Alzheimer's disease (AD) is an age-related neurodegenerative disorder featuring progressive cognitive, functional, and behavioral defects. Currently, more than 5.6 million Americans suffer from AD, and this number is projected to increase to 15.0 million by 2060. Despite several clinical interventions have been approved for treatment of AD, unfortunately they have demonstrated only modest effects in modifying the clinical symptoms for relatively short periods with none showing a clear therapeutic effect on disease progression. The lack of a clear understanding of the mechanisms driving the pathogenesis and progression of AD is a significant barrier to the development of innovative and effective therapies. The goal of this proposal is to address this gap by defining the role of senescence in brain aging and AD pathogenesis. My lab and those of others have shown that the number of senescent cells was markedly increased in the brain of AD patients and that the removal of senescent cells can prevent cognitive declines and attenuate AD pathology in preclinical animal models. These results suggest a critical role for senescent cells in AD pathogenesis and treatment. Based on evidence provided by us and others that 1) oxidative stress is a pathological feature of AD, and 2) increased numbers of senescent astrocytes have been identified in the brain of AD patients, we hypothesize that aging-associated oxidative stress leads to the accumulation of senescent cells in the brain, which in turn promote the pathogenesis and progression of AD via exacerbating amyloid beta (A?)-induced neurotoxicity and tau pathology. Therefore, pharmacological elimination of senescent cells can be exploited as a new strategy for AD prevention and treatment.
There Specific Aims are proposed to test this hypothesis:
in Aim 1 we will determine if there is greater cell type-specific senescence burden in AD as compared to healthy aging brains, in Aim 2 we will elucidate the mechanisms by which senescent cells influence AD pathogenesis and progression, and in Aim 3 we will evaluate the therapeutic potential of selective senolytic agents to prevent and mitigate AD progression and cognitive declines. Successful completion of this project will provide novel insights into the mechanisms by which senescent cells affect brain aging and drive the pathogenesis of AD. More importantly, we anticipate that outcomes of this study will substantially facilitate the development of new and more efficacious strategies for AD prevention and treatment.
The goal of this proposal is to elucidate how senescent cells affect brain aging and the pathogenesis of Alzheimer's disease (AD). Results of the proposed studies will facilitate the discovery and development new molecular targets for AD prevention and treatment.
