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：
JOSEPH EL EL-KHOURY
金额：
$ 35.96万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
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

来源：
https://reporter.nih.gov/project-details/7997222
关键词：
Address Adult Adverse effects Affect Age Aging Alzheimer&apos s Disease Amyloid beta-Protein Astrocytes Atherosclerosis Binding Blood Blood - brain barrier anatomy Blood Vessels Bone Marrow Bone Marrow Transplantation Brain Brain region Breeding CD36 gene Cells Complex Critiques Data Development Disease Endothelial Cells Endothelium Enzymes Evaluation Experimental Designs Family Female Functional disorder Future Genes Goals Grant Human In Vitro Individual Inflammatory Inflammatory Response Insulinase Interferons Interleukin-1 Lasers Manuscripts Measures Mediating Medicine Microglia Mus Myelogenous Nature Neprilysin Neurons Neurotoxins Paper Pathogenesis Pathology Pathway interactions Patients Peptidyl-Dipeptidase A Plasma Play Principal Investigator Production Published Comment Publishing Regulation Reporting Risk Role Senile Plaques Societies Suggestion System TNF gene Testing Therapeutic Time Transgenic Mice Transgenic Organisms Transplantation cell type cytokine design economic impact enzyme activity enzyme pathway health economics human APH-1 protein human PEN-2 protein in vitro Model in vivo laser capture microdissection male member monocyte neurotoxicity nicastrin protein novel programs receptor research study response scavenger receptor secretase therapeutic target

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）：β淀粉样蛋白（A2）与阿尔茨海默病（AD）患者大脑中的小胶质细胞和内皮细胞的相互作用是由A2的特异性受体介导的，并且可能在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以及上调促进 A2 形成的酶（如 2 和 3 分泌酶）的表达和活性来参与 AD 发病机制。内皮细胞与 A2 结合会导致血管功能障碍，并促进循环 A2 的运输及其在大脑中的积累。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 CD36 是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 CD36-A2 相互作用在 AD 发病机制中的确切作用，我们将 CD36-/- 小鼠与 PS1-APP 双转基因小鼠进行培育，这些小鼠会加速出现 AD 样病理。对所得 PS1-APP-CD36-/- 小鼠的分析表明，与具有正常 CD36 表达的年龄匹配的 PS1-APP 小鼠相比，它们大脑中 A2 的水平显着降低。 PS1-APP-CD36-/-小鼠大脑中 A2 水平的降低与老年样斑块数量以及与这些斑块相关的炎症反应的显着减少相关，这表明 CD36 表达和/或CD36-A2 相互作用调节 A2 积累以及这些小鼠中 AD 样病理的后续发展。该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。 A2 在大脑中的积累受到三种途径的调节：生成 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 CD36 在这 3 条途径中的每条途径中的作用。我们还将确定通过使用 CD36+/+ 小鼠的骨髓移植用 CD36+/+ 小胶质细胞重新填充 PS1-APP-CD36-/- 的大脑来恢复 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种新的 CD36 依赖性调节脑内 A2 水平的途径。由于人类大脑中的 CD36 表达与 A2 水平相关，并且由于 CD36 靶向治疗正在探索用于 AD 以外的疾病，这些实验还将帮助我们确定靶向 CD36 是否可以用作疾病修饰治疗策略，以阻止或延缓 AD 的进展。叙述：阿尔茨海默病的有效且安全的治疗方法仍然难以捉摸。了解 CD36 缺陷如何预防小鼠患阿尔茨海默病样疾病，是重要且关键的第一步，这将使我们能够设计 CD36 靶向疗法，阻止或延缓这种毁灭性疾病的进展，从而有助于限制其对健康和经济的重大影响对受影响的个人、他们的家庭和社会。