Optimized Circadian Rhythms for the Prevention of Alzheimer's Disease

老年学假说认为，衰老本身就是罹患高血压的主要危险因素。 与年龄有关的慢性病，包括阿尔茨海默病；因此，推迟 衰老可以延缓包括阿尔茨海默病在内的疾病。这项建议将审查互惠关系 昼夜节律紊乱(CRD)和AD病理之间的关系。昼夜节律，这是 与细胞代谢密切相关，协调表达 以及支持正常细胞功能和神经修复的多条通路的功能 和周围组织。昼夜节律随着年龄的增长而恶化，阿尔茨海默氏症患者表现出 打乱了昼夜节律。然而，CRD在AD中的因果作用尚不清楚。这项提议将 评估昼夜节律紊乱和AD病理之间的关系，将测试 昼夜节律的改善延缓了阿尔茨海默病的发生和发展。并将尝试 确定潜在的分子机制。 利用果蝇遗传工具建立果蝇AD模型的研究 将用于测试遗传或环境CRD对慢性阻塞性肺疾病的发病和严重性的影响 阿尔茨海默病患者多器官功能下降。CRD的一个特征是缺少对 昼夜动物的白天时间。为了恢复老年苍蝇、动物的昼夜节律 将受到限时喂食(TRF)的限制，在TRF中，苍蝇只在 日间12h。TRF不会减少每天的卡路里摄入量，并提供了一个分子签名，即 与卡路里限制下的不同。疾病的发病和严重程度将在TRF中进行评估， 以及即刻喂食(ALF)果蝇，以确定TRF是否对AD进行有效的行为干预。至 检测介导CRD和TRF在AD病理中相反作用的分子通路， 这些果蝇的时间序列转录本将被分析以寻找候选途径。这个 这些途径的功能意义将通过表达功能和遗传增益来测试 阿尔茨海默病果蝇功能等位基因缺失。我们新的体内转基因果蝇疾病 结合超微结构、功能、代谢和转录组技术的模型将 对AD生产中加速老化的机制基础产生公正的见解。 该项目的成功完成将使我们从分子水平上更深入地了解 昼夜节律与阿尔茨海默病遗传风险的相互作用。此外，这项研究 将评估行为干预的有效性，这将具有很高的潜在 人类领养。

Geroscience hypothesis posits that aging itself is the underlying major risk factor for age-related chronic diseases, including Alzheimer's Disease (AD); therefore, delaying aging delays disease, including AD. This proposal will examine the reciprocal relationship between circadian rhythm disruption (CRD) and AD pathology. Circadian rhythms, which are intimately interlinked with cellular metabolism, orchestrate the coordinated expression and function of multiple pathways that support normal cellular function and repair in both neural and peripheral tissues. Circadian rhythms deteriorate with aging, and Alzheimer's patients show disrupted circadian rhythm. However, the causal role of CRD for AD is not clear. The proposal will assess the relationship between circadian rhythm disruption and AD pathology, will test whether improvement in circadian rhythms delay the onset and progression of AD. and will attempt to identify underlying molecular mechanisms. Well-characterized Drosophila melanogaster (fruit fly) models of AD with Drosophila genetic tools will be used to test the impact of genetic or environmental CRD on the onset and severity of the multiorgan functional decline in AD. One feature of CRD is the lack of feeding consolidation to daylight hours in diurnal animals. To restore aspects of circadian rhythm in older flies, animals will be subject to time-restricted feeding (TRF) in which food is provided to flies only during the 12 h day time. TRF does not reduce daily caloric intake and imparts a molecular signature that is distinct from that under caloric restriction. Disease onset and severity will be assessed in TRF, and ad lib fed (ALF) flies to determine if TRF is an effective behavioral intervention for AD. To test the molecular pathways mediating the opposite effects of CRD and TRF on AD pathologies, time-series transcriptomes from these flies will be analyzed to find candidate pathways. The functional significance of these pathways will be tested by expressing genetic gain of function and loss of function alleles in AD flies. Our novel in vivo genetic-transgenic Drosophila disease model coupled with ultrastructural, functional, metabolic, and transcriptome techniques will generate unbiased insights into the mechanistic basis of accelerated aging in production of AD. Successful completion of this project will provide a deeper molecular understanding of the interaction between circadian rhythm and genetic risk of AD. Additionally, this research will assess the efficacy of a behavioral intervention that would have a high potential for adoption in humans.