Defining the cell-autonomous role of caveolin-1 in adult hippocampal neurogenesis in Alzheimer's Disease

项目总结/摘要： 全世界95%以上的阿尔茨海默病（AD）病例是散发的晚发型（LOAD）影响个体 年龄65岁或以上。AD最早的临床症状之一是依赖于大脑皮层的海马神经元损害， 记忆在人的一生中，海马体中保存着大量的神经干细胞和祖细胞 (NSCs/NPC）通过成年海马的过程分化为颗粒细胞神经元（GC）。 神经发生（AHN）。AHN对于海马的可塑性和记忆功能至关重要，就像新生的GC一样。 在记忆印迹细胞中招募。众所周知，AHN在AD小鼠模型中受损， AD小鼠中AHN的增强挽救了海马依赖性记忆功能。然而，机制 AD中AHN的潜在妥协尚不清楚。小窝蛋白-1（Caveolin-1，Cav-1）是一种在哺乳动物中富含的支架蛋白。 内皮小窝。我们和其他人已经表明，海马中Cav-1表达的减少诱导了海马神经元的凋亡。 AD样病理和记忆缺陷。我们实验室的初步研究表明，AHN在全球Cav中受损， 1敲除小鼠和在该模型中内皮Cav-1的恢复不能恢复NSC库 提示Cav-1在AHN中具有新的自主作用。重要的是，我的初步结果显示，细胞- 海马NSC/NPCs中Cav-1的自主缺失损害了关键的AD相关基因的表达。 包括淀粉样前体蛋白、β-分泌酶（BACE-1）和磷脂酰肌醇结合网格蛋白在内的蛋白质 组装蛋白（PICALM），晚发性AD的遗传危险因素。这个项目将检验假设， Cav-1以细胞自主的方式调节AHN， AD可能是神经发生缺陷的基础。利用新生成的小鼠模型， 在NSC中缺失Cav-1（NestinCreERT 2;Cav-1 lox/lox），目的1中的研究将建立细胞自主作用 在AHN的Cav-1。目的2阐明Cav-1在两种AD大鼠海马神经干细胞/神经前体细胞中的命运 模型，APPswePS 1 ΔE9和APPKINL-G-F/NL-G-F，并确定Cav-1如何调节表达和膜 AD相关蛋白脂筏定位与AD海马神经干细胞表型的关系总的来说，这 该项目将提供对Cav-1作为AHN的一种新的和必要的调节剂的迫切见解，并建立 Cav-1的改变是否有助于AD中海马NSC/NPCs功能的损伤。这个项目 提示恢复AHN中Cav-1水平可能有助于减轻AD的记忆缺陷。

PROJECT SUMMARY/ABSTRACT: Over 95% of Alzheimer’s Disease (AD) cases worldwide are sporadic, late onset (LOAD) affecting individuals age 65 years or older. One of the earliest clinical symptoms of AD is impairment in hippocampus-dependent memory. Throughout life, the hippocampus notably maintains a pool of neural stem and progenitor cells (NSCs/NPCs) that differentiate into granule cell neurons (GCs) through the process of adult hippocampal neurogenesis (AHN). AHN is imperative for hippocampal plasticity and memory function as newly born GCs are recruited in memory engram cells. It is well-known that AHN is impaired in mouse models of AD and augmentation of AHN in AD mice rescues hippocampus-dependent memory function. However, the mechanisms underlying compromise in AHN in AD are not clear. Caveolin-1 (Cav-1) is a scaffolding protein abundant in endothelial caveolae. We and others have shown that reductions in Cav-1 expression in the hippocampus induce AD-like pathology and memory deficits. Preliminary studies in our lab show that AHN is impaired in a global Cav- 1 knockout mouse and restoration of endothelial Cav-1 in this model does not restore the pool of NSCs suggesting a novel autonomous role of Cav-1 in AHN. Importantly, my preliminary results show that cell- autonomous deletion of Cav-1 in hippocampal NSCs/NPCs compromises expression of critical AD-linked proteins including amyloid precursor protein, β-secretase (BACE-1) and phosphatidylinositol binding clathrin assembly protein (PICALM), a genetic risk factor of late onset AD. This project will examine the hypothesis that Cav-1 regulates AHN in a cell-autonomous manner and that altered expression of neurogenic Cav-1 in AD may underlie deficits in neurogenesis. Utilizing a newly generated mouse model harboring conditional deletion of Cav-1 in NSCs (NestinCreERT2;Cav- 1lox/lox), studies in Aim 1 will establish the cell-autonomous role of Cav-1 in AHN. Aim 2 will elucidated the fate of Cav-1 in hippocampal NSCs/NPCs derived from two AD models, APPswePS1ΔE9 and APPKINL-G-F/NL-G-F, and determine how Cav-1 regulates expression and membrane lipid raft localization of AD-linked protein and phenotype of hippocampal NSCs/NPCs in AD. Taken together, this project will provide imperative insight into Cav-1 as an novel and essential regulator of AHN and establish whether alterations in Cav-1 contribute to impairments in hippocampal NSCs/NPCs function in AD. This project implies that restoring Cav-1 level in AHN may help attenuate memory deficits in AD.