Progesterone and estrogen regulate Alzheimer-like neuropathology in female 3xTg-AD mice

Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormone therapy may reduce this risk. However,the effects of progesterone both alone and in combination with estrogen on AD neuropathology remain unknown. In this study, we used the triple transgenic mouse model of AD (3xTg-AD) to investigate the individual and combined effects of estrogen and progesterone on β-amyloid (Aβ) accumulation, tau hyperphosphorylation, and hippocampal-dependent behavioral impairments. In gonadally intact female 3xTg-AD mice, AD-like neuropathology was apparent by 3 months of age and progressively increased through age 12 months, a time course that was paralleled by behavioral impairment. Ovariectomy-induced depletion of sex steroid hormones in adult female 3xTg-AD mice significantly increased Aβ accumulation and worsened memory performance. Treatment of ovariectomized 3xTg-AD mice with estrogen, but not progesterone, prevented these effects. When estrogen and progesterone were administered in combination, progesterone blocked the beneficial effect of estrogen on Aβ accumulation but not on behavioral performance. Interestingly, progesterone significantly reduced tau hyperphosphorylation when administered both alone and in combination with estrogen. These results demonstrate that estrogen and progesterone independently and interactively regulate AD-like neuropathology and suggest that an optimized hormone therapy may be useful in reducing the risk of AD in postmenopausal women.