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: 10180840
• 负责人: Dudley William Lamming
• 金额: $ 44.47万
• 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/10180840
• 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; 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; Pharmaceutical Preparations; Population; Presenile Alzheimer Dementia; Prevalence; Process; Research; Resources; Risk; Risk Factors; Role; Signal Transduction; Sirolimus; Sirtuins; Societies; Testing; Thinness; Whole Organism; Work; age related; base; brain cell; 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/antagonist; 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 与年龄相关的疾病是西方社会发病和死亡的主要原因，而老龄化是一个 阿尔茨海默病（AD）发展的重要危险因素。热量限制（CR），一种饮食 在延缓或预防与年龄相关的疾病的同时延长寿命的干预措施可以减缓或预防AD 动物模型，但众所周知，低热量饮食很难维持。在过去的十年里，显着 在识别小分子方面已经取得了进展，这些小分子可以模仿 CR 饮食的一些好处， 延长寿命和/或健康寿命。越来越多的证据表明这些老年保护剂可能能够治疗或 预防阿尔茨海默病，但仍然存在重大问题。该提案响应 PAR-18- 596，将解决有关使用老年保护剂治疗 AD 的主要悬而未决的问题，因为我们解决了 “老年科学方法治疗阿尔茨海默病”的高度优先主题。 在这里，我们将严格测试四种老年保护剂，涵盖广泛的机制，包括 在两种 AD 小鼠模型中抑制 mTOR、激活 AMPK 以及诱导 Sirtuins。作为研究 到目前为止，我们已经利用基于早发型 AD 中发现的突变的疾病模型来研究老年保护剂 将在早发性 AD 小鼠模型（3xTg）中对这些老年保护剂进行比较研究 小鼠，以及 MODEL-AD 联盟最近开发的一种新型迟发性 AD 小鼠模型。晚的- 阿尔茨海默病的发病代表了大多数人类阿尔茨海默病病例，因此评估了老年保护剂在治疗中的功效 AD 的迟发模型至关重要。 2 型糖尿病的发生会显着增加迟发性 AD 的风险，并且 老年人肥胖和糖尿病的患病率持续增加。重要的是，许多老年保护剂 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次 老年保护剂对小鼠认知、AD 病理、虚弱和整体代谢健康的评估 饮食引起的肥胖 AD 模型。最后，大脑和神经元中的葡萄糖代谢被破坏 AD 患者，最近的研究发现了葡萄糖摄取缺陷和线粒体功能障碍。我们将 利用一组新型代谢生物​​传感器来识别代谢信号缺陷的精确性质 早期和晚期 AD 小鼠模型的神经元，并进一步确定老年保护剂是否可以恢复 单细胞水平的正常代谢。 从长远来看，这里提出的工作将显着推进老年科学方法的概念 AD 的研究，提高了我们对老年保护剂在早期和晚发 AD 模型中的功效的理解， 瘦小鼠和饮食引起的肥胖，以及整个有机体和单个神经元的水平。 我们不仅将确定老年保护剂用于未来的临床评估，而且我们将建立一个整体方法 这对于未来逆转或预防 AD 策略的临床前评估非常宝贵。