Estrogen amelioration of A?-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ER?, 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 ER? is localized in the mitochondria and ER? knock down disrupts mitochondrial functions. Because a selective ER? modulator (DPN) can activate PKA, and localized PKA signaling in the mitochondrial membrane regulates mitochondrial structure and functions, we reasoned that ER? signaling in the mitochondrial membrane rescues many of the mitochondrial defects caused by soluble A? oligomer. We now report that DPN treatment in primary hippocampal neurons attenuates soluble A?-oligomer induced dendritic mitochondrial fission and reduced mobility. Additionally, A? 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 ER? 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? signaling pathway may be a useful mitochondria-directed therapeutic target for AD.

SUBMITTER: Sarkar S 

PROVIDER: S-EPMC4464937 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other