Targeting a lipid-mediated pro-longevity pathway as Alzheimer's therapy

摘要阿尔茨海默病（AD）是一种慢性神经退行性疾病，导致60%至70%的痴呆症病例，是美国第六大死亡原因。AD通常在65岁以上的个体中表现，并且发病率随年龄增加而增加。目前，有五种FDA批准的阿尔茨海默病药物只能暂时缓解症状，但不能预防或延缓疾病进展。因此，开发有效的AD疗法代表了迫切的医学需求。虽然AD的病因仍然难以捉摸，但衰老是已知的最大风险因素。因此，改善健康老龄化的策略可以作为AD管理的有效手段。在这项提案中，我们将通过关注一种天然存在的脂质分子，油酰乙醇胺（OEA）来询问这个想法，我们最近发现它可以提高秀丽隐杆线虫的寿命和健康寿命。重要的是，OEA及其信号通路从蠕虫到哺乳动物（包括人类）是高度保守的，并且OEA已被证明可调节摄食和体重，并抑制啮齿动物中高脂饮食诱导的肥胖和代谢功能障碍。我们的建议得到了强有力的科学前提的支持，因为脂质代谢和储存的改变在衰老过程中变得普遍，而中年肥胖及其代谢合并症，如高胰岛素血症，糖尿病和脂质代谢改变会增加迟发性AD的风险。因此，促进代谢健康和长寿的脂质调节剂如OEA可能是预防和治疗AD的有希望的靶点。这个多PI应用程序结合了三个在衰老生物学和脂质代谢（Meng Wang），AD小鼠模型（Hui Zheng）和药物化学（Jin Wang）方面具有杰出专业知识的个人，并建立在我们正在进行的合作基础上。我们将一起1）阐明OEA在AD C中的作用。Elegans模型，并开发和测试新的和高效的OEA类似物; 2）确定OEA类似物在AD小鼠模型中的治疗效果;和3）理解OEA类似物在高代谢应激条件下在AD中的作用。我们的建议是高度创新的，因为它提出了一个新的概念，通过一种新的脂质介导的机制，将长寿化合物用于AD治疗。它也非常重要，因为它与治疗直接相关，并解决了医疗需求未得到满足的疾病。

Abstract Alzheimer's disease (AD) is a chronic neurodegenerative disease that causes 60% to 70% of cases of dementia and is the 6th leading cause of death in the United States. AD usually manifests in individuals over 65 years old and the incidence increases with age. Currently, there are five FDA-approved Alzheimer's drugs that only provide temporary symptomatic relief but do not prevent or delay the disease progression. Thus, developing effective therapies of AD represent an urgent medical need. Although the etiology of AD remains elusive, aging is the greatest known risk factor. As such, strategies that improve healthy aging may serve as effective means for AD management. In this proposal, we will interrogate this idea by focusing on a naturally occurring lipid molecule, oleoylethanolamide (OEA), that we recently identified to improve lifespan and healthspan in Caenorahbditis elegans. Importantly, OEA and its signaling pathways are highly conserved from worm to mammals, including humans, and OEA has been shown to regulate feeding and body weight and inhibit high-fat diet induced obesity and metabolic dysfunctions in rodents. Our proposal is supported by strong scientific premise because alterations in lipid metabolism and storage become prevalent during aging, while midlife obesity and its metabolic comorbidities such as hyperinsulinemia, diabetes, and altered lipid metabolism increase the risk of late-onset AD. Thus, lipid regulators that promote metabolic health and longevity like OEA may be a promising target for the prevention and treatment of AD. This multi-PI application joins force of three individuals with outstanding expertise in aging biology and lipid metabolism (Meng Wang), AD mouse models (Hui Zheng), and medicinal chemistry (Jin Wang), and is built on our ongoing collaborations. Together we will 1) elucidate the effects of OEA in AD C. elegans models and develop and test new and highly potent OEA analogs; 2) determine the therapeutic effect of OEA analogs in AD mouse models; and 3) understand the role of OEA analogs in AD under high metabolic stress conditions. Our proposal is highly innovative as it addresses a new concept to apply pro- longevity compounds for AD therapy through a novel lipid-mediated mechanism. It is also highly significant as it is directly therapeutically relevant and tackles a disease of unmet medical needs.