Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK.
Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, Surrey TW20 0EX, UK.
Neurobiol Dis. 2017 Oct;106:63-75. doi: 10.1016/j.nbd.2017.06.011. Epub 2017 Jun 21.
Alzheimer's disease is the most prevalent form of dementia in the elderly but the precise causal mechanisms are still not fully understood. Growing evidence supports a significant role for Aβ42 oligomers in the development and progression of Alzheimer's. For example, intracellular soluble Aβ oligomers are thought to contribute to the early synaptic dysfunction associated with Alzheimer's disease, but the molecular mechanisms underlying this effect are still unclear. Here, we identify a novel mechanism that contributes to our understanding of the reported synaptic dysfunction. Using primary rat hippocampal neurons exposed for a short period of time to Aβ42 oligomers, we show a disruption in the activity-dependent phosphorylation cycle of SynapsinI at Ser9. SynapsinI is a pre-synaptic protein that responds to neuronal activity and regulates the availability of synaptic vesicles to participate in neurotransmitter release. Phosphorylation of SynapsinI at Ser9, modulates its distribution and interaction with synaptic vesicles. Our results show that in neurons exposed to Aβ42 oligomers, the levels of phosphorylated Ser9 of SynapsinI remain elevated during the recovery period following neuronal activity. We then investigated if this effect could be targeted by a putative therapeutic regime using valproic acid (a short branch-chained fatty acid) that has been proposed as a treatment for Alzheimer's disease. Exposure of Aβ42 treated neurons to valproic acid, showed that it restores the physiological regulation of SynapsinI after depolarisation. Our data provide a new insight on Aβ42-mediated pathology in Alzheimer's disease and supports the use of Valproic acid as a possible pharmaceutical intervention for the treatment of Alzheimer's disease.
阿尔茨海默病是老年人中最常见的痴呆症形式，但确切的致病机制仍不完全清楚。越来越多的证据支持 Aβ42 寡聚体在阿尔茨海默病的发展和进展中起重要作用。例如，细胞内可溶性 Aβ 寡聚体被认为有助于与阿尔茨海默病相关的早期突触功能障碍，但这种效应的分子机制仍不清楚。在这里，我们确定了一个新的机制，有助于我们理解所报道的突触功能障碍。使用短暂暴露于 Aβ42 寡聚体的原代大鼠海马神经元，我们显示 SynapsinI 在 Ser9 的活性依赖性磷酸化循环受到破坏。SynapsinI 是一种突触前蛋白，对神经元活动作出反应，调节突触小泡的可用性，以参与神经递质释放。SynapsinI 在 Ser9 的磷酸化，调节其分布和与突触小泡的相互作用。我们的结果表明，在暴露于 Aβ42 寡聚体的神经元中，SynapsinI 的 Ser9 磷酸化水平在神经元活动后的恢复期间仍然升高。然后，我们研究了这种效应是否可以通过使用丙戊酸（一种短支链脂肪酸）的潜在治疗方案来靶向，丙戊酸已被提议作为阿尔茨海默病的治疗方法。暴露于 Aβ42 处理的神经元的丙戊酸表明，它在去极化后恢复了 SynapsinI 的生理调节。我们的数据为阿尔茨海默病中 Aβ42 介导的病理学提供了新的见解，并支持使用丙戊酸作为治疗阿尔茨海默病的一种可能的药物干预。
