Department of Biology, Western University, London, Ontario, N6A 5B7, Canada.
Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, N6A 5C1, Canada.
Sci Rep. 2018 Nov 20;8(1):17081. doi: 10.1038/s41598-018-35114-y.
A key pathological feature of Alzheimer's disease (AD) is the accumulation of the neurotoxic amyloid beta (Aβ) peptide within the brains of affected individuals. Previous studies have shown that neuronal cells selected for resistance to Aβ toxicity display a metabolic shift from mitochondrial-dependent oxidative phosphorylation (OXPHOS) to aerobic glycolysis to meet their energy needs. The Src homology/collagen (Shc) adaptor protein p66Shc is a key regulator of mitochondrial function, ROS production and aging. Moreover, increased expression and activation of p66Shc promotes a shift in the cellular metabolic state from aerobic glycolysis to OXPHOS in cancer cells. Here we evaluated the hypothesis that activation of p66Shc in CNS cells promotes both increased OXPHOS and enhanced sensitivity to Aβ toxicity. The effect of altered p66Shc expression on metabolic activity was assessed in rodent HT22 and B12 cell lines of neuronal and glial origin respectively. Overexpression of p66Shc repressed glycolytic enzyme expression and increased both mitochondrial electron transport chain activity and ROS levels in HT22 cells. The opposite effect was observed when endogenous p66Shc expression was knocked down in B12 cells. Moreover, p66Shc activation in both cell lines increased their sensitivity to Aβ toxicity. Our findings indicate that expression and activation of p66Shc renders CNS cells more sensitive to Aβ toxicity by promoting mitochondrial OXPHOS and ROS production while repressing aerobic glycolysis. Thus, p66Shc may represent a potential therapeutically relevant target for the treatment of AD.
阿尔茨海默病（AD）的一个关键病理学特征是，在受影响个体的大脑中积累了神经毒性淀粉样β（Aβ）肽。先前的研究表明，对 Aβ毒性具有抗性的神经元细胞表现出代谢转变，从依赖线粒体的氧化磷酸化（OXPHOS）转变为有氧糖酵解，以满足其能量需求。Src 同源性/胶原（Shc）衔接蛋白 p66Shc 是线粒体功能、ROS 产生和衰老的关键调节因子。此外，p66Shc 的表达和激活增加促进了癌细胞中细胞代谢状态从有氧糖酵解向 OXPHOS 的转变。在这里，我们评估了这样一个假设，即 CNS 细胞中 p66Shc 的激活既促进了 OXPHOS 的增加，又增强了对 Aβ毒性的敏感性。改变的 p66Shc 表达对代谢活性的影响分别在神经元和神经胶质来源的啮齿动物 HT22 和 B12 细胞系中进行了评估。p66Shc 的过表达抑制了糖酵解酶的表达，并增加了 HT22 细胞中线粒体电子传递链的活性和 ROS 水平。当在 B12 细胞中敲低内源性 p66Shc 的表达时，观察到相反的效果。此外，p66Shc 在两种细胞系中的激活都增加了它们对 Aβ毒性的敏感性。我们的研究结果表明，p66Shc 的表达和激活通过促进线粒体 OXPHOS 和 ROS 产生，同时抑制有氧糖酵解，使 CNS 细胞对 Aβ毒性更敏感。因此，p66Shc 可能代表治疗 AD 的潜在治疗相关靶点。
