Brain Endogenous Estrogen Levels Determine Responses to Estrogen Replacement Therapy via Regulation of BACE1 and NEP in Female Alzheimer’s Transgenic Mice

Abstract

Estrogens have been found to improve memory and reduce risk of dementia, although conflicting results such as failure of estrogen replacement therapy for treatment of Alzheimer’s disease (AD) also has been reported. Only recently, our published human brain studies showed a depletion of brain estrogen in women with Alzheimer’s disease, while other studies have demonstrated cognitive impairment believed to be caused by inhibition of endogenous estrogen synthesis in females. To investigate whether the shortage of brain estrogen alters the sensitivity of response to estrogen replacement therapy, we have used genetic and surgical animal models to examine the response of estrogen treatment in AD neuropathology. Our studies have shown that early treatment with 17β-estradiol (E2) or genistein could reduce brain amyloid levels by increasing Aβ clearance in both APP23 mice with genetic deficiency of aromatase (APP/Ar+/−), in which the brains contains non-detectable levels of estrogen, and in APP23 mice with an ovariectomy (APP/OVX), in which the brains still contain certain levels of estrogen. However, only APP/Ar+/− mice showed a great reduction in brain amyloid plaque formation after E2 or genistein treatment along with downregulation of beta secretase (BACE1) mRNA and protein expression. Our results suggest that early and long-term usage of E2 and/or genistein may prevent AD pathologies in a dependent manner on endogenous brain estrogen levels in aged females.

Estrogen receptors alpha (ERα) and beta (ERβ): Subtype-selective ligands and clinical potential

“…The low estrogen concentration in APP23 mice with genetic deficiency of aromatase is characterized by a more severe formation of Aβ plaques and an extensive AD neuropathology than that found in ovaricetomized mice, suggesting that the deficiency of endogenous estrogens in the brain could increase the risk of Alzheimer’s disease. This estrogen-deficient mouse model was even more sensitive to the reduction of plaque formation by genistein than by endogenous estrogens, thus supporting the beneficial effect of this exogenous phytoestrogen [123]. An intriguing study of genistein on brains of ovariectomized rats showed that genistein mimicked the estradiol-induced effects by enhancing place learning, but it also impaired response learning compared to untreated animals.…”

The neuroprotective actions of oestradiol and oestrogen receptors

“…Thus, in H19-7 hippocampal cells, the inhibition of aromatase prevents the neuroprotective action of exogenous oestradiol 126 . In addition, the neuroprotective action of circulating oestradiol in a mouse model of Alzheimer's disease is significantly reduced in ArKO mice that have undetectable levels of brain oestradiol 127 . Further studies are necessary to clarify the role of brain oestradiol synthesis in the neuroprotective outcome of hormone therapy.…”

Aromatase/Seladin-1 Interactions in Human Neuronal Cell Culture, the Hippocampus of Healthy Rats and Transgenic Alzheimer’s Disease Mice

“…Although in vitro research demonstrated the neurotrophic and neuroprotective effects of estrogen on neurodegenerative diseases, such as AD, the data obtained from the clinical studies is conflicted [10-16]. After observing a reduction in brain estrogen in female patients with AD, estrogen/hormone replacement therapy has been utilized [12, 17-19]. Early trials supported the idea that patients with AD could benefit from estrogen therapy according to its improving effects on memory and cognitive functions; however, these studies were conducted on perimenopausal women or healthy postmenopausal women [19, 20].…”