CD36 in Alzheimer's Disease

脑内β-淀粉样蛋白与小胶质细胞和血管内皮细胞的相互作用 阿尔茨海默病患者S病(AD)是由Aβ受体介导的，可能在AD中发挥作用 在阿尔茨海默病发病机制中的关键作用。小胶质细胞被Abeta激活以产生 致炎细胞因子和神经毒素。Aβ诱导的细胞因子参与AD 通过增加神经毒素的产生和上调其基因的表达来实现其发病机制 促进Abeta形成的酶的活性，如Beta和Gamma分泌酶。内皮细胞 与Abeta结合导致血管功能障碍并促进循环Abeta及其受体的转运 积聚到大脑中。出于这些原因，阻断Abeta与其细胞的相互作用 受体是治疗阿尔茨海默病的潜在策略。 我们发现CD36是一种关键的受体，它介导小胶质细胞和 含Abeta的内皮细胞。为了确定CD36-Abeta相互作用在 AD的发病机制，我们用PS1-APP双转基因小鼠培育了CD36-/-小鼠 加速的AD样病理。对产生的PS1-APP-CD36-/-小鼠的分析表明 与年龄匹配的人相比，他们大脑中的Abeta水平显著降低 CD36表达正常的PS1-APP小鼠。PS1大脑中Abeta水平的下降- APP-CD36-/-小鼠与老年性类风湿关节炎的数量显著减少相关 斑块，以及与这些斑块相关的炎症反应，提示CD36 表达和/或CD36-Abeta相互作用调节Abeta的积累和随后的 这些小鼠的AD样病理的发展。这笔赠款的总体目标是确定 CD36调节PS1-APP小鼠脑内Aβ水平的机制(S)。积累 大脑中的Abeta受三条途径调节，产生Abeta的酶，产生Abeta的酶 降解Abeta，以及Abeta穿过内皮和血脑屏障的流入/流出。我们 将确定CD36在这三条途径中的每一条中的作用。我们还将确定是否恢复 重组pS1-APP-CD36-/-脑内CD36介导的炎症反应 使用CD36+/+小鼠骨髓移植的CD36+/+小胶质细胞将恢复AD样细胞 这些小鼠的病理学。 从这些实验中获得的数据将有助于破译这种新型的CD36依赖 调节脑内Abeta水平的途径。由于CD36在人脑中的表达 与Abeta水平相关，由于CD36靶向疗法正在探索用于疾病 除了AD，这些实验还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，以阻止或延缓阿尔茨海默病的进展。

The interactions of beta amyloid (Abeta) with microglia and endothelial cells in the brains of patients with Alzheimer¿s disease (AD) are mediated by specific receptors for Abeta and may play critical roles in the pathogenesis of AD. Microglia are activated by Abeta to produce proinflammatory cytokines and neurotoxins. Abeta-induced cytokines participate in AD pathogenesis by increasing neurotoxin production and up-regulating the expression and activities of the enzymes that promote Abeta formation such as beta and gamma secretase. Endothelial cell binding to Abeta leads to vascular dysfunction and promotes transport of circulating Abeta and its accumulation into the brain. For these reasons, blocking the interactions of Abeta 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 Abeta. To determine the exact role of CD36-Abeta 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 Abeta in their brain when compared to age matched PS1-APP mice with normal CD36 expression. The decrease in Abeta 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 inflammtory response associated with these plaques, suggesting that CD36 expression and/or CD36-Abeta interactions regulate Abeta 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 Abeta levels in PS1-APP mice. Accumulation of Abeta in the brain is regulated by three pathways, enzymes that generate Abeta, enzymes that degrade Abeta, and the influx/efflux of Abeta 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 tranplant 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 Abeta levels. Since CD36 expression in human brains correlates with Abeta 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.