Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid.

TitleOvarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid.
Publication TypeJournal Article
Year of Publication2012
AuthorsYao J, Irwin R, Chen S, Hamilton R, Cadenas E, Brinton RDiaz
JournalNeurobiol Aging
Date Published2012 Aug
Keywords3-Hydroxyacyl CoA Dehydrogenases, Aging, Alzheimer Disease, Amyloid beta-Peptides, Animals, Brain, Estradiol, Female, Mice, Mice, Knockout, Mitochondria, Oxidative Stress

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 nontransgenic (nonTg) and 3xTgAD female mouse brain. Depletion of ovarian hormones by ovariectomy (OVX) in nontransgenic 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 β-amyloid (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 Alzheimer's disease (AD), which was prevented by E2. These findings provide a plausible mechanism for increased risk of Alzheimer's disease in premenopausally oophorectomized women while also suggesting a therapeutic strategy for prevention.

Alternate JournalNeurobiol. Aging
PubMed ID21514693
PubMed Central IDPMC3181273
Grant List2R01AG032236 / AG / NIA NIH HHS / United States
R01 AG032236 / AG / NIA NIH HHS / United States
R01 AG032236-07 / AG / NIA NIH HHS / United States
5P01AG026572 / AG / NIA NIH HHS / United States
P01 AG026572-04 / AG / NIA NIH HHS / United States
P01 AG026572 / AG / NIA NIH HHS / United States
Faculty Member Reference: 
Roberta Diaz Brinton, Ph.D