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

Abstract

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.

Progesterone attenuates Aβ 25–35 -induced neuronal toxicity via JNK inactivation and progesterone receptor membrane component 1-dependent inhibition of mitochondrial apoptotic pathway

“…It is likely that mitochondrial abnormalities may be a common pathway leading to neuronal dysfunction in many neurodegenerative diseases, including AD. There is accumulating evidence that Ab alters the expression of genes from Bcl-2 family, Abbreviations: AD, Alzheimer's disease; Ab [25][26][27][28][29][30][31][32][33][34][35] , b-amyloid peptide [25][26][27][28][29][30][31][32][33][34][35] ; PROG, progesterone; RU486, 11 b-(4-dimethylamino) phenyl-17 b-hydroxy-17-(1-propynyl) estra-4,9-dien-3-one; AG205, 3-chloro-N-[7-(2-chlorobenzoyl)-2,3-dihydro-1,4-benzodioxin-6-yl]benzamide; DMSO, dimethyl sulfoxide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bro-mide; SP600125, anthra [1,9-cd]pyrazol-6(2H)-one; DMEM, Dulbecco's Modified Eagle Medium; PBS, phosphate-buffered saline; Rh123, 3,6-diamino-9-[2-(methoxycarbonyl) phenyl] xanthyliumchloride.…”

Sex Hormones and Alzheimer’s Disease

“…The direct progesterone protecting actions against AD development and/or progression include regulation of β-amyloid metabolism by reducing Aβ production and decreasing the pool of soluble Aβ by enhancement of the non-amyloidogenic α-secretase pathway, decreasing Aβ accumulation through modulation of γ-secretases activities and increasing Aβ clearance by enhancing insulin-degrading enzyme expression and downregulation of β-secretase gene expression [85,86]. At the same time, progesterone reduces tau hyperphosphorylation and the serum level of endogenous progesterone is inversely correlated with tau accumulation, and at the same time, progesterone administration in transgenic AD mice improved cognitive performance in object recognition and T-maze task [87].…”

Evaluating the Role of Hormone Therapy in Postmenopausal Women with Alzheimer’s Disease

“…There are just a few preclinical studies in which HT (estrogen and progesterone) was tested to treat experimental AD and they were performed on transgenic mouse models of AD [52,53] (Table 2).…”