Estrogen Regulation of Mitochondrial Function is Pivotal for Protection Against Alzheimer's Disease

Estradiol (E 2 ) is neuroprotective against neurodegenerative insults associated with calcium dysregulation and increased oxidative damage. These neuroprotective effects of E 2 are dependent upon intact mitochondrial function. In this study, we used a combined biochemical and proteomic approach to investigate the impact E 2 on mitochondrial function and regulation of neurodegenerative pathology. We demonstrated that E 2 −treatment increased whole brain mitochondrial respiratory activity while simultaneously reducing oxidative stress. These effects were coupled to coordinated regulation of the mitochondrial proteome, including increased expression of pyruvate dehydrogenase and ATP‐synthase, as determined by 2D gel electrophoresis. Further E 2 regulation of mitochondrial efficiency was correlated with increased defense against mitochondrial toxins. E 2 pretreatment of primary hippocampal neurons significantly prevented neuronal death induced by the mitochondrial toxins 3‐Nitropropionic Acid and Antimycin. E 2 pretreatment of primary hippocampal neurons prevented glutamate‐ and βA‐induced mitochondrial/cytosolic translocation of cytochrome c and Bax. Results of these analyses indicate that mitochondria play a pivotal role in estrogen‐induced neuroprotection against neurodegenerative insults associated with late onset Alzheimer's disease. Supported By: 5RO1MH067159 (to RDB and JN), 1Po1 AG026572 (Project 1; to JN and RDB), and 5P01 AG14751‐10 (Project 2; to C. Finch and RDB)