PRESENILINS, APOPTOSIS AND AMYLOID BETA PROTEIN

大多数早发性家族性阿尔茨海默病（AD）病例是由高度相关基因早老素-1 （PS1）、早老素-2 （PS1）和早老素-2 （PS2）的突变引起的，这些基因编码被预测为具有6或8个跨膜结构域的完整膜蛋白。由于早老素突变占遗传性早发性阿尔茨海默病的大多数病例，了解早老素的正常功能以及这些蛋白质的突变如何导致阿尔茨海默病是阿尔茨海默病研究的核心问题。就阿尔茨海默病而言，促球蛋白前活性的两个方面受到了特别的关注。首先，早老素突变体已被证明可以改变较长且可能更具致病性的淀粉样蛋白Abeta肽变体（即Abeta1-42/43）的相对水平。其次，突变型早老素已被证明可促进细胞凋亡。关于早老素在细胞凋亡中的作用，有证据表明PS2的cooh末端与尚未确定的蛋白之间的蛋白-蛋白相互作用负责细胞凋亡的激活。本研究的重点是鉴定和表征与早老素的COOH末端相互作用的蛋白，介导它们对细胞凋亡的影响，并可能改变较长Abeta变体的相对水平。具体目的如下：1)鉴定和表征与早老素cooh末端相互作用的蛋白；2)研究相互作用蛋白在早老素介导的细胞凋亡中的作用；3)剖析相互作用蛋白在早老素介导的长β变异体增加中的作用；4)阐明早老素介导的凋亡与早老素介导的较长Abeta变异体增加之间的关系。

The majority of early-onset familial Alzheimer disease (AD) cases are caused by mutations in the highly related genes presenilin-1 (PS1) and presenilin-2 (PS1) and presinilin-2 (PS2) which encode what are predicted to be integral membrane proteins with six or eight membrane spanning domains. Because the presenilin mutations account for the majority of cases of inherited early onset forms of AD, understanding the normal function of the presenilins and how mutations in these proteins lead to Alzheimer disease are central questions in Alzheimer's research. In terms of AD, two aspects of presinilin activity have received particular attention. First, mutant presenilin has been shown to alter the relative levels of the longer and potentially more pathogenic amyloid Abeta peptide variants (i.e., Abeta1-42/43). Second, mutant presenilin has been shown to promote apoptosis. With regard to the role of presenilins in apoptosis, there is evidence suggesting that a protein-protein interaction between the COOH-terminus of PS2 and as yet unidentified protein(s) is responsible for activation for apoptosis. This proposal focuses on identifying and characterizing protein(s) which interacts with the COOH- terminus of the presenilins, mediating their effects on apoptosis and, possibly, on altering the relative levels of the longer Abeta variants. The specific aims are as follows: 1) To identify and characterize proteins that interact with the COOH-terminus of the presenilins; 2) To study the role of interactor protein(s) in presenilin-mediated apoptosis; 3) To dissect the role of interactor protein(s) in presenilin-mediated increases in longer Abeta variants; and, 4) To elucidate the relationship between presinilin-mediated apoptosis and presenilin-mediated increases in longer Abeta variants.