Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid

Abstract

Previously, we demonstrated that reproductive senescence was associated with mitochondrial deficits comparable to those of female triple-transgenic Alzheimer’s mice (3xTgAD). Herein, we investigated the impact of chronic ovarian hormone deprivation and 17β-estradiol (E2) replacement on mitochondrial function in non-transgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nonTg mice significantly decreased brain bioenergetics, and induced mitochondrial dysfunction and oxidative stress. In 3xTgAD mice, OVX significantly exacerbated mitochondrial dysfunction and induced mitochondrial β-amyloid and Aβ−binding-alcohol-dehydrogenase (ABAD) expression. Treatment with E2 at OVX, prevented OVX-induced mitochondrial deficits, sustained mitochondrial bioenergetic function, decreased oxidative stress, and prevented mitochondrial β-amyloid and ABAD accumulation. In vitro, E2 increased maximal mitochondrial respiration in neurons and basal and maximal respiration in glia. Collectively, these data demonstrate that ovarian hormone loss induced a mitochondrial phenotype comparable to a transgenic female model of AD, which was prevented by E2. These findings provide a plausible mechanism for increased risk of AD in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention.

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“…The drop in estrogens levels during menopause is thought to deeply affect Review s giatti and others Progestins in the brain mitochondrial respiration and ATP generation. In agreement, OVX mice displayed decreased mitochondrial bioenergetics, a condition that could be reversed by estrogen treatment, when administered immediately after surgical procedure (Yao et al 2012). Also PROG can modulate mitochondrial functions.…”

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