Targeting P21-Highly-Expressing Senescent Cells In Vivo for Improving Cognitive Function in the Alzheimers Diseases

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Project Summary Alzheimer's disease (AD) is the most common age-dependent neurodegenerative disease. Currently, no disease-modifying therapy is available to treat AD effectively in clinic. New therapeutic targets are desired for AD treatment and prevention. Delaying the fundamental aging process might simultaneously alleviate a range of age-related diseases, including AD. The accumulation of senescent cells in various tissues is one of the most prominent features of aging. Clearance of senescent cells can slow down biological aging process and various clinically-relevant consequences. However, the role and underlying mechanisms of senescent cells in AD is not fully understood. To examine the relationship between senescent cells and AD, we have generated and validated a novel “p21-Cre” transgenic mouse model containing a p21 (a key marker for cellular senescence) promoter driving a Cre fused to a tamoxifen-inducible estrogen receptor (ER) element. This novel model enables us to monitor, kill or modulate p21-highly-expressing (p21high) cells in vivo without affecting other cells. In our preliminary studies, we find that p21high cells accumulate in AD brains. In this study, we will test our central hypothesis that targeting p21high cells will alleviate AD and cognitive dysfunction. We will use p21-Cre mouse models to examine the role of p21high cells in AD. This project will have a broad impact on both aging and AD research by determining how p21high cells contribute to AD. Using multiple in vivo models, we expect to gain a comprehensive understanding of p21high cells in AD in vivo. Results from this work will also enable future testing of pharmacological interventions that eliminate these cells to treat not only AD, but also a wide range of age-related diseases.