Geroscience approaches to mitigate tauopathy in aged mouse brain

项目摘要/摘要 阿尔茨海默病的发病率随着年龄的增长而急剧增加。与平均水平 由于整体医疗保健的改善和出生于年的大量美国人，预期寿命增加 在二战后的十年里，阿尔茨海默氏症患者的数量预计将达到危险年龄 快速爬升。因此，了解为什么以及如何衰老的大脑更容易受到 使人衰弱的阿尔茨海默病发病机制。然而，目前对衰老过程的研究是具有挑战性的。 转基因小鼠模型，因为病理学不能在以后的年龄启动。在此项目中，我们将使用 在小鼠不同时期产生tau表达、沉积和聚集(tau病)的新模型 生命的各个阶段。我们将使用卡路里限制和雷帕霉素治疗，这两种方法已知 延长寿命和减缓生物衰老的速度，以确定这些治疗是否延缓 在该模型中观察到了神经退行性变和认知障碍的表型。我们会 确定大脑中细胞衰老发生的地点和时间，以及哪些细胞类型屈从于 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解剖)，以提高这些发现的严谨性。人类阿尔茨海默病 而对照的死后大脑样本将被用来验证与人类状况的相关性。最后，我们 将决定是否可以通过消耗衰老细胞来缓解这种相互作用的表型。已被占用 总之，这些实验将为将阿尔茨海默病的发病机制降至最低的新方法提供支持。

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.