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

项目总结 阿尔茨海默病(和相关的痴呆症ADRDS)是老年人痴呆症的主要原因 65岁。到目前为止，试图开发治疗这种疾病的疗法，但结果令人失望 临床试验。与这种疾病相关的神经病理包括蛋白毒素物种水平的增加 β-淀粉样蛋白(A-β)和tau。β和tau都被独立地假设为主要 导致ADRD相关神经变性的因素，尽管尚不清楚这些“蛋白质病”是不是 导致这些疾病的原因。神经毒性蛋白当然与细胞内和细胞外有关 蛋白质以缠结和斑块的形式聚集。这些病理特征包含着其他不可溶的， 聚集的细胞蛋白。我们和其他人已经证明，增加蛋白质的不溶性是 正常衰老。进入“不解体”的蛋白质富含决定寿命的功能，但事实并非如此 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”是一种 将对正常衰老过程的研究与对慢性进行性疾病等的研究统一起来的概念 作为AD。老年科学方法的一个组成部分是，衰老可能是多种人类慢性病的原因。 因此，针对衰老的干预措施将为不同的疾病提供新的治疗途径 包括ADRDS。我们之前已经确定了数十种化合物，它们可以延长 线虫，并有初步数据表明，其中一些化合物促进一般蛋白质 神经疾病的动态平衡和抑制方面。在这里，我们建议更好地利用这一资源 了解正常衰老和ADRDS之间的关系，同时也开发新的潜在治疗方法。我们 建议在线虫A-β和tau神经毒性模型中初步测试衰老干预的效果。 在基于人类细胞的ADRDS模型中。然后我们将筛选对与年龄相关的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 先导化合物子集中的途径和机制。最后，我们将利用ADRDS的小鼠模型， 评估老化干预在前1-2个先导化合物中的有效性。通过承担这样一个 “老年学方法”，我们的目标是开发新的方法来针对最早的蛋白质组变化。 这导致了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.