Effects of Long-Term 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) Treatment on Cognition and Neuropathology in a 12-month-old 3xTg-AD Mouse Model of Alzheimer’s Disease
Age-related decline in circulating testosterone levels has been associated with an increased risk of developing Alzheimer’s disease (AD). Previous studies have highlighted the neuroprotective effects of testosterone and dihydrotestosterone supplementation in AD rodent models. Recent in vitro work demonstrated that the neurosteroid metabolite of testosterone, 5α-androstane-3α,17β-diol (3α-diol), may also be neuroprotective against AD by reducing β-amyloid-induced neurotoxicity. However, the protective potential of 3α-diol against AD-related pathology in vivo remains largely uncharacterized. This thesis investigated the effects of long-term continuous treatment of 3α-diol in a 12-month-old triple transgenic AD (3xTg-AD) mouse model. 3α-diol treatment improved object recognition memory in 3xTg-AD males, differentially enhanced locomotion in wild-type mice, increased CA3 apical dendritic spine density in females, and increased CA1 apical dendritic branching in 3xTg-AD males. The findings presented in this thesis suggest that long-term 3α-diol treatment may be neuroprotective against cognitive and morphological AD-related deficits in a sex-specific manner.