Novel mechanisms of NSAID action in Alzheimer disease

这项新的申请是为了申请五年的支持，以寻求非类固醇抗炎药(NSAIDs)在阿尔茨海默病(AD)中的新作用机制，AD是最常见的与年龄相关的痴呆疾病。越来越多的证据表明，非甾体抗炎药在治疗或预防AD方面具有有益的作用。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抑制环氧合酶(COX)是其有益作用的原因。我们的工作假说表明，某些非甾体抗炎药通过环氧合酶(COX)不依赖的机制，选择性地降低大脑中致病的42种淀粉样β-肽(Abeta42)的水平，从而在AD治疗中发挥作用。在初步研究中，我们发现几种非甾体抗炎药在高于COX抑制所需浓度的情况下降低了培养液或培养细胞中的Abeta42水平。然而，并不是所有的非类固醇抗炎药都有这种特性，包括较新的COX-2选择性抑制剂。事实上，非甾体抗炎药能够通过靶向基因缺失降低环氧合酶-2和环氧合酶-2缺陷细胞中的Abeta42水平。重要的是，体外结果已经在转基因小鼠的非类固醇抗炎药的短期研究中得到了证实，从而证明了体内组织培养资金的生理学相关性。因此，我们假设Abeta42的减少和抗炎作用是平行的机制，共同有助于非类固醇抗炎药在AD中的明显疗效。该计划将通过三个项目严格检验这一假设：1)确定非甾体类抗炎药降低Abeta42的细胞机制，2)识别最大限度地提高Abeta42还原性能的化合物，并在体内测试这些和现有的非类固醇抗炎药，以及3)在人体中表征这些降低Abeta42的效果。

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.