Ovarian hormone loss induces bioenergetic deficits and mitochondrial β-amyloid

Jia Yao, Ronald Irwin, Shuhua Chen, Ryan Hamilton, Enrique Cadenas, Roberta Diaz Brinton

Research output: Contribution to journalArticlepeer-review

96 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1507-1521
Number of pages15
JournalNeurobiology of Aging
Volume33
Issue number8
DOIs
StatePublished - Aug 2012
Externally publishedYes

Keywords

  • Alzheimer's
  • Bioenergetics
  • Estrogen
  • Mitochondria
  • Ovariectomy
  • Oxidative stress

ASJC Scopus subject areas

  • General Neuroscience
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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