¿，这表明hPreP可能通过降解和清除线粒体A¿在预防阿尔茨海默病的淀粉样蛋白病理方面具有潜在的重要性。到目前为止，尚不清楚PreP是否最终与阿尔茨海默病的发病有关：PreP活性是否在阿尔茨海默病的大脑中发生改变，以及PreP活性是否在线粒体a¿积累中起关键作用。在这项R21探索性/发育性研究计划中，我们将研究PreP修饰、表达及其酶活性是否发生在AD大脑中，以及PreP表达和活性水平是否与线粒体A¿积累和淀粉样蛋白病理相关。此外，我们将研究A¿和氧化应激对PreP活性的影响，并通过体外神经元培养模型确定PreP活性是否有助于线粒体A¿的积累。本研究的目的是确定PreP在AD发病机制中的意义，重点关注PreP的表达/活性、线粒体A¿积累、氧化应激和线粒体功能，利用控制良好的AD和非AD大脑、过表达A¿的转基因AD小鼠和新型基因操纵神经元培养（获得/失去PreP功能）。研究结果将对阿尔茨海默病淀粉样蛋白病理研究产生重大影响。

DESCRIPTION (provided by applicant): Mitochondrial dysfunction is one of the early features in Alzheimer's disease (AD) affected brain. Recent studies have highlighted the role of mitochondrial A¿ in AD pathogenesis. A¿ progressively accumulates in the mitochondria of AD brain and transgenic mutant amyloid precursor protein (mAPP) mice overexpressing A¿, which is linked to mitochondrial and neuronal malfunction in AD. Thus, accumulation of A¿ in mitochondria may be an initiating pathological event leading to mitochondrial and neuronal perturbation. PreP, mitochondrial peptidasome, is the novel mitochondrial peptidase responsible for degrading presequences and other short unstructured peptides in mitochondria. Human PreP homologue, hPreP, located in brain mitochondria, is capable of degrading A¿ in vitro, suggesting that hPreP may potentially be of importance in preventing amyloid pathology of Alzheimer disease through its degradation and clearance of mitochondrial A¿. So far, it is unknown whether PreP is ultimately implicated in causing AD: whether PreP activity is altered in Alzheimer's disease brain and whether PreP activity plays a key role in mitochondrial A¿ accumulation. In this R21 exploratory/developmental research proposal, we will investigate whether alterations in PreP modification, expression and its enzyme activity occur in the AD brains and whether levels of PreP expression and activity are correlated to the accumulation of mitochondrial A¿ and amyloid pathology. Furthermore, we will examine the effect of A¿ and oxidative stress on PreP activity and to determine whether PreP activity contributes to the accumulation of mitochondrial A¿ using in vitro neuronal culture model. The goal of this proposal is to determine the significance of PreP in the AD pathogenesis, focusing on expression/activity of PreP, mitochondrial A¿ accumulation, oxidative stress, and mitochondrial function, utilizing well-controlled AD and non-AD brains, transgenic AD mice overexpressing A¿, and novel genetically manipulated neuron culture (gaining/losing PreP function). The outcomes of the studies will have a major impact on the amyloid pathology in the AD field. PUBLIC HEALTH RELEVANCE: The goal of this project is to investigate whether alternations in PreP expression and enzyme activity occur in the AD brains associated with accumulation of mitochondrial A¿ and amyloid pathology, to assess the effect of PreP activity on A¿ accumulation in mitochondria and mitochondrial/neuronal function, and to create novel neuronal cell lines with altered PreP levels and enzymatic activity. The outcomes of the proposed studies will have a major impact in the field of AD and aging particular.