TY - JOUR
T1 - Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1
AU - Sarkar, Saumyendra
AU - Jun, Sujung
AU - Simpkins, James W.
N1 - Funding Information:
The authors acknowledge the support for this project of NIH, United States grants P01 AG022550, P01 AG027956, P20 GM109098 and U54GM104942.
Funding Information:
The authors acknowledge the support for this project of NIH , United States grants P01 AG022550 , P01 AG027956 , P20 GM109098 and U54GM104942 .
Publisher Copyright:
© 2015 Elsevier B.V. All rights reserved.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
KW - AKAP1
KW - Alzheimer's disease
KW - Estrogen receptor β
KW - Mitochondrial Fission And Fusion
KW - Mitochondrial Movement
KW - PKA
UR - http://www.scopus.com/inward/record.url?scp=84929643029&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84929643029&partnerID=8YFLogxK
U2 - 10.1016/j.brainres.2015.04.059
DO - 10.1016/j.brainres.2015.04.059
M3 - Article
C2 - 25964165
AN - SCOPUS:84929643029
SN - 0006-8993
VL - 1616
SP - 101
EP - 111
JO - Brain research
JF - Brain research
ER -