CD36 in Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)患者大脑中的β-淀粉样蛋白(A2)与小胶质细胞和内皮细胞的相互作用是由A2的特定受体介导的，可能在AD的发病机制中发挥关键作用。小胶质细胞被A2激活，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的发病。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聚。因此，阻断A2与其细胞受体的相互作用是治疗AD的一种潜在的治疗策略。 我们发现CD36是介导小胶质细胞和血管内皮细胞与A2相互作用的关键受体。为了确定CD36-A2相互作用在AD发病机制中的确切作用，我们用PS1-APP双转基因小鼠培育了CD36-/-小鼠，这些小鼠出现了加速的AD样病理。对产生的PS1-APP-CD36-/-小鼠的分析表明，与CD36表达正常的年龄匹配的PS1-APP小鼠相比，它们大脑中的A2水平显著降低。PS1-APP-CD36-/-小鼠脑内A2水平的下降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有关，这表明CD36表达和/或CD36-A2相互作用调节A2的积累和随后AD样病理的发展。这项资助的总体目标是确定CD36调节PS1-APP小鼠脑内A2水平的机制(S)。A2在大脑中的积累受到三条途径的调节，即产生A2的酶，降解A2的酶，以及A2通过内皮和血脑屏障的流入/流出。我们将确定CD36在这三个途径中的每一个中的作用。我们还将确定通过使用CD36/小鼠的骨髓移植将CD36/小胶质细胞重新填充到PS1-APP-CD36-/-的脑中来恢复CD36介导的炎症反应是否会恢复这些小鼠的AD样病理。 从这些实验中获得的数据将有助于破译这一新的依赖CD36的调节脑内A2水平的途径。由于CD36在人脑中的表达与A2水平相关，而且CD36靶向治疗正在探索用于治疗AD以外的疾病，这些实验也将帮助我们确定靶向CD36是否可以用作一种疾病修正治疗策略，以阻止或延缓AD的进展。叙述： 治疗阿尔茨海默病的有效和安全的疗法仍然难以捉摸。了解CD36缺乏如何保护小鼠免受阿尔茨海默氏样疾病的影响，是重要和关键的第一步，将使我们能够设计CD36靶向治疗，阻止或延缓这种毁灭性疾病的进展，从而帮助限制其对受影响的个人、他们的家庭和社会的重大健康和经济影响。

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.