Geroscience approaches to mitigate tauopathy in aged mouse brain

项目总结/文摘

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.