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Analysis of the relationship between Amyloid β protein and cholesterol in Alzheimer's disease.

阿尔茨海默病β淀粉样蛋白与胆固醇的关系分析。

基本信息

批准号：
15590891
负责人：
URAKAMI Katsuya
金额：
$ 1.92万
依托单位：
National University Corporation Tottori University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2005
项目状态：
已结题

项目摘要

Alzheimer's disease (AD) is one of the most frequent neurodegenerative disorders in elder people. Familial AD is known to be caused by mutations in the amyloid β protein precursor (APP), Presenilin 1 or 2, though these causes of AD are relatively uncommon. But those genetic risk factors account for less than 2% of all AD causes, remaining are sporadic AD.Amyloid β protein (Aβ) is one of the abnormally accumulated proteins in AD's brain. Aβ fibril formation and deposition long have been linked to the neuropathogenesis of AD. And abnormal processing of APP and increase in Aβ may play a major role in the pathogenesis of the hereditary forms and also that of sporadic AD.We investigate the relationship between APP, Aβ and cholesterol to find the evidence that cholesterol may play a role in the cleavage of APP. We made APP-overexpressed CHO cells and npc1 defected CHO (nCHO) cells by transfect the wild type, Swedish and Tottori (D678N) type mutated APP. Npc1 is defected in Niemann-Pick disease type C, which has lack in intracellular transport and maintenance of homeostasis of cholesterol. We analyzed intracellular quantity, synthesis and esterification of cholesterol, but excess APP had no effects directly. Then we determined intracellular APP levels and production Aβ in different intracellular cholesterol background using both cells with extracellular stimulation of Aluminum, LDL and oxidative stress.Despite no relationship APP, Aβ and Aluminum, more sensitive against Aluminum in nCHO cells compared normal cells. Exposure of excess LDL induced the cleavage of APP by β-secretase in nCHO cells, which indicated Aβ production. Intracellular APP levels on the oxidative stress were decreased in CHO cells but not affected in nCHO. Fewer lipids in nCHO of membrane in nCHO may prevent the oxidative attack against cell membrane.The disruption of cholesterol homeostasis might accelerate and strengthen the risks in AD.

阿尔茨海默病（Alzheimer's disease，AD）是老年人最常见的神经退行性疾病之一。已知家族性AD是由淀粉样β蛋白前体（APP）早老素1或2的突变引起的，尽管AD的这些原因相对罕见。但这些遗传因素仅占AD病因的不到2%，其余为散发性AD。淀粉样β蛋白（Amyloid β protein，Aβ）是AD患者脑内异常聚集的蛋白质之一。长期以来，Aβ原纤维的形成和沉积与AD的神经发病机制有关。本研究通过研究APP、Aβ与胆固醇之间的关系，寻找胆固醇参与APP裂解的证据。瑞典和鸟取（D 678 N）型突变的APP。Npc 1在C型尼曼-皮克病中有缺陷，该疾病缺乏胆固醇的细胞内转运和稳态维持。分析了细胞内胆固醇的含量、合成及酯化反应，但过量APP对胆固醇的合成无直接影响。然后，我们用铝、低密度脂蛋白（LDL）和氧化应激刺激两种细胞，在不同的细胞内胆固醇背景下，测定细胞内APP水平和Aβ的产生，尽管APP、Aβ与铝无关，但nCHO细胞对铝的敏感性高于正常细胞。在nCHO细胞中，过量LDL暴露诱导β-分泌酶切割APP，这表明Aβ产生。在CHO细胞中，氧化应激引起的细胞内APP水平降低，但在nCHO中不受影响。nCHO中膜脂的减少可能阻止了细胞膜的氧化攻击，胆固醇稳态的破坏可能加速和加强AD的风险。