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 目前的治疗方法不能改变阿尔茨海默病（AD）的病程，AD是一种破坏性的神经退行性疾病， 这种疾病影响了美国580万人和全世界4400万人。因此，紧急 研究的目标是确定神经变性的控制点，这可能是有针对性的减缓 AD进展。在这个应用中，我们提出测试的假设，酶N-酰基乙醇胺 酸性酰胺酶（NAAA）就是其中的一个焦点。NAAA是一种溶酶体脂质水解酶，可转化 棕榈酰乙醇酰胺（PEA）转化为棕榈酸酯。PEA是一种内源性神经保护性核受体激动剂， 受体PPAR-α，而棕榈酸酯通过抑制转录共- PGC 1 α是神经元能量代谢和存活的关键调节因子。初步实验已经 表明散发性AD患者和各种动物的NAAA转录异常升高 神经变性模型，包括AD的5xfAD模型。在相同的模型中，我们发现， 药理学NAAA抑制和/或遗传NAAA缺失发挥显著的保护作用。基于 根据这些结果，我们推测NAA调节的脂质信号传导功能障碍可能是 参与AD的发病机制。我们有三个具体目标。目标1.表征NAAA调节的 AD小鼠模型中的脂质信号传导。使用5xfAD和Tau P301 S小鼠，两个小鼠系，其捕获 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， 调节的脂质信号传导，其可能先于和/或伴随神经退行性改变， 认知障碍目标2.确定药理学NAAA抑制在小鼠模型中的影响， AD.我们将评估长期施用化合物ARN 19702和ARN 16186的影响， 我们的团队发现的脑渗透性NAAA抑制剂-分子，形态和行为 在5xfAD和Tau P301 S小鼠中的疾病进展标志物。目标3.确定基因的影响 AD小鼠模型中的NAAA缺失。使用我们的条件性NAAA-/-小鼠，我们将产生NAAA- 用5xfAD缺陷型和Tau P301 S小鼠来评估NAAA缺失对疾病进展的影响。在 目标2和3，我们还将探索NAAA作用的分子和细胞底物 使用单细胞RNA测序检测抑制/缺失。拟议的研究将阐明 在AD的发病机制中，NAAA调节的脂质信号传导，如果我们的假设得到证实， NAAA作为治疗这种疾病的新的分子靶点。