New Evidence of Mitochondria Dysfunction in the Female Alzheimer's Disease Brain: Deficiency of Estrogen Receptor-β

Accumulating evidence suggests that mitochondria are important targets for the actions of estrogens and studies indicated that localization of estrogen receptor beta (ER beta) in neuronal mitochondrial (mtER beta) might directly affect neuronal mitochondrial function in vitro. However, it is unknown what expression levels and how important mtER beta is in the human brain, particularly in a brain with Alzheimer's disease (AD). In the present study, using rapidly autopsied human brain tissue, we found that the frontal cortices of female AD patients exhibited significantly reduced mtER beta, along with reduced mitochondrial cytochrome C oxidase activity, and increased protein carbonylation compared to that in normal controls. The correlation between mtER beta expression and mitochondrial cytochrome C oxidase activity in the female human brain is significant. To understand the possible mechanisms of mtER beta in AD-related mitochondrial dysfunction, using ER beta KO mice as a model, we found that lack of ER beta enhanced brain reactive oxygen species generation and reduced mitochondrial membrane potential under A beta peptide insult compared to brain mitochondria from wild-type control mice. Our studies, for the first time, demonstrated neuronal mtER beta expression in the human brain and the deficiency of mtER beta in the female AD brain is associated with the dysfunction of mitochondria. Our results from ER beta KO mice demonstrated that ER beta depletion-induced mitochondrial dysfunction is mediated through increasing reactive oxygen generation and reduction of mitochondria membrane potential. These results indicate that ER beta depletion impairs mitochondrial function in mice, and reduction of brain mtER beta may significantly contribute to the mitochondrial dysfunction involved in AD pathogenesis in women.