ACAT inhibitors regulate palmitoylated APP and Abeta production

ACAT 抑制剂调节棕榈酰化 APP 和 Abeta 的产生

基本信息

批准号：
8631103
负责人：
RUDOLPH Emile TANZI
金额：
$ 36.53万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-23 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8631103
关键词：
Abeta synthesis Acyl Coenzyme A Affect Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animal Model Animals Atherosclerosis Biological Assay Brain Cardiovascular Diseases Cell membrane Cells Cellular biology Cholesterol Cholesterol Esters Clinical Trials Cultured Cells Data Development Diffuse Drug Targeting Endosomes Enzymes Fatty Acids Generations Genetic Goals Golgi Apparatus Human Kinetics Link Membrane Microdomains Minor Mus Names Neuroglia Neurons Pathogenesis Pathology Pathway interactions Phase III Clinical Trials Physiologic pulse Prevention Prevention therapy Process Production Proteins Proteomics Regulation Reporting Senile Plaques Series Sterol O-Acyltransferase Structure Testing Therapeutic Thioflavin S Transferase Transgenic Mice Treatment Efficacy aged amyloid pathology amyloid precursor protein processing avasimibe base beta-site APP cleaving enzyme 1 improved in vivo inhibitor/antagonist insight mouse model novel novel strategies overexpression palmitoylation prevent research study secretase trafficking

项目摘要

DESCRIPTION (provided by applicant): Enzymes in the cholesterol pathway have emerged as effective drug targets for the prevention and treatment of Alzheimer's disease (AD). Although statins reduced beta-amyloid (A?) in cells and animal models, so far yielded disappointing results in phase III clinical trials for AD. A cholesterol-modifying enzyme named acyl-coenzyme A: cholesterol acyltransferase (ACAT) is becoming an exciting target for AD therapy and atherosclerosis. All three classes of existing ACAT inhibitors, knockdown of ACAT in cells and in AD mouse models reduce A? production. We have recently made considerable progress toward understanding the mechanism by which ACAT inhibition decreases A? levels. Specifically, we have found that the amyloid precursor protein (APP) is modified by the addition of a fatty acid in a process called palmitoylation. We were able to show that palmitoylation of APP is highly regulated by ACAT activity. In addition, we have identified a series of novel ACAT inhibitors. The overarching goal of this application is to elucidate the precise mechanism of action and therapeutic efficacy of ACAT inhibitors in AD, with particular focus on our novel compounds. To this end, we propose to use an integrated approach of cell biology and in vivo animal models. We will identify the palmitoylating enzyme of APP and ask whether ACAT inhibitors affect its expression or localization. We will also study how palmitoylated APP gives rise to A? and how ACAT inhibitors specifically reduce this process. Lastly, we will test the therapeutic potential of our novel ACAT inhibitors in animal models of AD and how ACAT inhibition regulates palmitoylated APP in vivo. Collectively, the goal of these experiments is to provide the necessary mechanistic and in vivo data for further development of ACAT inhibitors as a therapeutic strategy for AD and perhaps cardiovascular disease.

描述（由申请人提供）：胆固醇途径中的酶已成为预防和治疗阿尔茨海默氏病（AD）的有效药物靶标。尽管他汀类药物在细胞和动物模型中降低了β-淀粉样蛋白（A？），但到目前为止，在AD的III阶段临床试验中产生了令人失望的结果。一种称为酰基辅酶A：胆固醇酰基转移酶（ACAT）的胆固醇改良酶正成为AD疗法和动脉粥样硬化的令人兴奋的靶标。所有三类现有的ACAT抑制剂，细胞中ACAT的敲低和AD小鼠模型中的敲低降低了A？生产。我们最近在了解ACAT抑制降低A的机制方面取得了长足的进步？水平。具体而言，我们发现淀粉样蛋白前体蛋白（APP）通过在称为棕榈酰化的过程中添加脂肪酸来改变。我们能够证明APP的棕榈酰化受ACAT活性的高度调节。此外，我们已经确定了一系列新型的ACAT抑制剂。该应用的总体目标是阐明ACAT抑制剂在AD中的精确作用机理和治疗功效，特别关注我们的新型化合物。为此，我们建议使用细胞生物学和体内动物模型的综合方法。我们将确定APP的棕榈酰化酶，并询问ACAT抑制剂是否影响其表达或定位。我们还将研究棕榈酰化应用如何产生A？以及ACAT抑制剂如何特异性减少此过程。最后，我们将在AD动物模型中测试新型ACAT抑制剂的治疗潜力，以及ACAT抑制如何调节体内棕榈酰化应用。总的来说，这些实验的目的是提供必要的机械和体内数据，以进一步开发ACAT抑制剂作为AD和可能心血管疾病的治疗策略。