The functional role of FLAP in Alzheimer's Disease

描述（由申请人提供）：本申请的范围是开发一种新的临床前治疗策略和候选药物，用于未来的临床试验，以治疗或预防阿尔茨海默病（AD）。阿尔茨海默病在世界范围内影响着越来越多的人，目前还没有治愈的方法。5-脂氧合酶（5LO）是一种在中枢神经系统（CNS）中大量存在的酶，其激活取决于一种称为FLAP （5-LO激活蛋白）的膜相关蛋白的存在。在大脑中，flap依赖的5LO激活随着年龄的增长而增加，这是患AD的最强危险因素之一。有趣的是，与对照组相比，AD大脑中的这些水平甚至更高。另一方面，最近我们发现遗传上缺乏5LO酶活性导致AD动物模型中淀粉样蛋白2 （A2）水平显著降低。综上所述，这些数据表明该途径参与了AD的发病机制，并支持了我们的中心假设：FLAP/5LO酶途径在AD的发展中起功能作用；它的药理调节是一种新的阿尔茨海默病治疗靶点。这项原理验证研究的目的是验证FLAP在阿尔茨海默病的神经生物学中是一个新的和功能重要的分子靶点。通过这种临床前类型的研究，我们想要验证FLAP药物抑制将改善AD样神经病理和AD转基因小鼠模型的行为缺陷的假设。为了实现这一目标，我们将使用一种选择性FLAP抑制剂，即MK-591，以达到以下具体目的：具体目的1：验证早期FLAP药理抑制将延迟或阻止年轻APP转基因小鼠ad样神经病理和行为缺陷的发展的假设。特异性目的2：在ad样神经病理和行为缺陷建立后，评估皮瓣药理抑制对APP转基因小鼠的作用。通过这些研究，我们打算完成皮瓣抑制剂作为AD潜在治疗药物临床前开发的第一步。如果我们证明MK-591给药导致脑淀粉样变性的调节（减少），并改善该AD模型中的行为障碍，我们的发现将为随后更全面的项目提交（即u01）提供生物学基础，其中将测试和比较几种不同的FLAP抑制剂在该模型以及其他AD模型中的疗效。作为未来研究计划的一部分，我们还将专注于临床前优化（剂量、疗效）和对临床诊断为轻度认知障碍（MCI）和AD的个体进行任何已确定的先导化合物的测试。这些研究，如果成功，最终可能导致调查新药（IND）申请到食品和药物管理局。

DESCRIPTION (provided by applicant): The scope of this proposal is to develop a novel pre-clinical therapeutic strategy with a candidate drug for future clinical testing to treat or prevent Alzheimer's disease (AD). AD affects a growing number of individuals worldwide and there is no cure for it. 5-Lipoxygenase (5LO) is an enzyme abundantly present in the central nervous system (CNS), where its activation depends on the presence of a membrane associated protein called FLAP (5-LO activating protein). In the brain, FLAP-dependent 5LO activation increases with aging, one of the strongest risk factors for developing AD. Interestingly, these levels are even higher in AD brains compared with controls. On the other hand, recently we have shown that genetic absence of 5LO enzymatic activity results in a significant reduction of Amyloid 2 (A2) levels in an animal model of AD. Taken together these data suggest an involvement of this pathway in the AD pathogenesis, and support our central hypotheses: FLAP/5LO enzymatic pathway plays a functional role in AD development; its pharmacological modulation represents a novel AD therapeutic target. The objective of this proof-of-principle study is to validate FLAP as a novel and functionally important molecular target in the neurobiology of AD. With this pre-clinical type of studies we want to test the hypothesis that FLAP pharmacological inhibition will ameliorate the AD-like neuropathology and behavioral deficits of a transgenic mouse model of AD. To achieve this goal, we will use a selective FLAP inhibitor, i.e. MK-591, in the following specific aims: Specific Aim 1: Test the hypothesis that early FLAP pharmacological inhibition will delay and or prevents the development of AD-like neuropathology and behavioral deficits in young APP transgenic mice. Specific Aim 2: Assess the efficacy of FLAP pharmacological inhibition in APP transgenic mice after the AD-like neuropathology and behavioral deficits are established. With these studies we intend to complete the initial step in the pipeline for the pre-clinical development of FLAP inhibitors as potential therapeutics for AD. If we demonstrate that MK-591 administration results in a modulation (decrease) of brain amyloidosis, and improvement of behavioral impairments in this AD model, our findings will represent the biologic basis for a subsequent and more comprehensive project submission (i.e., UO1) where several different FLAP inhibitors will be tested and compared for efficacy in this as well as in other AD models. As part of this future research program we will also focus on the pre-clinical optimization (doses, efficacy) and testing of any of the identified lead compounds in individuals with a clinical diagnosis of mild cognitive impairment (MCI) and AD. These studies, if successful, could ultimately lead to an investigation new drug (IND) application to the Food and Drug Administration. PUBLIC HEALTH RELEVANCE: Alzheimer's disease (AD) is a disorder of the brain that causes a dramatic loss of cognitive function and affects millions of elderly individuals worldwide. However, its causes(s) remain unknown and there is no cure for it. Five-Lipoxygenase Activating Protein (FLAP) is an indispensable part of an important enzymatic pathway whose levels are increased in AD when compared with control brains, and for this reason it could be directly involved in the development of the disease. MK-591 is a potent, specific and selective drug orally active that blocks FLAP and prevents the activation of this enzymatic pathway. With these proof-of-principle studies we want to test that FLAP is a novel target for AD prevention and/or treatment. To this end, we will administer MK-591 to a transgenic mouse model of AD and look for its potential beneficial effects on brain pathology (amyloid beta levels and deposition) as well as behavioral deficits in these animals. If we prove that a FLAP inhibitor ameliorates the phenotype of these mice, our findings will provide the biological basis for future human studies with this class of drugs in AD. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.