Delay of Alzheimer's phenotypes by interventions that increase lifespan

拟议项目的目的是评估遗传和药物操作是否 延长寿命同样会延缓阿尔茨海默病模型的病理发病 (Ad)，最终目标是为这种毁灭性和昂贵的疾病开发更好的治疗方法 疾病。目前对这种疾病没有有效的治疗方法，这种疾病正在走向破产 美国卫生系统在不到30年的时间里，尽管做出了巨大和昂贵的努力， 制药公司。拟议的研究采取了与以下方法不同的方法 制药公司，这是基于特定的目标。相反，拟议的研究， 对NIH PAR-18-596的回应是基于这样的概念，即由于年龄是AD的主要风险因素， 而在人类中产生AD的基因在模型生物中产生病理，其时间进程 随着寿命的延长，延长寿命的操作也可能推迟人类阿尔茨海默病的发病。 事实上，我们和其他人已经证明了一些基因操作和药物 延长模型器官中线虫的寿命也可以延缓标准转基因模型中的症状 这些发现中的一些已经导致了目前在人类AD上的临床试验。然而，只有一个 在已知可以延长寿命的手法中，有很小一部分被评估了它们的效果 论AD模型中的损伤。因此，我们建议通过评估来解决这一缺陷 可靠延长寿命的遗传和药物操作对三种不同疾病的影响 秀丽线虫AD模型：肌肉特异性人类Abeta1-42(标准模型)和神经元特异性 人类Abeta和Tau，都与人类AD有关。我们还将反过来评估药物是否会 已经发现在肌肉特异的Abeta模型中保护也将在神经元中保护- 特定型号的AD并能延长寿命。在成功的基础上取得了少量的同类 我们和其他人进行的研究导致了人类阿尔茨海默病的临床试验，我们预计 目前提出的研究将极大地增加可用药物和药物靶点，承诺 治疗人类阿尔茨海默病。

The purpose of the proposed project is to assess if genetic and pharmacological manipulations that increase lifespan will similarly delay the onset of pathologies in models of Alzheimer's Disease (AD), with the ultimate goal of developing better treatments for this devastating and expensive disease. There are currently no effective treatments for this disease, which is on course to bankrupt the American health system in less than 30 years, despite tremendous and expensive efforts by pharmaceutical companies. The proposed studies take a different approach than taken by pharmaceutical companies, which have been based on specific targets. Instead the proposed studies, in response to NIH PAR-18-596, is based on the concept that since age is the major risk factor for AD, and genes that produce AD in humans produce pathologies in model organisms whose time-course scales with lifespan, manipulations that increase lifespan might also delay the onset of AD in humans. Indeed we and others have already demonstrated that some genetic manipulations and drugs that increase lifespan in the model organ C. elegans also delay symptoms in a standard transgenic model of AD, and some of these discoveries have led to current clinical trials in human AD. However, only a very small fraction of manipulations known to increase lifespan have been assessed for their effects on impairments in models of AD. We therefore propose to address this deficiency by assessing effects of genetic and pharmacological manipulations that reliably increase lifespan on three different C. elegans models of AD: muscle-specific human Abeta 1-42 (standard model), and neuronal-specific human Abeta and Tau, both implicated in human AD. We will also conversely assess if drugs we have already discovered to protect in the muscle-specific Abeta model will also protect in the neuron- specific models of AD and to increase lifespan. Based on the success of the small number of similar studies which we and others have carried out, leading to clinical trials in human AD, we anticipate that the presently proposed studies will vastly increase the available drugs and drug targets promising to treat human AD.