CELLULAR FUNCTIONS OF ALZHEIMER'S DISEASE PROTEINS

描述（改编自应用程序）：遗传证据表明 三种蛋白质，β-淀粉样前体蛋白（β-APP）和两种 同源早老素（PS-1和PS-2）在阿尔茨海默病病因学中的作用 （AD）。调查人员此前曾根据其他国家的先例提出， 发育系统，一种或多种形式的β-APP和PS-1（或PS-2） 可能是正常生理学中细胞间信号系统的组成部分。 邻近细胞表面的β-APP和PS-1或PS-2会结合到 彼此特异性地通过它们的细胞外结构域突出， 细胞表面形成膜并产生信号。β-淀粉样蛋白（Abeta） 这种相互作用后其他事件的蛋白水解副产物。的 目前的建议是基于PI和同事已经证明的证据， 这一提议的β-APP：PS介导的细胞间信号传导事件。培养 用β-APP、PS-1或PS-2瞬时转染的细胞， 适当混合，并分析蛋白酪氨酸激酶活性， 和净蛋白质酪氨酸磷酸化，与抗体特异性 磷酸酪氨酸（Ptyr）。在混合beta-APP后的几分钟内 用PS-1或PS-2转染的细胞转染细胞， 提取物显示蛋白酪氨酸激酶 活性，并在蛋白质底物的Ptyr修饰，没有出现 在控制。此外，酪氨酸修饰的蛋白质的光谱 磷酸化作用因PS-1或PS-2参与而异 与β-APP的特异性细胞间结合，这意味着PS-1和PS-2 在正常生理学中有独特而非多余的功能。的 具体的目的是研究β-APP和 PS，确定信号的方向，识别非受体 酪氨酸激酶介导的，并表征src激酶的作用， 过程

DESCRIPTION (adapted from the application): Genetic evidence has implicated three proteins, the beta-amyloid precursor protein (beta-APP) and the two homologous presenilins (PS-1 and PS-2), in the etiology of Alzheimer's disease (AD). The investigator had previously proposed based on precedents in other developmental systems, that one or more forms of beta-APP and PS-1 (or PS-2) may be components of an intercellular signaling system in normal physiology. beta-APP and PS-1 or PS-2 on the surfaces of neighboring cells would bind to one another specifically through their extra-cellular domains protruding from the cell surface membranes and generate a signal. beta-amyloid (Abeta) would be a proteolytic by-product of other events following this interaction. The present proposal is based on evidence that the PI and colleagues have shown for this proposed beta-APP: PS-mediated intercellular signaling event. Cultured cells, transiently transfected with either beta-APP, PS-1 or PS-2, were appropriately mixed, and were analyzed for protein tyrosine kinase activity, and for net protein tyrosine phosphorylation, with antibodies specific for phosphotyrosine (Ptyr). Within several minutes after mixing the beta-APP transfected cells with either the PS-1 or PS-2 transfected cells, the cell extracts showed significant transient increases in protein tyrosine kinase activity, and in Ptyr modification of protein substrates, that did not appear in controls. Furthermore, the spectrum of proteins modified by tyrosine phosphorylation differs depending on whether PS-1 or PS-2 is involved in the specific intercellular binding to beta-APP, which implies that PS-1 and PS-2 have distinct, rather than redundant, functions in normal physiology. The specific aims are to study the intercellular interactions between beta-APP and the PS, to determine the direction of signal, to identify the non-receptor tyrosine kinases that mediate it and to characterize the role of src kinases in the process.