Novel mechanisms of NSAID action in Alzheimer disease

这项新的申请是要求五年的支持，以寻求非甾体抗炎药（NSAID）在阿尔茨海默病（AD）中的新作用机制，阿尔茨海默病是年龄相关痴呆疾病的最常见形式。越来越多的证据表明，NSAID在治疗或预防AD方面具有有益作用。NSAID在AD中的作用机制尚不清楚，尽管人们普遍认为其抗炎特性和环氧合酶（考克斯）抑制是其有益作用的原因。我们的工作假设表明，某些NSAID通过选择性降低脑中致病性42个氨基酸种类的淀粉样β-肽（A β 42）的水平，通过环加氧酶（考克斯）非依赖性机制，可用于AD治疗。在初步研究中，我们发现几种NSAID在高于考克斯抑制所需浓度时降低培养基或培养细胞中的A β 42水平。然而，并非所有NSAID都具有这种特性，包括较新的考克斯-2选择性抑制剂。事实上，NSAID能够通过靶向基因缺失降低考克斯-2和考克斯-2缺陷细胞中的A β 42水平。重要的是，体外结果已在转基因小鼠中NSAID的短期研究中得到证实，从而证明了体内组织培养资金的生理相关性。因此，我们假设，A β 42减少和抗炎作用是并行的机制，共同促成了NSAID在AD中的明显疗效。该计划将通过三个项目严格测试这一假设：1）定义NSAID减少A β 42的细胞机制，2）确定最大化A β 42减少特性的化合物，并在体内测试这些和现有的NSAID，3）表征这些A β 42在人类受试者中的降低作用。

This new application is to request for five years support to pursue a novel mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease (AD), the most common form of age- related dementing illness. Increasing evidence suggests that NSAIDs have beneficial effects in the treatment or prevention of AD. The mechanisms of NSAID action in AD are unknown although it is widely believed that their anti-inflammatory properties and cyclo-oxygenase (COX) inhibition account for their beneficial effects. Our working hypothesis states that certain NSAIDs are useful in AD therapy by selectively reducing the levels of the pathogenic 42 amino acid species of amyloid beta-peptide (Abeta42) in brain through a cyclo-oxygenase (COX) independent mechanism. In preliminary studies, we found that several NSAIDs reduced the levels of Abeta42 in medium or cultured cells at concentrations above that required for COX inhibition. However, this property was not shared by all NSAIDs, including the newer COX-2 selective inhibitors. Indeed, NSAIDs were able to reduce Abeta42 levels in cell deficient in COX-2 and COX-2 by targeted gene deletions. Importantly, the in vitro results have been confirmed in short term studies of NSAIDs in transgenic mice, thereby demonstrating the physiological relevance of the tissue cultured funding in vivo. Therefore, we hypothesize that Abeta42 reduction and anti-inflammatory effects are parallel mechanisms that together contribute to the apparent efficacy of NSAIDs in AD. The program will rigorously test this hypothesis through three Projects: 1) define the cellular mechanisms that underlie Abeta42 reduction by NSAIDs, 2) identify compounds that maximize the Abeta42 reducing property and test these and existing NSAIDs in vivo, and 3) characterize these Abeta42 lowering effects in human subjects.