Progesterone and Estrogen Regulate Alzheimer-Like Neuropathology in Female 3xTg-AD Mice

Abstract

Estrogen depletion in postmenopausal women is a significant risk factor for the development of Alzheimer's disease (AD), and estrogen-based hormonetherapymayreducethisrisk.However,theeffectsofprogesteronebothaloneandincombinationwithestrogenonADneuropathology 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 ␤-amyloid (A␤) 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 A␤ 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 A␤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.

Progesterone receptors: Form and function in brain

“…Our results suggest that continuous E 2 , but not P 4 treatment attenuates the acceleration of Aβ accumulation and memory deficits observed in ovariectomized mice. More importantly, in animals receiving both hormones, P 4 blocked the beneficial effect of E 2 on Aβ accumulation [2].…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Ovariectomy significantly increased Ab accumulation and worsened memory performance, while chronic estradiol treatment prevented these effects. In addition, progesterone administration reduced tau phosphorylation, while when added in combination with estradiol prevented the effect of estrogen on Ab accumulation but not on behavioural performance [33].…”

Astroglia in dementia and Alzheimer's disease

“…75,79 Cognitive deficits in the 3xTg-AD model correlate with the accumulation of intraneuronal Ab. 80,81 It has to be noted, however, that all animal models of AD developed so far have some limitations, the most serious one being the absence of significant neuronal loss. This may reflect some intrinsic differences between human and animal brain, shorter lifespan of experimental animals or influence of other yet unknown factors.…”