VESICULAR LOCALIZATION AND FUNCTION OF PRESENILIN 1 FRAGMENT

阿尔茨海默病(AD)是由异质性遗传引起的，可能 环境因素。 虽然这种疾病的病因仍不清楚，但有几条线路 证据表明，细胞的完整性和数量 维持神经元囊泡轴浆运输的细胞器， 包括内质网(ER)、高尔基体、内体和大而致密 核心囊泡(LCDCV)在AD中受损。这些观察结果表明 那些影响神经细胞囊泡运输的因素 也可能与阿尔茨海默病的发生有关。这个假设， 在不忽视病理意义和后果的同时 神经原纤维缠结(NFTs)和神经炎斑块(NPs)，它 强调需要寻找神经元蛋白的异常 NFTs和NPs形成的上游运输。联谊会 阿尔茨海默病淀粉样前体蛋白(APP)与细胞骨架 其轴浆运输增加了家族性AD的可能性 (FAD)连锁APP突变改变了细胞的功能和囊泡运输 应用程序。早老素L(Psl)是一种未知的完整膜蛋白 功能。它在翻译后被切割，产生N-末端 片段和C-末端片段。许多PSL突变体被认为与 FAD的发展。 我们获得了PSL蛋白水解性片段的初步数据 在LDCV、嗜铬颗粒(CG)和体树突状细胞中表达 笼状蛋白包裹的囊泡(SDCCV)表明该蛋白在 在囊泡功能中的作用。这一观察结果提出了一种可能性，即 FAD PSL突变可能干扰这些小泡的功能。 这项建议的目的是进一步研究水泡 PSL及其蛋白水解物片段的定位 PSL具有泡囊功能的假说及其检验效果 囊泡运输中与FAD相关的PSL突变。我们的结果是 研究应进一步加深对参与的机制的理解 阿尔茨海默病的神经病理学

Alzheimer disease (AD) is caused by heterogeneous genetic and probably environmental factors. Although the etiology of the disease is still not clear, several lines of evidence indicate that the integrity and number of cellular organelles that sustain neuronal vesicular axoplasmic transport, including endoplasmic reticulum (ER), Golgi, endosomes, and large dense core vesicles (LCDCVs) are compromised in AD. These observation suggest those factors that compromise that comprise neuronal vesicular transport may also be causally involved in the development of AD. This hypothesis, while does not disregard the pathological significance and consequence of neurofibrillary tangles (NFTs) and neuritic plaques (NPs), it emphasizes the need to search for abnormalities in neuronal protein transport upstream of the formation of NFTs and NPs. The association of the Alzheimer's amyloid precursor protein (APP) with the cytoskeleton and its axoplasmic transport raise the possibility that familial AD (FAD)-linked APP mutations alter the function and vesicular transport of APP. Presenilin l (PSl) is an integral membrane protein of unknown function. It is cleaved post-translationally to yield an N-terminal fragment and a C-terminal fragment. Many PSl mutants have been linked to the development of FAD. We obtained preliminary data that PSl proteolytic fragments are expressed in LDCVs, chromaffin granules (CGs), and somatodendritic clathrin coated vesicles (SDCCVs) suggesting that this protein play a role in vesicular function. This observation raises the possibility that the FAD PSl mutations may interfere with the function of these vesicles. The purpose of this proposal is to further examine the vesicular localization of PSl and its proteolytic fragments, to test the hypothesis that PSl has a vesicular function and to examine the effects of FAD-linked PSl mutations on vesicular transport. The results of our research should further out understanding of the mechanisms involved in the neuropathology of AD.