Geroscience approaches to mitigate tauopathy in aged mouse brain

项目概要/摘要 老年痴呆症的发病率随着年龄的增长而急剧增加。平均 由于整体医疗保健的改善和出生在美国的大部分人， 第二次世界大战后的十年达到了风险年龄，预计阿尔茨海默病患者的数量将 快速爬升。因此，了解老年人的大脑为什么以及如何更容易受到 削弱阿尔茨海默病发病机制。然而，在目前的环境中研究衰老过程是具有挑战性的。 转基因小鼠模型，因为病理学不能在较晚的年龄开始。在这个项目中，我们将使用 新的模型，其中tau蛋白表达，沉积和聚集（tau蛋白病）在小鼠中产生， 生命周期的各个阶段。我们将使用热量限制和雷帕霉素治疗，这两种方法是已知的， 延长寿命和减缓生物衰老的速度，以确定这些治疗是否能延缓衰老。 在该模型中观察到tau蛋白病、神经变性和认知障碍的表型。我们将 确定大脑中细胞衰老发生的位置和时间，以及哪些细胞类型屈服于 衰老我们将使用三种方法来评估衰老细胞的存在（组织学，细胞分离 技术和激光捕获显微切割），以提高这些发现的严谨性。人类阿尔茨海默 和对照死后大脑样本将用于验证与人体状况的相关性。最后我们 将确定tau蛋白病表型是否可以通过耗尽衰老细胞来减轻。采取 总之，这些实验将为减少阿尔茨海默病发病机制的新方法提供支持。

Project Summary/Abstract The incidence of Alzheimer’s disease increases dramatically as a function of age. With the average life expectancy increasing due to improved medical care overall and the large group of Americans born in the decade following World War 2 reaching the age of risk, the number of Alzheimer patients is expected to climb rapidly. It is therefore critical to understand why and how the aged brain is more susceptible to debilitating Alzheimer pathogenesis. However, it is challenging to study aging processes in current transgenic mouse models because pathology cannot be initiated at later ages. In this project, we will use a new model where tau expression, deposition and aggregation (tauopathy) are produced in mice at different stages of the lifespan. We will use calorie restriction and rapamycin treatment, two methods known to extend lifespan and slow the rate of biological aging, to determine whether these treatments delay the phenotype of tauopathy, neurodegeneration and cognitive impairment observed in this model. We will determine where and when cellular senescence occurs in brain and which cell types succumb to senescence. We will use three methods to assess the presence of senescent cells (histology, cell isolation technology and laser capture microdissection) to enhance the rigor of these findings. Human Alzheimer and control postmortem brain samples will be used to verify relevance to the human condition. Finally, we will determine whether the tauopathy phenotype can be mitigated by depletion of senescent cells. Taken together, these experiments will provide support for new methods of minimizing Alzheimer pathogenesis.