The functional role of FLAP in Alzheimer's Disease

FLAP 在阿尔茨海默病中的功能作用

• 批准号: 8114511
• 负责人: DOMENICO PRATICO
• 金额: $ 22.95万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8114511
• 关键词: Ablation; Affect; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Arachidonate 5-Lipoxygenase; Area; Behavioral; Biochemical; Biological; Brain; Brain Diseases; Brain Pathology; Cerebellum; Clinical; Cognition; Complex; Critiques; Data; Deposition; Development; Disease; Dose; Elderly; Enzymes; Evaluation; Future; Genetic; Goals; Hippocampus (Brain); Human; In Vitro; Individual; Investigation; Lead; Lipoxygenase; MK 0591; Membrane Proteins; Molecular Target; Mus; Nerve Degeneration; Neuraxis; Neurobiology; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Protein Inhibition; Proteins; Publishing; Regimen; Research Design; Risk Factors; Role; Staging; Study Section; Testing; Tg2576; Therapeutic; Transgenic Mice; Transgenic Organisms; United States Food and Drug Administration; Update; Writing; amyloid pathology; base; behavioral impairment; clinical Diagnosis; cognitive function; comparative efficacy; drug candidate; efficacy testing; enzyme activity; improved; in vivo; inhibitor/antagonist; interest; meetings; mild neurocognitive impairment; mind control; mouse model; neuropathology; new therapeutic target; novel; novel therapeutics; pre-clinical; prevent; programs; research clinical testing; therapeutic target; transgenic model of alzheimer disease

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.

描述（由申请人提供）：该提案的范围是开发一种新的临床前治疗策略，使用候选药物进行未来的临床测试，以治疗或预防阿尔茨海默病（AD）。 AD 影响着全世界越来越多的人，并且无法治愈。 5-脂氧合酶 (5LO) 是一种大量存在于中枢神经系统 (CNS) 中的酶，其激活取决于称为 FLAP（5-LO 激活蛋白）的膜相关蛋白的存在。在大脑中，FLAP 依赖性 5LO 激活随着年龄的增长而增加，这是发生 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，5LO 酶活性的遗传缺失会导致 AD 动物模型中淀粉样蛋白 2 (A2) 水平显着降低。综上所述，这些数据表明该途径参与 AD 发病机制，并支持我们的中心假设：FLAP/5LO 酶途径在 AD 发展中发挥功能作用；其药理学调节代表了一种新的 AD 治疗靶点。这项原理验证研究的目的是验证 FLAP 作为 AD 神经生物学中新型且功能重要的分子靶点。通过这种临床前类型的研究，我们想要检验以下假设：FLAP 药理学抑制将改善 AD 转基因小鼠模型的 AD 样神经病理学和行为缺陷。为了实现这一目标，我们将使用选择性 FLAP 抑制剂，即 MK-591，以实现以下具体目标： 具体目标 1：测试早期 FLAP 药物抑制将延迟和或阻止 AD 样神经病理学和行为学发展的假设年轻 APP 转基因小鼠的缺陷。具体目标 2：在建立 AD 样神经病理学和行为缺陷后，评估 APP 转基因小鼠中 FLAP 药理抑制的功效。通过这些研究，我们打算完成 FLAP 抑制剂作为 AD 潜在疗法的临床前开发的第一步。如果我们证明 MK-591 给药可调节（减少）脑淀粉样变性并改善该 AD 模型中的行为障碍，我们的研究结果将代表后续更全面的项目提交（即 UO1）的生物学基础，其中将测试并比较几种不同的 FLAP 抑制剂在此模型以及其他 AD 模型中的功效。作为未来研究计划的一部分，我们还将重点关注临床前优化（剂量、功效）并在临床诊断为轻度认知障碍 (MCI) 和 AD 的个体中测试任何已确定的先导化合物。这些研究如果成功，最终可能会向美国食品和药物管理局提交新药研究 (IND) 申请。 公共健康相关性：阿尔茨海默病 (AD) 是一种大脑疾病，会导致认知功能严重丧失，影响全世界数百万老年人。然而，其原因仍不清楚，也无法治愈。五脂氧合酶激活蛋白（FLAP）是重要酶通路中不可或缺的一部分，与对照大脑相比，其水平在 AD 中升高，因此它可能直接参与疾病的发展。 MK-591 是一种有效、特异性和选择性的口服活性药物，可阻断 FLAP 并阻止该酶途径的激活。通过这些原理验证研究，我们想要测试 FLAP 是否是 AD 预防和/或治疗的新靶点。为此，我们将向 AD 转基因小鼠模型施用 MK-591，并寻找其对这些动物的大脑病理学（β 淀粉样蛋白水平和沉积）以及行为缺陷的潜在有益影响。如果我们证明 FLAP 抑制剂可以改善这些小鼠的表型，我们的研究结果将为未来此类药物治疗 AD 的人类研究提供生物学基础。 免责声明：请注意，以下评论是由审稿人在研究部分会议之前准备的，并且以基本上未经编辑的形式提供。 虽然审稿人有机会根据小组的讨论更新或修改他们的书面评估，但不能保证个人批评在会议讨论后得到更新。 因此，评论可能无法完全反映小组讨论结束时个别审稿人的最终意见或小组的最终多数意见。因此，讨论的简历和摘要是审稿人在会议上实际认为关键的内容的最终决定。