dementias of the Alzheimer's Type

阿尔茨海默氏型痴呆

• 批准号: 6619425
• 负责人: GEORGE M. MARTIN
• 金额: $ 32.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6619425
• 关键词: Alzheimer's disease; aging; amyloid proteins; binding proteins; gene targeting; genetically modified animals; human tissue; immunocytochemistry; intracellular transport; laboratory mouse; messenger RNA; neurofibrillary tangles; phosphorylation; polymerase chain reaction; protein isoforms; protein structure function; protein transport; tau proteins; tissue /cell culture; transcription factor

A variety of gene products have been implicated in the pathogenesis of dementias of the Alzheimer type (DAT), the most common forms of dementias in the elderly. A key unsolved problem has been how these several proteins may interact to cause the two major types of pathology, deposits of beta amyloid (Ab) and the collections of abnormal forms of tau protein, the main constituent of neurofibrillary tangles (NFT). The present proposal addresses the potential role of an adaptor protein called FE65 in such interactions. FE65p (FE65 protein) binds to an intracellular domain of the precursor protein (bPP) of Ab and to several other proteins. When overexpressed, it increases the rate of bPP trafficking and Ab production. Our new evidence [using FE65 (FE65 gene) knockout mice] also supports a role for FE65 in the regulation of the expression of a kinase implicated in the altered phosphorylation of tau protein (glycogen synthase kinase-3b or tau protein kinase I) (GSK-3b). We have also found cytochemical evidence for the co-localization of FE65p with tau in DAT brains. Using our FE65 knockout mice, we now propose to investigate the mechanisms whereby FE65 regulates expression of GSK-3b and several other candidate genes. We suggest that this regulation is via CP2/LBP-1/LSF (CP2) transcription elements, since FE65p directly binds to CP2. We will also investigate the role of FE65 on Ab production/deposition and the rate of bPP internalization, using FE65 knockout mice and knockout mice crossed with the Tg2576 line, which overexpress a familial DAT mutant bPP.

多种基因产物与阿尔茨海默型痴呆（DAT）的发病机制有关，这是老年人最常见的痴呆形式。 一个未解决的关键问题是这几种蛋白质如何相互作用导致两种主要类型的病理学：β淀粉样蛋白（Ab）的沉积和异常形式的tau蛋白的聚集，tau蛋白是神经原纤维缠结（NFT）的主要成分。 本提案解决了称为 FE65 的接头蛋白在此类相互作用中的潜在作用。 FE65p（FE65 蛋白）与 Ab 前体蛋白 (bPP) 的胞内结构域以及其他几种蛋白结合。 当过度表达时，它会增加 bPP 运输和抗体产生的速率。 我们的新证据 [使用 FE65（FE65 基因）敲除小鼠] 也支持 FE65 在调节与 tau 蛋白（糖原合酶激酶 - 3b 或 tau 蛋白激酶 I）（GSK-3b）磷酸化改变有关的激酶表达中的作用。 我们还发现了 FE65p 与 tau 在 DAT 大脑中共定位的细胞化学证据。使用我们的 FE65 敲除小鼠，我们现在建议研究 FE65 调节 GSK-3b 和其他几个候选基因表达的机制。 我们认为这种调节是通过 CP2/LBP-1/LSF (CP2) 转录元件进行的，因为 FE65p 直接与 CP2 结合。 我们还将使用 FE65 敲除小鼠和与 Tg2576 系杂交的敲除小鼠来研究 FE65 对 Ab 产生/沉积的作用以及 bPP 内化率，Tg2576 系过度表达家族性 DAT 突变体 bPP。