CD36 in Alzheimer's Disease

CD36 在阿尔茨海默病中的作用

基本信息

  • 批准号:
    7997222
  • 负责人:
  • 金额:
    $ 35.96万
  • 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:
    2008-01-01 至 2012-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The interactions of beta amyloid (A2) with microglia and endothelial cells in the brains of patients with Alzheimer's disease (AD) are mediated by specific receptors for A2 and may play critical roles in the pathogenesis of AD. Microglia are activated by A2 to produce proinflammatory cytokines and neurotoxins. A2-induced cytokines participate in AD pathogenesis by increasing neurotoxin production and up-regulating the expression and activities of the enzymes that promote A2 formation such as 2 and 3 secretase. Endothelial cell binding to A2 leads to vascular dysfunction and promotes transport of circulating A2 and its accumulation into the brain. For these reasons, blocking the interactions of A2 with its cellular receptors is a potential therapeutic strategy for AD. We identified CD36 as a key receptor that mediates cellular interactions of microglia and endothelial cells with A2. To determine the exact role of CD36-A2 interactions in the pathogenesis of AD, we bred CD36-/- mice with PS1-APP double transgenic mice that develop accelerated AD-like pathology. Analysis of the resulting PS1-APP-CD36-/- mice showed that they have a significant reduction in the level of A2 in their brain when compared to age matched PS1-APP mice with normal CD36 expression. The decrease in A2 levels in the brains of PS1- APP-CD36-/- mice was associated with a significant reduction in the number of senile-like plaques, and in the inflammatory response associated with these plaques, suggesting that CD36 expression and/or CD36-A2 interactions regulate A2 accumulation and the subsequent development of AD-like pathology in these mice. The overall goal of this grant is to identify the mechanism(s) by which CD36 regulates intracerebral A2 levels in PS1-APP mice. Accumulation of A2 in the brain is regulated by three pathways, enzymes that generate A2, enzymes that degrade A2, and the influx/efflux of A2 across the endothelium and the blood brain barrier. We will determine the role of CD36 in each of these 3 pathways. We will also determine if restoring the CD36-mediated inflammatory response by repopulating the brain of PS1-APP-CD36-/- with CD36+/+ microglia using bone marrow transplant from CD36+/+ mice will restore AD-like pathology in these mice. The data obtained from these experiments will help decipher this novel CD36-dependent pathway for regulation of intracerebral A2 levels. Since CD36 expression in human brains correlates with A2 levels and since CD36 targeted therapeutics are being explored for diseases other than AD, these experiments will also help us determine if targeting CD36 can be used as a disease modifying therapeutic strategy to stop or delay progression of AD. Narrative: Effective and safe therapies for Alzheimer's disease remain elusive. Understanding how CD36 deficiency protects from Alzheimer's-like disease in mice, is an important and key first step that will allow us to design CD36 targeted therapies that will stop or delay the progression of this devastating disease and therefore help limit its significant health and economic impact on afflicted individuals, their families and society.
描述(由申请人提供):阿尔茨海默病(AD)患者脑中β淀粉样蛋白(A2)与小胶质细胞和内皮细胞的相互作用由A2的特异性受体介导,可能在AD的发病机制中起关键作用。小胶质细胞被A2激活以产生促炎细胞因子和神经毒素。A2诱导的细胞因子通过增加神经毒素的产生和上调促进A2形成的酶如2和3分泌酶的表达和活性参与AD发病机制。内皮细胞与A2的结合导致血管功能障碍,并促进循环A2的运输及其在脑中的积累。由于这些原因,阻断A2与其细胞受体的相互作用是AD的潜在治疗策略。 我们确定了CD 36作为介导小胶质细胞和内皮细胞与A2的细胞相互作用的关键受体。为了确定CD 36-A2相互作用在AD发病机制中的确切作用,我们将CD 36-/-小鼠与PS1-APP双转基因小鼠进行了繁殖,这些小鼠发展出加速的AD样病理。对所得PS1-APP-CD 36-/-小鼠的分析显示,与具有正常CD 36表达的年龄匹配的PS1-APP小鼠相比,它们的脑中A2水平显著降低。PS1-APP-CD 36-/-小鼠脑中A2水平的降低与老年样斑块数量的显著减少以及与这些斑块相关的炎症反应的显著减少相关,表明CD 36表达和/或CD 36-A2相互作用调节A2积累以及这些小鼠中AD样病理学的后续发展。这项资助的总体目标是确定CD 36调节PS1-APP小鼠脑内A2水平的机制。A2在脑中的积累受三种途径调节,产生A2的酶,降解A2的酶,以及A2穿过内皮和血脑屏障的流入/流出。我们将确定CD 36在这3种途径中的作用。我们还将确定通过使用来自CD 36 +/+小鼠的骨髓移植用CD 36 +/+小胶质细胞重新填充PS1-APP-CD 36-/-的脑来恢复CD 36介导的炎症反应是否将恢复这些小鼠中的AD样病理。 从这些实验中获得的数据将有助于破译这种新的CD 36依赖性途径调节脑内A2水平。由于人脑中的CD 36表达与A2水平相关,并且由于CD 36靶向治疗正在探索用于AD以外的疾病,因此这些实验也将帮助我们确定靶向CD 36是否可以用作疾病修饰治疗策略以阻止或延迟AD的进展。叙述: 有效和安全的治疗阿尔茨海默病的方法仍然难以捉摸。了解CD 36缺陷如何保护小鼠免受阿尔茨海默病样疾病的影响是重要而关键的第一步,这将使我们能够设计CD 36靶向疗法,以阻止或延迟这种毁灭性疾病的进展,从而有助于限制其对患病个体,家庭和社会的重大健康和经济影响。

项目成果

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JOSEPH EL EL-KHOURY其他文献

JOSEPH EL EL-KHOURY的其他文献

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{{ truncateString('JOSEPH EL EL-KHOURY', 18)}}的其他基金

Deciphering the role of Microglia in Glioblastoma
破译小胶质细胞在胶质母细胞瘤中的作用
  • 批准号:
    10584233
  • 财政年份:
    2022
  • 资助金额:
    $ 35.96万
  • 项目类别:
Deciphering the role of Microglia in Glioblastoma
破译小胶质细胞在胶质母细胞瘤中的作用
  • 批准号:
    10708972
  • 财政年份:
    2022
  • 资助金额:
    $ 35.96万
  • 项目类别:
Deciphering the role of Microglia in Glioblastoma
破译小胶质细胞在胶质母细胞瘤中的作用
  • 批准号:
    10416151
  • 财政年份:
    2021
  • 资助金额:
    $ 35.96万
  • 项目类别:
Role of SCARF1 in apoptotic cell clearance and prevention of autoimmunity
SCARF1 在凋亡细胞清除和预防自身免疫中的作用
  • 批准号:
    9230810
  • 财政年份:
    2015
  • 资助金额:
    $ 35.96万
  • 项目类别:
Role of SCARF1 in apoptotic cell clearance and prevention of autoimmunity
SCARF1 在凋亡细胞清除和预防自身免疫中的作用
  • 批准号:
    9424643
  • 财政年份:
    2015
  • 资助金额:
    $ 35.96万
  • 项目类别:
Toll-Like Receptor Signaling in Alzheimer's Disease
阿尔茨海默病中的 Toll 样受体信号转导
  • 批准号:
    8679097
  • 财政年份:
    2013
  • 资助金额:
    $ 35.96万
  • 项目类别:
Generation of a comprehensive panel of reagents for research on scavenger recepto
生成用于清除剂受体研究的综合试剂组
  • 批准号:
    8058800
  • 财政年份:
    2009
  • 资助金额:
    $ 35.96万
  • 项目类别:
Generation of a comprehensive panel of reagents for research on scavenger recepto
生成用于清除剂受体研究的综合试剂组
  • 批准号:
    7787085
  • 财政年份:
    2009
  • 资助金额:
    $ 35.96万
  • 项目类别:
Generation of a comprehensive panel of reagents for research on scavenger recepto
生成用于清除剂受体研究的综合试剂组
  • 批准号:
    7928276
  • 财政年份:
    2009
  • 资助金额:
    $ 35.96万
  • 项目类别:
Generation of a comprehensive panel of reagents for research on scavenger recepto
生成用于清除剂受体研究的综合试剂组
  • 批准号:
    7883973
  • 财政年份:
    2009
  • 资助金额:
    $ 35.96万
  • 项目类别:

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