dementias of the Alzheimer's Type

多种基因产物与老年痴呆症最常见的阿尔茨海默型痴呆症（DAT）的发病机制有关。一个关键的尚未解决的问题是，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）的沉积和异常形式的tau蛋白的集合，神经原纤维缠结（NFT）的主要成分。目前的建议解决了称为FE65的接头蛋白在这种相互作用中的潜在作用。FE65p （FE65蛋白）结合到Ab前体蛋白（bPP）的胞内结构域和其他几种蛋白。当过度表达时，它会增加bPP的贩运率和Ab的产生。我们的新证据[使用FE65基因敲除小鼠]也支持FE65在调节与tau蛋白（糖原合成酶激酶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。我们还发现了在DAT大脑中FE65p与tau共定位的细胞化学证据。使用我们的FE65敲除小鼠，我们现在提议研究FE65调节GSK-3b和其他几个候选基因表达的机制。我们认为这种调控是通过CP2/LBP-1/LSF （CP2）转录元件进行的，因为FE65p直接与CP2结合。我们还将研究FE65对Ab产生/沉积和bPP内化率的作用，使用FE65敲除小鼠和敲除小鼠与Tg2576系杂交，Tg2576系过表达家族DAT突变体bPP。

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.