LRP AND APP PROCESSING IN NEURODEGENERATION

描述(申请人提供)：淀粉样β-肽(AB)在大脑中的积累和毒性是阿尔茨海默病(AD)发病机制的中心事件。低密度脂蛋白受体相关蛋白(LRP)与β-淀粉样前体蛋白(APP)相互作用，调节其内向AB的转运和加工。LRP也是大脑中载脂蛋白E(ApoE)的主要受体，apoE调节AB清除、胆固醇代谢和细胞信号。以前的研究已经在外周血中检测到大量的功能性可溶性LRP(SLRP)，我们的初步工作也在人脑和脑脊液中检测到了SLRP。分子和细胞研究已经确定了LRP通过基质金属蛋白酶(MMPs)以及b-和g-分泌酶进行Notch/APP样的顺序加工。我们的长期目标是了解LRP蛋白分解是如何在大脑中调节的，以及在AD中是如何调节的，以及这些蛋白降解事件和加工产物如何影响其在载脂蛋白E代谢和信号传递中的功能，以及APP运输和加工到AB。我们的初步研究表明，G-分泌酶的裂解产物APP胞内域(AICD)通过直接与LRP启动子结合来调节LRP的表达和功能。我们的研究还发现了一种新的接头蛋白，分类连接蛋白17(SNX17)，它调节LRP和APP的内吞转运和加工。我们的中心假设是，在AD中，LRP和APP的蛋白降解过程受到病理配体和转运事件的失调调节，这反过来又损害了LRP在脑内载脂蛋白E代谢和信号传递中的表达和功能。我们提出了四个特定的目标来验证我们的假设：1)鉴定LRP脱落酶并研究改变的LRP脱落对载脂蛋白E代谢和信号的功能影响；2)研究在AD小鼠模型中以及在衰老和人类AD过程中LRP的表达、脱落和蛋白分解是如何改变的；3)研究APP加工产物和其他g-分泌酶裂解事件如何调节LRP的表达和功能；以及4)分析神经元接头蛋白改变的LRP和APP的细胞内运输如何影响它们的蛋白降解处理、apoE代谢和AB产生。总之，这些研究应该使我们能够确定LRP在衰老和AD期间大脑中的表达、处理和功能的机制和调节。我们提出的研究也可能为AD的诊断和治疗确定新的靶点。公共卫生相关性：我们建议的主要目标是了解载脂蛋白E受体LRP如何进行蛋白质分解处理，以及这些细胞事件是如何在大脑中调节的。因为载脂蛋白E是阿尔茨海默病的主要危险因素，而阿尔茨海默病是导致老年人痴呆的主要原因，我们的结果可能为阿尔茨海默病的诊断和/或治疗提供知识。

DESCRIPTION (provided by applicant): Amyloid beta-peptide (AB) accumulation and toxicity in the brain are central events in the pathogenesis of Alzheimer's disease (AD). The low-density lipoprotein receptor-related protein (LRP) interacts with beta-amyloid-precursor protein (APP) and regulates its endocytic trafficking and processing to AB. LRP is also a major receptor in the brain for apolipoprotein E (apoE), which modulates AB clearance, cholesterol metabolism, and cellular signaling. Previous studies have detected abundant functional soluble LRP (sLRP) in peripheral and our preliminary work has detected sLRP in human brain and cerebral spinal fluid (CSF). Molecular and cellular studies have defined Notch/APP-like sequential processing of LRP by matrix metalloprotease (MMP) and by b- and g-secretases. Our long-term goal is to understand how LRP proteolysis is regulated in the brain and dysregulated in AD, and how these proteolytic events and processing products impact its function in apoE metabolism and signaling, as well as APP trafficking and processing to AB. Our preliminary studies have shown that a g-secretase cleavage product, APP intracellular domain (AICD), regulates LRP expression and function by directly binding to LRP promoter. Our studies also identified a novel adaptor protein, sorting nexin 17 (SNX17), that modulates endocytic trafficking and processing of both LRP and APP. Our central hypothesis is that LRP and APP proteolytic processing is dysregulated in AD by pathological ligands and trafficking events, and that this in turn impairs LRP expression and function in apoE metabolism and signaling in the brain. We propose four specific aims to test our hypothesis: 1) to identify LRP shedding enzymes and examine the functional impact of altered LRP shedding on apoE metabolism and signaling; 2) to examine how LRP expression, shedding, and proteolysis are altered in AD mouse models and during aging and AD in humans; 3) to study how APP processing products and other g-secretase cleavage events regulate LRP expression and function; and 4) to analyze how altered endocytic trafficking of LRP and APP by neuronal adaptor proteins influences their proteolytic processing, apoE metabolism and AB production. Together, these studies should allow us to define the mechanism and regulation of LRP expression, processing and function in the brain during aging and AD. Our proposed studies may also identify novel targets for AD diagnosis and therapy. PUBLIC HEALTH RELEVANCE: The major objective of our proposal is to understand how an apoE receptor LRP undergoes proteolytic processing and how these cellular events are regulated in the brain. Because apoE is a major risk factor for Alzheimer's disease, a leading cause of dementia in elderly, our results may provide knowledge for diagnosis and/or therapy for Alzheimer's disease.