Novel mechanisms of NSAID action in Alzheimer disease

这项新申请旨在请求五年的支持，以探索非甾体抗炎药 (NSAID) 在阿尔茨海默病 (AD) 中的新作用机制，阿尔茨海默病是最常见的与年龄相关的痴呆症。越来越多的证据表明非甾体抗炎药对治疗或预防 AD 具有有益作用。 NSAID 在 AD 中的作用机制尚不清楚，但人们普遍认为其抗炎特性和环加氧酶 (COX) 抑制作用是其有益作用的原因。我们的工作假设表明，某些 NSAID 可通过环加氧酶 (COX) 独立机制选择性降低大脑中致病性 42 种氨基酸的淀粉样蛋白 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 NSAID 降低了培养基或培养细胞中 Abeta42 的水平，其浓度高于抑制 COX 所需的浓度。然而，并非所有 NSAID 都具有这种特性，包括较新的 COX-2 选择性抑制剂。事实上，NSAID 能够通过靶向基因删除来降低 COX-2 缺陷细胞和 COX-2 细胞中的 Abeta42 水平。重要的是，体外结果已在转基因小鼠的非甾体抗炎药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 Abeta42 减少和抗炎作用是平行机制，共同促成 NSAIDs 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) 定义 NSAID 降低 Abeta42 的细胞机制，2) 鉴定可最大限度地降低 Abeta42 特性的化合物，并在体内测试这些和现有的 NSAID，3) 表征这些在人类受试者中降低 Abeta42 的作用。

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.