Continuous and Cyclic Progesterone Differentially Interact with Estradiol in the Regulation of Alzheimer-Like Pathology in Female 3×Transgenic-Alzheimer’s Disease Mice

University of Southern California, 3715 McClintock Avenue, Los Angeles, California 90089-0191.
Endocrinology (Impact Factor: 4.5). 06/2010; 151(6):2713-22. DOI: 10.1210/en.2009-1487
Source: PubMed


Depletion of estrogens and progesterone at menopause has been linked to an increased risk for the development of Alzheimer's disease (AD) in women. A currently controversial literature indicates that although treatment of postmenopausal women with hormone therapy (HT) may reduce the risk of AD, several parameters of HT may limit its potential efficacy and perhaps, even exacerbate AD risk. One such parameter is continuous vs. cyclic delivery of the progestogen component of HT. Recent experimental evidence suggests that continuous progesterone can attenuate neural actions of estradiol (E(2)). In the present study, we compared the effects of continuous and cyclic progesterone treatment in the presence and absence of E(2) in ovariectomized 3xTg-AD mice, a transgenic mouse model of AD. We found that ovariectomy-induced hormone depletion increases AD-like pathology in female 3xTg-AD mice, including accumulation of beta-amyloid, tau hyperphosphorylation, and impaired hippocampal-dependent behavior. E(2) treatment alone prevents the increases in pathology. Continuous progesterone did not affect beta-amyloid levels when delivered alone but blocked the Abeta-lowering action of E(2). In contrast, cyclic progesterone significantly reduced beta-amyloid levels by itself and enhanced rather than inhibited the E(2) effects. These results provide new insight into the neural interactions between E(2) and progesterone that may prove valuable in optimizing HT regimens in postmenopausal women.

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    • "The pathogenesis of Alzheimer's disease is complicated by numerous factors, such as genes [2] [3] [4] , brain-derived neurotrophic factor [5] , neuroinflammation [6] , oxidative stress [7] , hormones [8] , gender [9] , and systemic disorders [10] [11] [12] . Autopsies of Alzheimer's disease patients show brain atrophy, particularly in the entorhinal cortex and hippocampus, and microscopy reveals abnormal cells with neurofibrillary tangles in these regions [13] . "
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    • "Furthermore, some meta-analyses have suggested that exercise interventions improve cognition in AD patients (Heyn et al., 2004). We did not found an exacerbation of the amyloid and p-tau parameters by ovariectomy, as has been reported by other authors in this mouse model at the younger age of 6 months (Carroll et al., 2010; Yao et al., 2012). This pathology was not significantly protected by physical exercise in either shamoperated or ovariectomized Tg mice. "
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    • "Interestingly, a cyclic delivery of progesterone in female transgenic AD mouse model not only significantly reduced Ab levels by itself, but also enhanced the neuroprotective roles of estrogens in AD pathology when in combination with estradiol treatment. In contrast, the continuous delivery of progesterone not only failed to alter Ab levels, but also inhibited the protective effects of estrogens against AD (Carroll et al., 2010). While the precipitous loss of ovarian estrogens and progestagens at menopause has been presumed to account for the increased female susceptibility to AD, recent studies in both animals and humans suggest that depletion of brain-derived, rather than circulating, estrogens act as more direct and significant risk factors (Yue et al., 2005). "
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