Regulation of y-secretase activity by modulatory proteins

γ分泌酶的催化亚基早老素-1(PS-1)或早老素-2(PS-2)的突变导致早期- 阿尔茨海默病(Eoad)的首发形式。然而，迟发性AD(负荷)的原因是积极的 调查。这两种类型的AD的病理特征和功能连接相似，提示 这种γ分泌酶可能在迟发性AD中起到致病作用。此外，γ的病理作用- Eoad中的分泌酶还没有完全阐明。只有一小部分γ-分泌酶复合体是催化的 活性和非活性复合体的功能和激活尚不清楚。这项建议的目标是 阐明γ-分泌酶调节蛋白在γ-分泌酶调节中的作用机制 并研究它们在AD中的作用。在这里，我们建议研究γ分泌酶活性是如何被激活的 脑血管疾病介导的低氧和γ-分泌酶激活蛋白。我们将澄清 GSAP调控γ分泌酶加工APP和Notch1的分子基础。我们将决定 HIF1α激活γ分泌酶的基本机制。最后，我们将通过以下方式来研究这些机制 GSAP-和HIF1α-调节AD模型小鼠的γ-分泌酶活性。这项提议的长期目标是 目的是阐明γ-分泌酶的调控机制，并鉴定新的γ-分泌酶调节蛋白 以及评估它们与AD的相关性。我们的研究集中在γ-分泌酶调节的分子基础上。 调节蛋白，对了解疾病的发病机制和 发展治疗学。

Mutations in presenilin-1 (PS1) or Presenilin-2 (PS-2), the catalytic subunit of γ-secretase, lead to the early- onset form of Alzheimer’s disease (EOAD). However, the causes of late-onset AD (LOAD) are under active investigation. The pathological features and functional connectivity of both forms of AD are similar, suggesting that γ-secretase may play a causative role in the late-onset form of AD. Moreover, the pathological role of γ- secretase in EOAD has not been fully elucidated. Only a small fraction of the γ-secretase complex is catalytically active and the function and activation of the inactive complex is unknown. The objectives of this proposal are to elucidate the mechanism of action of γ-secretase modulatory proteins (GSMPs) in the regulation of γ-secretase and examine their function in AD. Here we propose to investigate how γ-secretase activity is activated by cerebrovascular disease mediated hypoxia and γ-secretase activating protein (GSAP). We will elucidate the molecular basis of GSAP in modulation of γ-secretase for the processing of APP and Notch1. We will determine the underlying mechanism by which Hif1α activates γ-secretase. Lastly, we will investigate the mechanisms by which GSAP- and Hif1α- regulate γ-secretase activity in AD mouse models. The long-term goals of this proposal are to elucidate the mechanism of γ-secretase modulation and identify novel γ-secretase regulatory proteins as well as assess their relevance to AD. Our studies focus on the molecular basis of γ-secretase modulation by modulatory proteins and have potentially significant impacts on understanding the disease mechanism and developing therapeutics.