The lipid amidase NAAA as a therapeutic target for Alzheimer's disease

脂质酰胺酶 NAAA 作为阿尔茨海默病的治疗靶点

• 批准号: 10118584
• 负责人: Kim Green
• 金额: $ 232.86万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10118584
• 关键词: Acids; Address; Affect; Agonist; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Animal Experiments; Animal Model; Anti-Inflammatory Agents; Attenuated; Behavioral; Biological; Blood - brain barrier anatomy; Brain; Chronic; Cysteine; Disease; Disease Marker; Disease Progression; Energy Metabolism; Enzymes; Excision; Functional disorder; Genetic; Genetic Transcription; Goals; Hydrolase; Immune; Impaired cognition; Inflammation; Late Onset Alzheimer Disease; Lipid Biochemistry; Lipids; Medical Research; Modeling; Molecular; Morphology; Multiple Sclerosis; Mus; Natural Immunity; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Nuclear Receptors; PPAR alpha; Palmitates; Parkinson Disease; Pathogenesis; Persons; Pharmaceutical Preparations; Pharmacology; Process; Research; Role; Senile Plaques; Series; Severities; Signal Transduction; Symptoms; Testing; Transcription Coactivator; United States; age related; amidase; base; effective therapy; energy balance; enzyme activity; experimental study; inhibitor/antagonist; innovation; molecular targeted therapies; mouse model; novel; palmidrol; protective effect; single-cell RNA sequencing; tau Proteins; therapeutic target

PROJECT SUMMARY Current therapies do not alter the course of Alzheimer's disease (AD), a devastating neurodegenerative illness that affects 5.8 million people in the United States and 44 million people worldwide. Thus, an urgent goal for research is to identify points of control for neurodegeneration, which may be targeted to slow down AD progression. In this application, we propose to test the hypothesis that the enzyme N-Acylethanolamine Acid Amidase (NAAA) is one such focal point. NAAA is a lysosomal lipid hydrolase that converts palmitoylethanolamide (PEA) into palmitate. PEA is an endogenous agonist of the neuroprotective nuclear receptor PPAR-α, whereas palmitate promotes neurodegeneration by suppressing the transcription co- activator PGC1α, a key regulator of neuronal energy metabolism and survival. Preliminary experiments have shown that NAAA transcription is abnormally elevated in persons with sporadic AD and in various animal models of neurodegeneration, including the 5xfAD model of AD. In the same models, we found that pharmacological NAAA inhibition and/or genetic NAAA deletion exert marked protective effects. Based on these results, we hypothesize that dysfunctions in NAAA-regulated lipid signaling may be critically involved in the pathogenesis of AD. We have three specific aims. Aim 1. Characterize NAAA-regulated lipid signaling in mouse models of AD. Using 5xfAD and Tau P301S mice, two mouse lines that capture distinct aspects of AD pathology, we will identify age-dependent, regionally selective changes in NAAA- regulated lipid signaling, which might precede and/or accompany neurodegenerative alterations and cognitive impairment. Aim 2. Determine the impact of pharmacological NAAA inhibition in mouse models of AD. We will assess the impact of chronic administration of the compounds ARN19702 and ARN16186 – two brain-permeant NAAA inhibitors discovered by our team – on molecular, morphological and behavioral markers of disease progression in 5xfAD and Tau P301S mice. Aim 3. Determine the impact of genetic NAAA deletion in mouse models of AD. Using our conditional NAAA-/- mice, we will generate NAAA- deficient 5xfAD and Tau P301S mice to evaluate the impact of NAAA deletion on disease progression. In Aims 2 and 3, we will also explore molecular and cellular substrates for the effects of NAAA inhibition/deletion using single-cell RNA sequencing. The proposed studies will elucidate the functional roles of NAAA-regulated lipid signaling in the pathogenesis of AD and, if our hypothesis is verified, will validate NAAA as a novel molecular target for the treatment of this disorder.

项目摘要 当前的疗法不会改变阿尔茨海默氏病（AD）的病程，这是毁灭性的神经退行性的 影响美国580万人的疾病和全球4400万人。那，紧急 研究的目标是识别神经变性的控制点，这可能是针对性的 广告进展。在此应用中，我们建议测试酶N-酰基乙醇胺的假设 酸amidase（NAAA）就是这样的焦点。 NAAA是转化的溶酶体脂质水解酶 棕榈乙醇胺（PEA）进入棕榈酸酯。豌豆是神经保护核的内源性激动剂 受体PPAR-α，而棕榈酸酯通过抑制转录共同促进神经变性。 激活剂PGC1α，神经元能量代谢和存活的关键调节剂。初步实验具有 表明NAAA转录在零星AD和各种动物的人中绝对升高 神经变性的模型，包括AD的5XFAD模型。在同一型号中，我们发现 药理学NAAA抑制和/或遗传NAAA缺失执行明显的保护作用。基于 这些结果，我们假设NAAA调节的脂质信号的功能障碍可能是至关重要的 参与AD的发病机理。我们有三个具体的目标。目标1。特征是NAAA调节的 AD小鼠模型中的脂质信号传导。使用5xFAD和TAU P301S小鼠，两条捕获的鼠标线 AD病理学的不同方面，我们将确定NAAA-的年龄依赖性，区域选择性变化 受调节的脂质信号传导，可能之前和/或伴随神经退行性的改变，并且 认知障碍。目标2。确定药物NAAA抑制在小鼠模型中的影响 广告。我们将评估化合物ARN19702和ARN16186的慢性给药的影响 - 两个 我们的团队发现的脑部peremant NAAA抑制剂 - 关于分子，形态和行为的抑制剂 5XFAD和TAU P301S小鼠的疾病进展标记。目标3。确定通用的影响 AD小鼠模型中的NAAA缺失。使用条件NAAA - / - 小鼠，我们将生成NAAA- 缺乏5XFAD和TAU P301S小鼠评估NAAA缺失对疾病进展的影响。在 目标2和3，我们还将探索NAAA影响的分子和细胞底物 使用单细胞RNA测序抑制/缺失。拟议的研究将阐明功能作用 AD发病机理中NAAA调节的脂质信号传导的 NAAA是治疗该疾病的新分子靶标。