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

摘要 与年龄有关的疾病是西方社会发病率和死亡率的主要原因，而老龄化是一种 阿尔茨海默病(AD)的重要危险因素。卡路里限制(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，但低卡路里饮食是出了名的难以维持。在过去的十年里，意义重大 在识别能够模仿CR饮食的一些好处的小分子和 延长寿命和/或健康寿命。越来越多的证据表明，这些牙齿保护剂可能能够治疗或 预防阿尔茨海默氏症，但仍然存在重大问题。这项提案是对PAR-18的回应- 596将解决围绕AD使用齿轮保护剂的主要悬而未决的问题，因为我们解决了 “老年学治疗阿尔茨海默氏病”的高优先级专题。 在这里，我们将严格测试四个齿轮保护器，涵盖广泛的机制，包括 抑制mTOR，激活AMPK，以及诱导sirtuins在两种AD模型中的作用。作为研究 到目前为止，我们利用了基于在早发性AD中发现的突变的疾病模型 将在两种早发性AD小鼠模型3xTg中对这些基因保护剂进行比较研究 小鼠，以及最近由模型-AD联盟开发的一种新的迟发性AD小鼠模型。很晚了- 发病的阿尔茨海默病代表了人类阿尔茨海默病的大多数病例，因此评估了护脑剂在 迟发性阿尔茨海默病模型至关重要。 随着2型糖尿病的发展，晚发性阿尔茨海默病的风险显著增加， 肥胖和糖尿病在老年人中的患病率继续上升。重要的是，许多齿轮保护者 影响新陈代谢健康，改变血糖控制和身体成分。因此，我们将表演有史以来第一次 GERO保护剂对小鼠认知、AD病理、脆弱性和整体代谢健康的评估 饮食诱导肥胖的AD动物模型。最后，大脑和神经元中的葡萄糖代谢受到干扰。 AD患者，最近的工作发现葡萄糖摄取缺陷和线粒体功能障碍。我们会 利用一套新的代谢生物传感器来确定代谢信号缺陷的确切性质 早发和晚发AD模型小鼠的神经元，并进一步确定GERO保护剂是否能恢复 在单细胞水平上的正常代谢。 从长远来看，这里提出的工作将大大推进老年科学方法的概念 对阿尔茨海默病，提高我们对早发和晚发阿尔茨海默病模型中基因保护剂的有效性的理解 在瘦小鼠和饮食诱导肥胖的背景下，以及在整个有机体和单个神经元的水平上。 我们不仅将为未来的临床评估确定性别保护者，而且我们将建立一个全面的方法。 这对于未来逆转或预防AD的策略的临床前评估将是非常宝贵的。

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.