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

项目总结 目前的治疗方法不能改变阿尔茨海默病(AD)的病程，AD是一种毁灭性的神经退行性疾病 这种疾病影响着美国的580万人和全球的4400万人。因此，一个紧急的 研究的目标是确定神经退行性变的控制点，它可能有针对性地减缓 广告进展。在这个应用中，我们建议检验N-乙酰乙醇胺酶的假设 酸性酰胺酶(NAAA)就是这样一个焦点。NAAA是一种溶酶体脂水解酶，它能将 棕榈酰乙醇胺(PEA)转化为棕榈酸酯。豌豆是神经保护核团的内源性激动剂 受体PPAR-α，而棕榈酸通过抑制转录共... 激活剂Pgc1α，神经元能量代谢和存活的关键调节因子。初步实验已经 研究表明，在散发性AD患者和各种动物中，NAAA转录异常升高 神经退行性变模型，包括AD的5xfAD模型。在相同的模型中，我们发现 药物NAAA抑制和/或遗传NAAA缺失具有显著的保护作用。基于 这些结果，我们假设，NAAA调节的脂质信号功能障碍可能是至关重要的 参与了AD的发病机制。我们有三个具体目标。目的1.NAAA调节的特性 阿尔茨海默病小鼠模型中的脂质信号。使用5xfAD和Tau P301S小鼠，两个小鼠品系捕获 AD病理的不同方面，我们将确定NAAA-年龄相关的、区域选择性的变化- 调节的脂质信号，可能先于和/或伴随神经退行性改变和 认知障碍。目的2.确定药物抑制NAAA对小鼠脑出血模型的影响。 广告。我们将评估长期服用化合物ARN19702和ARN16186-Two的影响 我们团队发现的脑型NAAA抑制剂--分子、形态和行为 5xfAD和Tau P301S小鼠疾病进展的标记物。目标3.确定基因的影响 AD小鼠模型中NAAA的缺失。使用我们的条件NAAA-/-小鼠，我们将产生NAAA- 基因缺陷的5xfAD和Tau P301S小鼠，以评估NAAA缺失对疾病进展的影响。在……里面 目标2和3，我们还将探索NAAA的分子和细胞底物的影响 利用单细胞RNA测序技术抑制/缺失。拟议的研究将阐明这些功能的作用 NAAA调节的脂质信号在AD发病机制中的作用，如果我们的假设得到证实，将证实 NAAA作为治疗这种疾病的新的分子靶点。

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.