TARGETING SENESCENCE PATHWAYS IN ALZHEIMER'S DISEASE PROJECT SUMMARY Alzheimer's disease (AD) is the most common form of dementia, occurring in 10% of individuals over the age of 65 and affecting an estimated 5.5 million people in the United States. Currently, there is no treatment to stop, prevent, or reverse AD. Historically, AD has been understood by its end-stage disease phenotype, characterized clinically by dementia and pathologically by A? senile plaques and neurofibrillary tangles. CDKN2a is increased in peripheral blood of pre-AD patients and in the brain and peripheral blood of an AD mouse model mutant for APP (Tg-SwDI mouse model). A CDKN2a associated protein, P16Ink4a, increases with age and is involved in aging of multiple cells such as inhibition of stem cell self-renewal in several tissues. In a mouse model of AD, there is a neural progenitor cell defect and cognitive deficit that are corrected by targeting the Cdkn2a pathway, either directly via mutation of Cdkn2a or indirectly by making the AD mice haploinsufficient for Usp16. Usp16 is associated with decreased ubiquitination of Cdkn2a and accelerated senescence in the stem cell compartments regulated by Bmi1, which adds an ubiquitin mark to Cdkn2a needed for stem cells maintenance. These data expose an aberrant pathway in the Tg-SwDI model that may be targeted prior to signs of advanced disease. We hypothesize that modulating Cdkn2a levels can improve at least some of the cellular defects associated with AD. We further hypothesize that combining Cdkn2a inhibition with classical therapeutics will improve outcomes in AD. The following aims and questions will test these hypotheses and perhaps the role of Cdkn2a as a target in AD.
Aim 1 : Determine which neural cell population of the AD mouse model is rescued by Usp16 haploinsufficiency.
Aim 2 : Does inflammation contribute to the aging defects of the neural cell populations impacted by mutant APP? Aim 3: Does decreasing inflammation improve cognition in Usp16 haploinsufficient AD mice?
TARGETING SENESCENCE PATHWAYS IN ALZHEIMER'S DISEASE PROJECT NARRATIVE The goal of this application is to decipher the mechanism by which Cdkn2a contributes the pathologies of Alzheimer's disease (AD). Discoveries from this project could provide a new target and lead to new therapies for AD.
