Department of Pathogen Biology, Medical College, Henan University of Science and Technology, Luolong District, Luoyang, China.
Department of Immunology, Medical College, Henan University of Science and Technology, Luolong District, Luoyang, China.
J Alzheimers Dis. 2017;59(4):1255-1267. doi: 10.3233/JAD-170100.
The coexistence of neuronal mitochondrial pathology and synaptic dysfunction is an early pathological feature of Alzheimer's disease (AD). Cardiotrophin-1 (CT-1) has been shown to exhibit impressive neuroprotective effects. Previous studies have shown positive effects of CT-1 on brain glucose metabolism and cognition in APPswe/PS1dE9 transgenic mice; however, little is known about the effects of CT-1 on early synaptic mitochondrial dysfunction and resultant synaptic pathology in the brain. In this study, 4-month-old transgenic mice with brain tissue-specific CT-1 expression were used alone or in combination with APPswe/PS1dE9 transgenic mice to evaluate the effect of CT-1 on synaptic mitochondrial dysfunction and resultant synaptic pathology, and cryptic memory deficits in the APPswe/PS1dE9 transgenic mice. The potential mechanism of action of CT-1 was also examined. Young CT-1×APPswe/PS1dE9 transgenic mice exhibited improvements in long-term learning and memory ability and ameliorations of synaptic mitochondrial/synaptic impairments compared to young APPswe/PS1dE9 transgenic mice. Moreover, CT-1 upregulated the expression of AMPAR and increased AMP-activated protein kinase (AMPK) activity in the hippocampus of APPswe/PS1dE9 transgenic mice. However, AMPK inhibition through shRNA knockdown of AMPKα blocked the neuroprotective effects of CT-1 on the expression of AMPAR and mitochondrial/synaptic dysfunction in Aβ-treated mouse neurons. These results suggest that CT-1 may be a potent candidate for the early prevention and treatment of AD.
神经元线粒体病理学和突触功能障碍的共存是阿尔茨海默病（AD）的早期病理特征。心营养素-1（CT-1）已被证明具有令人印象深刻的神经保护作用。先前的研究表明 CT-1 对 APPswe/PS1dE9 转基因小鼠的大脑葡萄糖代谢和认知有积极影响；然而，关于 CT-1 对大脑早期突触线粒体功能障碍和由此产生的突触病理学的影响知之甚少。在这项研究中，使用脑组织特异性表达 CT-1 的 4 个月大的转基因小鼠单独或与 APPswe/PS1dE9 转基因小鼠一起评估 CT-1 对突触线粒体功能障碍和由此产生的突触病理学以及 APPswe/PS1dE9 转基因小鼠隐匿性记忆缺陷的影响。还检查了 CT-1 的潜在作用机制。与年轻的 APPswe/PS1dE9 转基因小鼠相比，年轻的 CT-1×APPswe/PS1dE9 转基因小鼠表现出长期学习和记忆能力的提高以及突触线粒体/突触损伤的改善。此外，CT-1 上调了 APPswe/PS1dE9 转基因小鼠海马体中 AMPAR 的表达，并增加了 AMP 激活蛋白激酶（AMPK）的活性。然而，通过 AMPKα 的 shRNA 敲低抑制 AMPK 阻断了 CT-1 对 Aβ 处理的小鼠神经元中 AMPAR 表达和线粒体/突触功能障碍的神经保护作用。这些结果表明，CT-1 可能是 AD 早期预防和治疗的有力候选药物。
