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病（AD）的有效药物靶点。尽管他汀类药物可以减少细胞和动物模型中的 β-淀粉样蛋白 (A?)，但迄今为止在 AD 的 III 期临床试验中取得的结果令人失望。一种名为酰基辅酶 A：胆固醇酰基转移酶 (ACAT) 的胆固醇修饰酶正在成为 AD 治疗和动脉粥样硬化的令人兴奋的目标。所有三类现有的 ACAT 抑制剂、细胞中和 AD 小鼠模型中 ACAT 的敲低都会减少 A?生产。最近，我们在了解 ACAT 抑制降低 A? 的机制方面取得了相当大的进展。水平。具体来说，我们发现淀粉样前体蛋白（APP）是通过在称为棕榈酰化的过程中添加脂肪酸来修饰的。我们能够证明 APP 的棕榈酰化受到 ACAT 活性的高度调控。此外，我们还发现了一系列新型 ACAT 抑制剂。本申请的首要目标是阐明 ACAT 抑制剂在 AD 中的精确作用机制和治疗功效，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。我们将鉴定 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APP如何产生A？以及 ACAT 抑制剂如何专门减少这一过程。最后，我们将测试新型 ACAT 抑制剂在 AD 动物模型中的治疗潜力，以及 ACAT 抑制如何在体内调节棕榈酰化 APP。总的来说，这些实验的目标是为进一步开发 ACAT 抑制剂作为 AD 和心血管疾病的治疗策略提供必要的机制和体内数据。