Using geroscience to understand and treat Alzheimer's disease

摘要： 对于老年痴呆症等年龄依赖性神经退行性疾病还没有有效的治疗方法 疾病（AD）。为了解决这一重大的公共卫生危机，《国家阿尔茨海默病项目法》（NAPA） 通过了“到2025年找到有效的干预措施来治疗和预防AD和相关痴呆症”。实现 这一目标在5年内需要一种或多种有效的药物，可能来自重新利用的药物， 这个应用的基础。痴呆症是随着年龄增长而发生的疾病。因此，衰老必须 纳入药物靶点验证策略，以确保靶点机制在 老年人和促进衰老和AD之间的相互作用的理解。识别 基于这一事实，NOT-AG-18-051计划的一个目标是“采用生命周期方法来理解 AD的保护机制和危险因素。在这个应用程序中，我们正式解决的目标， 通过将寿命研究与年龄相关的表型筛选平台相结合， 产生了延长寿命的化合物（老年保护剂），其中一种现在正在进行AD临床试验。 在过去的十年中，一种新的表型筛选平台，基于与 使用老化脑来鉴定在多种模型中具有治疗功效的化合物。 神经变性和痴呆。令人惊讶的是，这些新的合成化合物及其前体 减缓小鼠衰老，使其在基因转录和代谢组学水平上保持年轻， 其他模式生物的寿命。一种化合物J147的分子靶点与一种化合物J147的靶点相同。 一种能延长C.优雅J147已被用于“化学生物学”方法， 了解衰老本身的基本方面，因为它基本上涉及所有已知的分子 与老年保护剂二甲双胍和雷帕霉素以及热量限制相关的途径。因为 在这些新的观察中，我们推断，通过整合C.我们的小说 表型筛选平台，我们可以有效地识别额外的新的衰老途径以及AD 药物和药物靶点。为了加快将任何发现带到临床所需的时间，我们将筛选 ReFRAME库。这个独特的库由制药公司开发的12，000种化合物组成 工业，包括几乎所有曾经在人类和那些注册为研究药物 候选人这些药物最初将在神经毒性试验中进行筛选，该试验用作我们的主要筛选， 以前的药物发现工作。然后将在C中测定阳性命中的寿命。优雅当 必要时，我们将像过去一样进行目标识别。最后，路径验证 将在两种非常不同的衰老和痴呆小鼠模型中进行研究。这一协作努力 三个实验室之间使用一种新的方法来了解衰老和痴呆症之间的关系 以及所涉及的分子途径，并有可能发现新的AD药物。

Abstract: There are no effective treatments for age-dependent neurodegenerative conditions such as Alzheimer's disease (AD). To address this major public health crisis, the National Alzheimer's Project Act (NAPA) was passed to “find effective interventions to treat and prevent AD and related dementias by 2025.” To achieve this goal in 5 years one or more effective drugs are required, likely sourced from repurposed drugs that are the basis of this application. Dementias are diseases that occur with age. Therefore, aging must be incorporated into the drug target validation strategy to ensure that the target mechanism remains active in aged individuals and to facilitate an understanding of the interaction between aging and AD. The recognition of this fact led to the NOT-AG-18-051 initiative with one goal of “employing a lifespan approach to understand the mechanisms of protective and risk factors” for AD. In this application, we formally address the goals of both initiatives by integrating lifespan studies with an age-related phenotypic screening platform that has yielded compounds that extend lifespan (geroprotectors), one of which is now in AD clinical trials. During the last decade a novel phenotypic screening platform based upon 5 toxicities associated with the aged brain was used to identify compounds that have therapeutic efficacy in multiple models of neurodegeneration and dementia. Surprisingly, these new synthetic compounds as well as their precursors slow aging in mice, keeping them younger at both the gene transcription and metabolomics levels and extend lifespan in other model organisms. The molecular target of one compound, J147, is identical to the target of a compound that extends lifespan in C. elegans. J147 has since been used in a 'chemical biology' approach to understand fundamental aspects of aging itself, for it engages essentially all of the known molecular pathways associated with the geroprotectors metformin and rapamycin as well as caloric restriction. Because of these new observations, we reasoned that by integrating lifespan studies in C. elegans with our novel phenotypic screening platform we could efficiently identify additional new aging pathways as well as AD drugs and drug targets. To accelerate the time needed to bring any discoveries to the clinic we will screen the ReFRAME library. This unique library consists of 12,000 compounds developed by the pharmaceutical industry, including nearly all that have ever been in man and those registered as investigational drug candidates. These drugs will initially be screened in the neurotoxicity assay used as our primary screen in previous drug discovery efforts. Positive hits will then be assayed for longevity in C. elegans. When necessary, target identification will be carried out as we have done in the past. Finally, pathway validation studies will be done in two very distinct mouse models of aging and dementia. This collaborative effort between three laboratories uses a new approach to understand the relationship between aging and dementia and the molecular pathways involved, with the likelihood of identifying new AD drugs.