title: Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1.
abstract: Perturbations in dynamic properties of mitochondria including fission, fusion, and movement lead to disruption of energy supply to synapses contributing to neuropathology and cognitive dysfunction in Alzheimer׳s disease (AD). The molecular mechanisms underlying these defects are still unclear. Previously, we have shown that ERβ is localized in the mitochondria and ERβ knock down disrupts mitochondrial functions. Because a selective ERβ modulator (DPN) can activate PKA, and localized PKA signaling in the mitochondrial membrane regulates mitochondrial structure and functions, we reasoned that ERβ signaling in the mitochondrial membrane rescues many of the mitochondrial defects caused by soluble Aβ oligomer. We now report that DPN treatment in primary hippocampal neurons attenuates soluble Aβ-oligomer induced dendritic mitochondrial fission and reduced mobility. Additionally, Aβ treatment reduced the respiratory reserve capacity of hippocampal neuron and inhibited phosphorylation of Drp1 at its PKA site, which induces excessive mitochondrial fission, and DPN treatment ameliorates these inhibitions. Finally, we discovered a direct interaction of ERβ with a mitochondrial resident protein AKAP1, which induces the PKA-mediated local signaling pathway involved in increased oxidative phosphorylation and inhibition of mitochondrial fission. Taken together, our findings highlight the possibility that ERβ signaling pathway may be a useful mitochondria-directed therapeutic target for AD.
authors.affiliation: Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University Health Science Center, 1 Medical Center Drive, Morgantown, WV 20606, USA.
authors.forename: Saumyendra
authors.initials: S
authors.lastname: Sarkar
authors.affiliation: Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University Health Science Center, 1 Medical Center Drive, Morgantown, WV 20606, USA.
authors.forename: Sujung
authors.initials: S
authors.lastname: Jun
authors.affiliation: Department of Physiology and Pharmacology, Center for Basic and Translational Stroke Research, West Virginia University Health Science Center, 1 Medical Center Drive, Morgantown, WV 20606, USA. Electronic address: jwsimpkins@hsc.wvu.edu.
authors.forename: James W
authors.initials: JW
authors.lastname: Simpkins
mesh_terms: D054758:A Kinase Anchor Proteins / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D001921:Brain / Q000166:cytology; D002478:Cells, Cultured; D003712:Dendrites / Q000187:drug effects / Q000648:ultrastructure; D034281:Dynamins / Q000378:metabolism; D004622:Embryo, Mammalian; D047629:Estrogen Receptor beta / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D006801:Humans; D008928:Mitochondria / Q000187:drug effects*; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009474:Neurons / Q000648:ultrastructure*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D014162:Transfection
chemical_list: D054758:A Kinase Anchor Proteins; C486332:Akap1 protein, rat; D016229:Amyloid beta-Peptides; D047629:Estrogen Receptor beta; D004967:Estrogens; D024101:Mitochondrial Proteins; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C519851:Dnm1l protein, rat; D034281:Dynamins
keywords: AKAP1; Alzheimer׳s disease; Estrogen receptor β; Mitochondrial Fission And Fusion; Mitochondrial Movement; PKA