VESICULAR LOCALIZATION AND FUNCTION OF PRESENILIN 1 FRAGMENT

阿尔茨海默病（Alzheimer disease，AD）是一种异质性遗传病， 环境因素 虽然该病的病因尚不清楚，但几条线 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、内体和大致密核。 核心囊泡（LCDCV）在AD中受损。这些观察表明， 那些影响神经元囊泡运输的因素 也可能与AD的发展有关。这个假设， 而不忽视病理意义和后果 神经纤维缠结（NFT）和神经炎斑块（NP）， 强调需要寻找神经元蛋白质的异常 在NFT和NP形成的上游运输。联盟 阿尔茨海默氏症淀粉样前体蛋白（APP）与细胞骨架 及其轴浆转运增加了家族性AD （FAD）-连接APP突变改变的功能和囊泡运输 附录早老素1（Presenilin 1，PS1）是一种未知的整合膜蛋白， 功能其在裂解后裂解以产生N-末端 片段和C-末端片段。许多PS1突变体已经与 FAD的发展。 我们获得了初步数据，PS1蛋白水解片段是 表达于LDCV、嗜铬颗粒（CG）和体树突状细胞 网格蛋白包被的囊泡（SDCCV）表明这种蛋白质发挥作用， vesicular功能的作用。这一观察提出了一种可能性， FADPS 1突变可能干扰这些囊泡的功能。 这项建议的目的是进一步检查囊泡 PS1及其蛋白水解片段的定位，以测试 假设PS1具有囊泡功能，并检查其作用 FAD连锁的PS1突变对囊泡转运的影响。的成果 研究应进一步了解所涉及的机制， AD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.