Regulation of y-secretase activity by modulatory proteins

早老素-1（PS-1）或早老素-2（PS-2）（γ-分泌酶的催化亚基）的突变导致了早期- 阿尔茨海默病（EOAD）的发病形式。然而，晚发性AD（LOAD）的病因尚不活跃， 调查两种形式的AD的病理特征和功能连接相似，表明 γ-分泌酶可能在晚发型AD中起致病作用。此外，γ- EOAD中的分泌酶尚未完全阐明。只有一小部分的γ-分泌酶复合物催化 活性和功能和激活的非活性复合物是未知的。本提案的目标是 阐明γ-分泌酶调节蛋白（GSMPs）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， 脑血管病介导的缺氧与γ-分泌酶激活蛋白（GSAP）的关系。我们将阐明 GSAP调节γ-分泌酶加工APP和Notch 1的分子基础。我们将确定 HIF 1 α激活γ-分泌酶的潜在机制。最后，我们将通过以下方式研究其机制： GSAP-和Hif 1 α-在AD小鼠模型中调节γ-分泌酶活性。本提案的长期目标 目的是阐明γ-分泌酶调节的机制，并鉴定新的γ-分泌酶调节蛋白， 并评估其与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，并对理解疾病机制具有潜在的重大影响， 开发治疗方法。

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.