Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1.
Estrogen amelioration of Aβ-induced defects in mitochondria is mediated by mitochondrial signaling pathway involving ERβ, AKAP and Drp1.
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DOI：
10.1016/j.brainres.2015.04.059
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发表时间：
2015-08-07
期刊：
影响因子：
2.9
通讯作者：
Simpkins, James W.
中科院分区：
文献类型：
--
作者：
Sarkar, Saumyendra;Jun, Sujung;Simpkins, James W.
关键词：
线粒体包括裂变、融合和运动在内的动态特性的扰动导致突触能量供应中断，从而导致阿尔茨海默病（AD）的神经病理学和认知功能障碍。这些缺陷的分子机制尚不清楚。先前，我们已经证明ERβ位于线粒体中，ERβ敲低会破坏线粒体功能。由于选择性ERβ调节剂（selective ERβ modulator， DPN）可以激活PKA，而PKA信号在线粒体膜上的定位调节线粒体的结构和功能，我们推断ERβ信号在线粒体膜上修复了许多由可溶性a β低聚物引起的线粒体缺陷。我们现在报道，DPN治疗初级海马神经元减弱可溶性a β-寡聚物诱导的树突状线粒体裂变和降低流动性。此外，a β治疗降低了海马神经元的呼吸储备能力，抑制了Drp1在PKA位点的磷酸化，从而诱导线粒体过度分裂，DPN治疗改善了这些抑制作用。最后，我们发现ERβ与线粒体驻留蛋白AKAP1直接相互作用，诱导PKA介导的局部信号通路参与增加氧化磷酸化和抑制线粒体裂变。综上所述，我们的研究结果强调了ERβ信号通路可能是一个有用的线粒体导向的AD治疗靶点的可能性。
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.
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