Journal
BRAIN RESEARCH
Volume 1616, Issue -, Pages 101-111Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.brainres.2015.04.059
Keywords
Estrogen receptor beta; Alzheimer's disease; AKAP1; PKA; Mitochondrial Fission And Fusion; Mitochondrial Movement
Categories
Funding
- NIH, United States [P01 AG022550, P01 AG027956, P20 GM109098, U54GM104942]
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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 ER beta is localized in the mitochondria and ER beta knock down disrupts mitochondrial functions. Because a selective ER beta modulator (DPN) can activate PICA, and localized PICA signaling in the mitochondrial membrane regulates mitochondrial structure and functions, we reasoned that ER beta signaling in the mitochondrial membrane rescues many of the mitochondrial defects caused by soluble A beta oligomer. We now report that DPN treatment in primary hippocampal neurons attenuates soluble A beta-oligomer induced dendritic mitochondrial fission and reduced mobility. Additionally, A beta treatment reduced the respiratory reserve capacity of hippocampal neuron and inhibited phosphoxylation of Drp1 at its PICA site, which induces excessive mitochondrial fission, and DPN treatment ameliorates these inhibitions. Finally, we discovered a direct interaction of ER beta 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 ER beta signaling pathway may be a useful mitochondria-directed therapeutic target for AD. (C) 2015 Elsevier B.V. All rights reserved.
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