CD36 in Alzheimer's Disease

CD36 在阿尔茨海默病中的作用

• 批准号: 7743996
• 负责人: JOSEPH EL EL-KHOURY
• 金额: $ 36.33万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/7743996
• 关键词: Address; Adult; Adverse effects; Affect; Age; Aging; Alzheimer' s Disease; Amyloid; 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; Testing; Therapeutic; Time; Transgenic Mice; Transgenic Organisms; Transplantation; amyloid formation; 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

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）与阿尔茨海默氏病患者大脑中的小胶质细胞和内皮细胞的相互作用是由特异性受体的A2介导的，并且可能在AD的发病机理中起关键作用。小胶质细胞被A2激活以产生促炎性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并上调促进A2形成（例如2和3泌尿）的酶的表达和活性来参与AD发病机理。内皮细胞与A2结合会导致血管功能障碍，并促进循环A2及其积累到大脑的运输。由于这些原因，阻止A2与其细胞受体的相互作用是AD的潜在治疗策略。 我们将CD36鉴定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CD36-A2相互作用在AD发病机理中的确切作用，我们用PS1-APP双转基因小鼠饲养CD36 - / - 小鼠，这些小鼠会产生加速的AD样病理。对所得PS1-APP-CD36 - / - 小鼠的分析表明，与年龄匹配的与正常CD36表达的年龄相比，它们的A2水平显着降低。 PS1- APP-CD36 - / - 小鼠大脑中A2水平的降低与类似老年斑块的数量显着减少，以及与这些斑块相关的炎症反应，这表明CD36表达和/或CD36-A2相互作用调节A2的积累和随后的Ad-light Patherogy in thup-Ad-light Pathology in thullike Patherology in thullike Patherology in thullike Patherology in thullike Patherology in thullike Patherology。该赠款的总体目标是确定CD36调节PS1-APP小鼠中脑A2水平的机制。 A2在大脑中的积累受三种途径，即产生A2，降解A2的酶以及A2在整个内皮和血液脑屏障中的涌入/外排的调节。我们将确定CD36在这三个途径中的每种途径中的作用。我们还将通过将CD36+/+小鼠的骨髓移植物与CD36+/+小胶质细胞一起重新填充PS1-APP-CD36 - / - 是否通过将CD36介导的炎症反应恢复，将恢复这些小鼠中的AD-like病理学。 从这些实验中获得的数据将有助于解读这一新型CD36依赖性途径，以调节脑A2水平。由于人类大脑中的CD36表达与A2水平相关，并且正在探索除AD以外的其他疾病的CD36靶向疗法，因此这些实验还将帮助我们确定靶向CD36是否可以用作修改AD AD进展的疾病，以改变或延迟AD的进展。叙述： 对阿尔茨海默氏病的有效疗法仍然难以捉摸。了解CD36缺乏症如何保护小鼠中的阿尔茨海默氏症疾病，是一个重要而关键的第一步，它将使我们能够设计CD36的目标疗法，该疗法将阻止或延迟这种破坏性疾病的发展，从而有助于限制其对受苦的个人，家庭，家庭和社会的重大健康和经济影响。