Role of apoE structure and metabolism in neurodegeneration

apoE结构和代谢在神经退行性变中的作用

基本信息

  • 批准号:
    8235856
  • 负责人:
  • 金额:
    $ 37.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-03-01 至 2014-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Apolipoprotein (apo) E plays a key role in lipid metabolism and transport in plasma and the central nervous system. One of the three major human apoE isoforms, apoE4, is a major risk factor for Alzheimer's disease by as yet undefined mechanisms. Our long-range objective is to employ a structure-function approach to establish these mechanisms with the goal of identifying potential therapeutic interventions. This proposal focuses on two major areas related to this goal. First, we will extend the resolution of our x-ray diffraction and small-angle x- ray scattering model of apoE4 bound to phospholipids and compare the structures of apoE4 and apoE3 bound to lipid. Secondly, we will continue our studies in which we link the apoE4 structural property of domain interaction to neurodegeneration and functional and cognitive deficits. The brains of human apoE isoform knock in mice and our Arg-61 apoE mouse model in which domain interaction was introduced, contain lower levels of apoE4 and Arg-61 mouse apoE compared to apoE3 and mouse wild-type apoE, respectively. The lower levels were due to decreased secretion by astrocytes, in which the Arg-61 apoE was selectively degraded, inducing an unfolded protein stress response. Based on these studies, we hypothesize that domain interaction contributes to neurodegeneration through two effects on astrocytes. 1) Domain interaction is recognized as an abnormally folded protein, resulting in an endoplasmic reticulum stress response that leads to downstream effects on key biochemical pathways supporting neuronal integrity. 2) Decreased secretion of apoE4 results in lower levels of cholesterol to support synapse formation and neuronal maintenance. This hypothesis represents a novel paradigm in which apoE4 domain interaction contributes to neurodegeneration and functional and cognitive deficits, involving astrocytes in the absence of additional stressors. We believe that these effects are early events in apoE4 carriers and set the stage for more dramatic responses with the addition of brain stressors (e.g. age, ischemia or A2 toxicity). This paradigm links apoE structure with neurodegeneration and functional consequences and suggests that interference with domain interaction is a viable therapeutic approach. These studies hold the potential to determine the mechanisms by which apoE4 is associated with a high risk for Alzheimer's disease and other forms of neurodegeneration and for identifying therapeutic approaches to reduce this risk. PUBLIC HEALTH RELEVANCE: Apolipoprotein E4 (apoE4) a brain protein, is the major genetic risk factor for Alzheimer's disease although the basis for this association is unknown. Based on our apoE4 structure studies, we propose a new mechanism for this association involving astrocytes, which are cells in the brain that support and maintain nerve cells. These studies hold the potential to identify new therapeutic approaches to reverse the effects of apoE4 on Alzheimer's disease.
描述(由申请人提供):载脂蛋白(APO)E在血浆和中枢神经系统中的脂质代谢和运输中起关键作用。通过未定义的机制,三个主要的人类APOE同工型APOE4是阿尔茨海默氏病的主要危险因素。我们的远程目标是采用一种结构功能方法来建立这些机制,以确定潜在的治疗干预措施。该提案重点介绍了与该目标相关的两个主要领域。首先,我们将扩展X射线衍射的分辨率和与磷脂结合的APOE4的小角度X-射线散射模型,并比较与脂质结合的APOE4和APOE3的结构。其次,我们将继续我们的研究,其中我们将域相互作用的APOE4结构特性与神经变性以及功能和认知缺陷联系起来。与APOE3和小鼠野生型APOE相比,引入域相互作用的小鼠和我们的ARG-61 APOE小鼠模型的人APOE同工型敲击的大脑在其中引入了域相互作用。较低的水平是由于星形胶质细胞分泌的降低,其中ARG-61 APOE有选择性降解,从而诱导了展开的蛋白质应激反应。基于这些研究,我们假设域相互作用通过对星形胶质细胞的两种影响有助于神经变性。 1)域相互作用被认为是异常折叠的蛋白质,导致内质网应激反应,从而导致对支持神经元完整性的关键生化途径的下游影响。 2)APOE4分泌的降低导致胆固醇水平较低,以支持突触形成和神经元维持。该假设代表了一种新的范式,其中APOE4结构域的相互作用有助于神经变性,功能和认知缺陷,涉及星形胶质细胞,在没有其他应激源的情况下。我们认为,这些效果是APOE4载体中的早期事件,并通过增加脑压力源(例如年龄,缺血或A2毒性)为更具戏剧性的反应奠定了基础。该范式将APOE结构与神经变性和功能后果联系起来,并表明干扰域相互作用是一种可行的治疗方法。这些研究具有确定APOE4与阿尔茨海默氏病和其他形式的神经变性的高风险相关的机制的潜力,并确定识别降低这种风险的治疗方法。公共卫生相关性:载脂蛋白E4(APOE4)脑蛋白是阿尔茨海默氏病的主要遗传危险因素,尽管该关联的基础尚不清楚。基于我们的APOE4结构研究,我们为这种关联提出了一种涉及星形胶质细胞的新机制,即大脑中支持和维持神经细胞的细胞。这些研究具有鉴定新的治疗方法,以扭转APOE4对阿尔茨海默氏病的影响。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Understanding the basis for the association of apoE4 with Alzheimer's disease: opening the door for therapeutic approaches.
了解 apoE4 与阿尔茨海默氏病关联的基础:为治疗方法打开大门。
  • DOI:
    10.2174/156720509789207921
  • 发表时间:
    2009
  • 期刊:
  • 影响因子:
    2.1
  • 作者:
    Zhong,Ning;Weisgraber,KarlH
  • 通讯作者:
    Weisgraber,KarlH
Central Nervous System Lipoproteins: ApoE and Regulation of Cholesterol Metabolism.
An optimized negative-staining protocol of electron microscopy for apoE4 POPC lipoprotein.
  • DOI:
    10.1194/jlr.d002493
  • 发表时间:
    2010-05
  • 期刊:
  • 影响因子:
    6.5
  • 作者:
    Zhang L;Song J;Newhouse Y;Zhang S;Weisgraber KH;Ren G
  • 通讯作者:
    Ren G
Apolipoprotein E: from cardiovascular disease to neurodegenerative disorders.
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ROBERT W. MAHLEY其他文献

ROBERT W. MAHLEY的其他文献

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{{ truncateString('ROBERT W. MAHLEY', 18)}}的其他基金

Somatostatin (SST)-GABAergic Interneuron Therapy for Alzheimer's Disease with ApoE4
生长抑素 (SST)-GABA 能中间神经元治疗 ApoE4 治疗阿尔茨海默病
  • 批准号:
    9893103
  • 财政年份:
    2019
  • 资助金额:
    $ 37.26万
  • 项目类别:
Develop GABAergic Neuron Protectors for Treating ApoE4-Related Alzheimer's Disease
开发 GABA 能神经元保护剂来治疗 ApoE4 相关的阿尔茨海默病
  • 批准号:
    10056515
  • 财政年份:
    2019
  • 资助金额:
    $ 37.26万
  • 项目类别:
Somatostatin (SST)-GABAergic Interneuron Therapy for Alzheimer's Disease with ApoE4
生长抑素 (SST)-GABA 能中间神经元治疗 ApoE4 治疗阿尔茨海默病
  • 批准号:
    10011752
  • 财政年份:
    2019
  • 资助金额:
    $ 37.26万
  • 项目类别:
ApoE4 Structure Correctors as a Therapeutic Approach for Alzheimers Disease
ApoE4 结构校正剂作为阿尔茨海默病的治疗方法
  • 批准号:
    8460847
  • 财政年份:
    2012
  • 资助金额:
    $ 37.26万
  • 项目类别:
Targeting ApoE4 as a Therapeutic Strategy for Alzheimer's Disease
以 ApoE4 为靶点作为阿尔茨海默病的治疗策略
  • 批准号:
    8549072
  • 财政年份:
    2012
  • 资助金额:
    $ 37.26万
  • 项目类别:
Targeting ApoE4 as a Therapeutic Strategy for Alzheimer's Disease
以 ApoE4 为靶点作为阿尔茨海默病的治疗策略
  • 批准号:
    8420245
  • 财政年份:
    2012
  • 资助金额:
    $ 37.26万
  • 项目类别:
ApoE4 Structure Correctors as a Therapeutic Approach for Alzheimers Disease
ApoE4 结构校正剂作为阿尔茨海默病的治疗方法
  • 批准号:
    8328029
  • 财政年份:
    2012
  • 资助金额:
    $ 37.26万
  • 项目类别:
Role of apoE structure and metabolism in neurodegeneration
apoE结构和代谢在神经退行性变中的作用
  • 批准号:
    8036997
  • 财政年份:
    2008
  • 资助金额:
    $ 37.26万
  • 项目类别:
APOLIPOPROTEIN E IN NEUROBIOLOGY: CELLULAR MECHANISMS
神经生物学中的载脂蛋白 E:细胞机制
  • 批准号:
    7431632
  • 财政年份:
    2007
  • 资助金额:
    $ 37.26万
  • 项目类别:
Targeting Apolipoprotein E4-related Neuropathology
靶向载脂蛋白 E4 相关神经病理学
  • 批准号:
    6673321
  • 财政年份:
    2003
  • 资助金额:
    $ 37.26万
  • 项目类别:

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