dementias of the Alzheimer's Type

多种基因产物与阿尔茨海默型痴呆(DAT)的发病机制有关，DAT是老年人最常见的痴呆形式。一个关键的悬而未决的问题是，这几种蛋白质如何相互作用，导致两种主要类型的病理：β淀粉样蛋白(Ab)沉积和tau蛋白的异常形式聚集，tau蛋白是神经原纤维缠结(NFT)的主要成分。本提案涉及一种名为FE65的接头蛋白在这种相互作用中的潜在作用。FE65P(FE65蛋白)与抗体前体蛋白(BPP)的胞内结构域结合，并与其他几种蛋白结合。当过度表达时，它会增加BPP的贩运和抗体的产生。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(糖原合成酶-3b或tau蛋白激酶I)改变的磷酸化有关的一种激酶(GSK-3b)的表达中的作用。我们还发现了FE65p和tau在DAT脑中共同定位的细胞化学证据。利用我们的FE65基因敲除小鼠，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)转录元件实现的，因为FE65p直接与CP2结合。我们还将利用FE65基因敲除小鼠和与过表达家族性DAT突变BPP的Tg2576系杂交的FE65基因敲除小鼠，研究FE65对抗体产生/沉积和BPP内化速率的作用。

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.