ACAT inhibitors regulate palmitoylated APP and Abeta production

描述(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。尽管他汀类药物降低了β-淀粉样蛋白(A？)在细胞和动物模型中，到目前为止，AD的III期临床试验结果令人失望。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一个令人兴奋的靶点。所有三类现有的ACAT抑制剂，在细胞和AD小鼠模型中敲除ACAT后，A？制作。我们最近在理解ACAT抑制降低A？的机制方面取得了很大进展。级别。具体地说，我们发现淀粉样前体蛋白(APP)在一个称为棕榈酰化的过程中通过添加脂肪酸来修饰。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的ACAT抑制剂。这项应用的首要目标是阐明ACAT抑制剂在AD中的确切作用机制和治疗效果，特别是我们的新化合物。为此，我们建议使用细胞生物学和活体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的APP如何产生A？以及ACAT抑制剂是如何具体减少这一过程的。最后，我们将测试我们的新型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，这些实验的目的是为ACAT抑制剂的进一步开发提供必要的机制和体内数据，作为AD和心血管疾病的治疗策略。 公共卫生相关性：以胆固醇为基础的抗体降低剂正在成为治疗AD的有吸引力的治疗策略。这一建议直接测试了已建立的和新的ACAT抑制剂在降低神经元和AD动物模型中的β-淀粉样蛋白水平方面的机制。这些研究将极大地促进对以胆固醇为基础的治疗方法的理解和开发，以预防和治疗阿尔茨海默病，也许还有心血管疾病。

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. PUBLIC HEALTH RELEVANCE: Cholesterol-based Ab-lowering agents are emerging as attractive therapeutic strategies for AD. This proposal directly tests the mechanism of established and novel ACAT inhibitors in reducing beta-amyloid levels in neurons and AD animal models. These studies will greatly facilitate the understanding and development of cholesterol-based therapies for the prevention and treatment of Alzheimer's disease and perhaps cardiovascular disease.