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

定义 Caveolin-1 在阿尔茨海默病成人海马神经发生中的细胞自主作用

基本信息

项目摘要

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.
项目摘要/摘要: 全世界超过95%的阿尔茨海默病(AD)病例是散发性的、起病晚(负荷)的个体 年龄65岁或以上。阿尔茨海默病最早的临床症状之一是海马区依赖的损害 记忆。值得注意的是,在整个生命过程中,海马体都有一个神经干细胞库和祖细胞库 (神经干细胞/神经干细胞)通过成年海马区的突起分化为颗粒细胞神经元(GC) 神经发生(AHN)。AHN对新生的GCs的海马可塑性和记忆功能是必不可少的 在记忆印记细胞中招募。众所周知,在阿尔茨海默病和阿尔茨海默病小鼠模型中,Ahn受损 增强AD小鼠的Ahn可挽救海马区依赖的记忆功能。然而,这些机制 安哲秀在公元后的潜在妥协尚不清楚。Caveolin-1(Cav-1)是一种支架蛋白,丰富的 内皮小凹。我们和其他人已经证明,海马区Cav-1表达的减少会导致 类似AD的病理和记忆缺陷。我们实验室的初步研究表明,安在全球CAV- 1基因敲除小鼠和修复该模型中的内皮Cav-1不能恢复NSCs池 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NSCs/NPC中Cav-1的自主缺失影响AD相关关键蛋白的表达 包括淀粉样前体蛋白、β分泌酶和磷脂酰肌醇结合蛋白在内的蛋白质 装配蛋白(PICALM),晚发性AD的遗传危险因素。这个项目将检验这样一个假设 Cav-1以细胞自主的方式调节血管紧张素转换酶及神经源性Cav-1的表达变化 AD可能是神经发生缺陷的基础。利用新生成的包含条件的小鼠模型 在NSCs中删除Cav-1(NestinCreerT2;Cav-1lox/lox),目标1中的研究将确定细胞自主角色 Ahn的CAV-1病毒。目的2将阐明Cav-1在两个AD来源的海马神经干细胞/神经前体细胞中的命运 模型,APPSwePS1,ΔE9和APPKINL-G-F/NL-G-F,并确定CAV-1如何调节表达和膜 AD相关蛋白的脂筏定位及AD患者海马神经干细胞/神经前体细胞的表型总而言之,这是 该项目将提供对Cav-1作为Ahn的新的和必要的调节因子的迫切见解,并建立 Cav-1基因的改变是否导致AD患者海马神经干细胞/神经前体细胞功能受损。这个项目 提示恢复Ann中Cav-1的水平可能有助于减轻AD的记忆缺陷。

项目成果

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Terilyn Koehler Lawson Stephen其他文献

Terilyn Koehler Lawson Stephen的其他文献

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{{ truncateString('Terilyn Koehler Lawson Stephen', 18)}}的其他基金

Defining the cell-autonomous role of caveolin-1 in adult hippocampal neurogenesis in Alzheimer's Disease
定义 Caveolin-1 在阿尔茨海默病成人海马神经发生中的细胞自主作用
  • 批准号:
    10531351
  • 财政年份:
    2021
  • 资助金额:
    $ 5.43万
  • 项目类别:
Defining the cell-autonomous role of caveolin-1 in adult hippocampal neurogenesis in Alzheimer's Disease
定义 Caveolin-1 在阿尔茨海默病成人海马神经发生中的细胞自主作用
  • 批准号:
    10680607
  • 财政年份:
    2021
  • 资助金额:
    $ 5.43万
  • 项目类别:
Defining the cell-autonomous role of caveolin-1 in adult hippocampal neurogenesis in Alzheimer's Disease
定义 Caveolin-1 在阿尔茨海默病成人海马神经发生中的细胞自主作用
  • 批准号:
    10314269
  • 财政年份:
    2021
  • 资助金额:
    $ 5.43万
  • 项目类别:

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