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

总结 在西方社会，与衰老有关的疾病是发病和死亡的主要原因，而衰老是一个 阿尔茨海默病（AD）的发展的重要危险因素。卡路里限制（CR），一种饮食 在延缓或预防年龄相关疾病的同时延长寿命的干预，可以减缓或预防AD， 动物模型，但低热量饮食是出了名的难以维持。在过去的十年里， 在鉴定可以模拟CR饮食的一些益处的小分子方面已经取得了进展， 延长寿命和/或健康寿命。越来越多的证据表明，这些老年保护者可能能够治疗或 预防阿尔茨海默病，但仍然存在重大问题。这一提案是对PAR-18的回应， 596，将解决主要悬而未决的问题，围绕使用geroprotectors为AD，因为我们解决 一个高优先级的主题“老年科学方法阿尔茨海默病”。 在这里，我们将严格测试四种geroprotectors涵盖广泛的机制，包括 在两种AD小鼠模型中，对mTOR的抑制、AMPK的活化和沉默调节蛋白的诱导。为研究 到目前为止，我们已经利用了基于早发性AD中鉴定的突变的疾病模型， 将在早发性AD小鼠模型、3xTg小鼠模型和3xTg小鼠模型中对这些老年保护剂进行比较研究。 小鼠，以及最近由MODEL-AD联盟开发的迟发性AD的新型小鼠模型。晚- AD发作代表了AD的大多数人类病例，因此评估老年保护剂在治疗AD中的功效。 迟发性AD模型是至关重要的。 2型糖尿病的发生显著增加了迟发性AD的风险， 肥胖症和糖尿病的患病率在老年人中继续增加。重要的是，许多老年保护者 影响代谢健康，改变血糖控制和身体成分。因此，我们将首次 老年保护剂对小鼠的认知、AD病理、虚弱和整体代谢健康的评估 饮食诱导肥胖的AD模型。最后，葡萄糖代谢在大脑和神经元中被破坏， AD患者，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 利用一组新的代谢生物传感器来识别代谢信号缺陷的精确性质， 神经元的早期和迟发性小鼠模型的AD，并进一步确定是否geroprotectors可以恢复 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 提高我们对老年保护剂在早期和晚发性AD模型中的疗效的理解， 瘦小鼠和饮食诱导的肥胖的背景下，并在整个生物体和单个神经元的水平。 我们不仅将确定geroprotectors为未来的临床评估，但我们将建立一个整体的方法 这将是非常宝贵的临床前评估的战略，以扭转或预防AD的未来。

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.