dementias of the Alzheimer's Type

阿尔茨海默氏型痴呆

• 批准号: 6361368
• 负责人: GEORGE M. MARTIN
• 金额: $ 32.82万
• 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/6361368
• 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.

各种基因产物与阿尔茨海默氏症类型（DAT）的痴呆症的发病机理有关，这是老年人痴呆症的最常见形式。 一个关键的未解决的问题是，这些几种蛋白质如何相互作用，以引起两种主要类型的病理学，β-淀粉样蛋白（AB）的沉积物以及tau蛋白异常形式的集合，Tau蛋白（神经原纤维缠结的主要成分）（NFT）的主要成分。 本提案探讨了称为Fe65在这种相互作用中的衔接蛋白的潜在作用。 Fe65p（Fe65蛋白）与AB和其他几种蛋白质的前体蛋白（BPP）的细胞内结构域结合。 当过表达时，它会增加BPP贩运和AB产量的速度。 我们的新证据[使用Fe65（Fe65基因）基因敲除小鼠]还支持Fe65在调节Tau蛋白（糖基因合酶激酶-3b或Tau蛋白激酶I）（GSK）（GSK）（GSK）磷酸化的表达中的作用。 -3b）。 我们还发现了在DAT大脑中与Tau共定位Fe65p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和其他几种候选基因的机制。 我们建议该调节是通过CP2/LBP-1/LSF（CP2）转录元素，因为Fe65p直接与CP2结合。 我们还将使用Fe65基因敲除小鼠和与TG2576线的敲除小鼠进行FE65在AB产生/沉积和BPP内部化速率上的作用，从而过表达家族性数据突变体BPP。