Prostate cancer is the most common cancer and the second leading cause of cancer death in American men. Androgen deprivation therapy (ADT) is a widely applied strategy that can efficiently improve life span and quality of life for prostate cancer patients. However, recent large-scale epidemiologic studies revealed that patients with ADT have an increased risk of developing Alzheimer's disease (AD) compared to the general population, raising a severe public health concern. Age-related androgen depletion has been implicated in the pathogenesis of neurodegenerative diseases, including AD. However, the role of ADT for prostate cancer in AD onset and progression has not been clearly defined. Currently, there is no clinically-relevant animal model to directly examine the effect of ADT on AD development while treating prostate cancer. The primary objective of this project is to apply powerful mouse genetic approaches to establish a clinically-relevant tumor-bearing AD model and examine how ADT affects AD onset and progression. We have been studying a genetically engineered prostate cancer mouse model in which Pten is specifically deleted in prostate using PB-Cre [PB- Cre;Ptenloxp/loxp, Pten prostate conditional knockout (cKO) mice, referred to as PtencKO]. We found that the PtencKO line recapitulates prostate cancer features and responses to ADT treatment in human patients. By crossbreeding this line with a well-established AD model, we expect to create an ideal model to study the interaction between ADT and AD in the prostate cancer population. We will test the effect of ADT on AD-related cognitive abnormalities in Aim 1, amyloid-related neuropathological changes in Aim 2, and inflammation/immune responses in Aim 3. Successfully accomplishing the proposed study will create a unique mouse model that not only allows us to examine the complex interaction among ADT, AD and prostate cancer, but also may serve as an invaluable tool for evaluating potential clinical therapies aimed at reducing the negative effects of ADT.
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