Targeting Aging to prevent Alzheimer's Disease: the Geroscience Approach

项目摘要 阿尔茨海默病（以及相关的痴呆症ADRD）是老年人痴呆症的主要原因。 为65.迄今为止，开发治疗该病症的疗法的尝试已经产生了令人失望的结果， 临床试验与该疾病相关的神经病理学包括增加的蛋白毒性物质的水平， β-淀粉样蛋白（Aβ）和tau蛋白。Aβ和tau都被独立地假设为主要的 驱动ADRD相关神经退行性变的因子，尽管尚不清楚这些“蛋白质病”是否是ADRD相关神经退行性变的原因。 这些疾病的原因。神经毒性蛋白肯定与细胞内和细胞外 蛋白质以缠结和斑块的形式聚集。这些病理特征包含其他不溶性， 聚集的细胞蛋白质。我们和其他人已经表明，增加蛋白质不溶性是一个特点， 正常老化。进入“不溶物组”的蛋白质富含决定寿命的功能，但它是 不清楚正常的衰老过程和ADRD疾病过程是如何相关的。“老年科学”是一个 这一概念将对正常衰老过程的研究和对慢性进展性疾病的研究结合起来， 如AD。老年科学方法的一个组成部分是，衰老是多种人类慢性疾病的可能原因。 因此，针对衰老的干预措施将为不同疾病提供新的治疗途径 包括抗抑郁药我们以前已经确定了许多化合物，可以延长 线虫C.并有初步数据表明，这些化合物中的一些促进一般蛋白质 体内平衡和抑制神经疾病方面。在这里，我们建议利用这种资源，以更好地 了解正常衰老和ADRD之间的关系，并开发新的潜在疗法。我们 建议在C. Aβ和tau神经毒性的elegans模型， 在人类ADRD细胞模型中。然后，我们将筛选对年龄相关蛋白质不溶性的影响， 这些模型。我们将利用蠕虫强大的遗传学和生化技术来确定 途径和机制的一个子集的铅化合物。最后，我们将利用ADRD的小鼠模型， 评估前1-2种主要化合物对衰老干预的有效性。通过这样的承诺， “老年科学方法”，我们的目标是开发新的方法，针对最早的蛋白质稳定性变化 导致AD。

PROJECT SUMMARY Alzheimer’s disease (and related dementias ADRDs) are the leading cause of dementia in those over the age of 65. Attempts to develop therapeutics to treat the condition have, to date, yielded disappointing results in clinical trials. Neuropathologies associated with the disease include increased levels of proteotoxic species of both beta-amyloid (Aβ) and tau. Aβ and tau have both independently been hypothesized to be the primary agent driving ADRD-related neurodegeneration, although it is not clear that these “proteinopathies” are the cause of these disorders. Neurotoxic proteins are certainly associated with intracellular and extracellular protein aggregates in the form of tangles and plaques. These pathological features contain other insoluble, aggregated cellular proteins. We and others have shown that increased protein insolubility is a feature of normal aging. The proteins that enter the “insolublome” are enriched for lifespan determining functions, but it is not clear how normal aging processes and the ADRD disease processes are related. “Geroscience” is a concept that unites research on normal aging processes and research on chronic progressive diseases such as AD. Integral to the Geroscience approach is that aging is a likely cause of multiple human chronic diseases. It follows that interventions that target aging will provide novel therapeutic avenues for distinct diseases including ADRDs. We have previously identified scores of chemical compounds that extend the lifespan of the nematode C. elegans and have preliminary data that some of these compounds promote general protein homeostasis and suppress aspects of neurological disease. Here we propose to exploit this resource to better understand the relationship between normal aging and ADRDs but also to develop new potential therapies. We propose to initially test the efficacy of aging interventions in C. elegans models of Aβ and tau neurotoxicity and in human cell-based models of ADRDs. We will then screen for effects on age-related protein insolubility in these models. We will use the powerful genetics of the worm and biochemical techniques to determine pathways and mechanisms in a subset of lead compounds. Finally, we will utilize mouse models of ADRDs, to gauge the effectiveness of aging intervention in the top 1-2 lead compounds. By undertaking such a “Geroscience approach”, we aim to develop new methods to targeting the very earliest proteostatic changes that lead to AD.