Comparative analysis of geroprotective interventions in established and novel mouse models of Alzheimer's disease

已建立和新型阿尔茨海默病小鼠模型中老年保护干预措施的比较分析

• 批准号: 10414074
• 负责人: Dudley William Lamming
• 金额: $ 38.25万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414074
• 关键词: 3xTg-AD mouse; Acarbose; Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; American; Animal Model; Area; Biological Assay; Biosensor; Body Composition; Brain; Caloric Restriction; Calories; Cells; Cognition; Cognitive; Comparative Study; Complex; Data; Defect; Development; Diabetes Mellitus; Diet; Dietary Intervention; Disease; Disease Progression; Disease model; Early Onset Alzheimer Disease; Eating; Effectiveness; Elderly; Etiology; FRAP1 gene; Future; Geroscience; Goals; Health; Health system; Healthcare; High Fat Diet; Hippocampus (Brain); Human; Immunosuppression; Impairment; Incidence; Individual; Insulin Resistance; Intervention; Late Onset Alzheimer Disease; Lead; Longevity; Metabolic; Metabolism; Metformin; Molecular; Morbidity - disease rate; Mus; Mutation; National Institute of Neurological Disorders and Stroke; Nature; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathologic; Pathology; Persons; Pharmaceutical Preparations; Population; Prevalence; Process; Research; Resources; Risk; Risk Factors; Role; Signal Transduction; Sirolimus; Sirtuins; Societies; Testing; Thinness; Whole Organism; Work; age related; base; brain cell; brain dysfunction; cell type; cognitive function; comparative; design; diet-induced obesity; dietary restriction; drug testing; early onset; effective therapy; frailty; glucose metabolism; glucose uptake; glycemic control; healthspan; immune system function; improved; inhibitor; innovation; insight; mTOR inhibition; mitochondrial dysfunction; mortality; mouse model; neuronal metabolism; nicotinamide-beta-riboside; novel; novel strategies; preclinical evaluation; preservation; prevent; research clinical testing; sensor; side effect; small molecule; western diet

Summary Age-related diseases are the major causes of morbidity and mortality in Western society, and aging is a significant risk factor for the development of Alzheimer's disease (AD). Calorie restriction (CR), a dietary intervention which extends lifespan while delaying or preventing age-related disease, can slow or prevent AD in animal models, but reduced-calorie diets are notoriously difficult to sustain. Over the past decade, significant progress has been made in identifying small molecules that can mimic some of the benefits of a CR diet and extend lifespan and/or healthspan. There is growing evidence that these geroprotectors may be able to treat or prevent Alzheimer's disease, but significant questions remain. This proposal, which is responsive to PAR-18- 596, will address major outstanding questions surrounding the use of geroprotectors for AD, as we address the high-priority topic of a “Geroscience Approaches to Alzheimer's Disease.” Here, we will rigorously test four geroprotectors covering a broad range of mechanisms including the inhibition of mTOR, the activation of AMPK, and the induction of sirtuins in two mouse models of AD. As research into geroprotectors thus far has utilized models of disease based on mutations identified in early onset AD, we will perform a comparative study of these geroprotectors in both an early onset mouse model of AD, the 3xTg mouse, and a novel mouse model of late-onset AD recently developed by the MODEL-AD consortium. Late- onset AD represents the majority of human cases of AD, and thus assessing the efficacy of geroprotectors in late-onset models of AD is critical. The risk of late-onset AD is significantly increased by the development of type 2 diabetes, and the prevalence of both obesity and diabetes continues to increase in the elderly. Importantly, many geroprotectors affect metabolic health, altering glycemic control and body composition. We will therefore perform the first ever assessment of geroprotectors on cognition, AD pathology, frailty, and the overall metabolic health of mouse models of AD with diet-induced obesity. Finally, glucose metabolism is disrupted in the brains and neurons of AD patients, and recent work has identified defects in glucose uptake and mitochondrial dysfunction. We will leverage a set of novel metabolic biosensors to identify the precise nature of the metabolic signaling defects in the neurons of early and late-onset mouse models of AD, and further determine if geroprotectors can restore normal metabolism at the level of the single cell. In the long term, the work proposed here will significantly advance the concept of a geroscience approach to AD, improving our understanding of the efficacy of geroprotectors in early and late-onset models of AD, in lean mice and in the context of diet-induced obesity, and at the level of the whole organism and single neuron. Not only will we identify geroprotectors for future clinical evaluation, but we will establish an overall approach that will be invaluable for the preclinical evaluation of strategies to reverse or prevent AD in the future.

概括 与年龄有关的疾病是西方社会发病和死亡率的主要原因，衰老是 阿尔茨海默氏病（AD）发展的重要危险因素。卡路里限制（CR），饮食 延长寿命的干预措施，同时延迟或预防与年龄相关的疾病，可以放慢或防止AD 动物模型，但众所周知，减少热量的饮食很难维持。在过去的十年中，重要 在识别可以模仿CR饮食的一些好处的小分子方面取得了进展 延长寿命和/或HealthSpan。越来越多的证据表明，这些geropotectors可能能够治疗或 预防阿尔茨海默氏病，但仍然存在重大问题。该提案对Par-18-响应 - 596，将解决有关AD的使用者的主要问题，因为我们解决了 “阿尔茨海默氏病”的高优先级主题。 在这里，我们将严格测试四个涵盖各种机制的geropotectors MTOR的抑制作用，AMPK的激活和在两种AD小鼠模型中诱导Sirtuins。作为研究 迄今 将在AD的早期发作模型（3xtg）中对这些gero骨进行比较研究 小鼠，以及最近由Model-AD联盟开发的后期发作广告的新型小鼠模型。晚的- 发作AD代表了大多数人类AD病例，因此评估了Geroprotector的效率 AD的后期模型至关重要。 通过2型糖尿病的发展，晚期AD的风险显着增加 肥胖和糖尿病的患病率在古老的情况下持续增加。重要的是，许多药物保护剂 影响代谢健康，改变血糖控制和身体成分。因此，我们将执行有史以来的第一个 评估老师在认知，AD病理学，脆弱和小鼠整体代谢健康方面的评估 具有饮食引起的肥胖症的AD模型。最后，葡萄糖代谢在大脑和神经元中被破坏 AD患者以及最近的工作已经确定了葡萄糖摄取和线粒体功能障碍的缺陷。我们将 利用一组新型的代谢生物传感器来识别代谢信号缺陷的确切性质 AD的早期和晚期小鼠模型的神经元，并进一步确定Geroprotector是否可以恢复 单细胞水平的正常代谢。 从长远来看，这里提出的工作将大大提高Geroscience方法的概念 为了提高我们对早期和晚期模型中的geropotector效率的理解， 在饮食引起的肥胖症的背景下，在整个生物体和单个神经元的水平上。 我们不仅会识别出用于未来临床评估的老师保护剂，而且我们将建立一种总体方法 这对于对将来扭转或防止广告的策略进行临床前评估将是无价的。