Nicastrin and Presenilin-dependent gamma-secretase

阿尔茨海默病(AD)是一种进行性的老年人神经退行性疾病。 以13-淀粉样蛋白和神经纤维在海马区的沉积为特征 和大脑皮层。淀粉样前体蛋白(APP)的内切蛋白被α-和β-切割 分泌酶导致AI3多肽的产生，人们认为AI3多肽具有神经毒性。这个 早老素(PS1和PS2)，当突变时导致家族性AD，对 几种蛋白质的膜内蛋白分解，包括APP和Notch1。早衰者是 含有分泌酶的高分子量复合体的一部分。对这种7-分泌酶至关重要 复合体是另一种I型跨膜糖蛋白，称为尼古丁，与两种APP结合 和Notch1，并且是GLP-L/NOTCH信令所必需的。尼古丁缺乏的最新研究进展 果蝇证明尼古丁的丢失消除了对早老素的依赖 Notch的膜内蛋白分解。因此，我们假设尼古丁是需要的 哺乳动物中Notch1的蛋白降解过程和信号转导。我们计划首先确定是否 尼古丁水平降低对早老素介导的哺乳动物Notch信号的影响 产生尼古丁缺乏的小鼠，并表征减少的表型后果 尼卡斯特林。其次，因为研究表明NICASTN在APP中扮演着重要的角色 在此过程中，我们将测试尼古丁在早老素介导的APP 7-分泌酶切割中的作用 使用尼古丁基因敲除细胞。此外，我们将确定尼古丁的作用机制 影响早老素促进Notch和APP的跨膜切割。最后，为了 研究尼古丁在成人大脑中的活体作用，我们将产生并表征尼古丁 条件基因敲除小鼠。综上所述，这些努力的成果将具有重要的意义 尼古丁影响早老素机制对我们的启示 在促进依赖早老素的7-分泌酶在几个关键途径上的活性，包括 Noch和APP，以及尼古丁作为AD潜在治疗靶点的作用。

Alzheimer's disease (AD), a progressive neurodegenerative disorder of the elderly, is characterized by the deposition of 13-amyloid (AI_) and neurofibriUary tangles in the hippocampus and cerebral cortex. Endoproteolytic cleavages of amyloid precursor protein (APP) by _-and ?- secretases result in the generation of AI3 peptides that are believed to be neurotoxic. The presenilins (PS1 and PS2), which when mutated cause familial AD, are important for the intramembraneous proteolysis of several proteins, including APP and Notch1. The presenilins is part of a high molecular weight complex that contains the ?-secretase. Critical to this 7-secretase complex is another type I transmembrane glycoprotein, termed nicastrin that binds to both APP and Notch1 and is required for glp-l/notch signaling. Recent studies in nicastrin-deficient Drosophila demonstrate that the loss of nicastrin abolishes the presenilin-dependent intramembraneous proteolysis of Notch. Thus, we hypothesize that nicastrin is required for proteolytic processing and signaling of Notch1 in mammals. We plan first to determine whether reduced levels of nicastrin impact on presenilin-mediated Notch signaling in mammals by generating nicastrin.deficient mice and characterize the phenotypic consequences of reduction in nicastrin. Secondly, because studies indicated that nicastdn plays an important role in APP processing, we will test the role of nicastrin in presenilin-mediated 7-secretase cleavage of APP using nicastrin knockout cells. In addition, we will determine the mechanism whereby nicastrin influences presenilins to facilitate transmembrane cleavage of Notch and APP. Finally, to examine the in vivo role of nicastrin in adult brain, we will generate and characterize nicastrin conditional knockout mice. Taken together, outcomes from these efforts will have important implications toward our understanding of the mechanism whereby nicastrin influences presenilins in facilitating the presenilin-dependent 7-secretase activities on several critical pathways, including Notch and APP, as well as for nicastrin as a potential therapeutic target in AD.