Yin Yanling, Zhao Yuanyuan, Han Song, Zhang Nan, Chen Hanyu, Wang Xiaomin
Department of Neurobiology and Beijing Institute for Brain Disorders, School of Basic Medical Sciences, Capital Medical University, Beijing, PR China.
Core Facility Center, Capital Medical University, Beijing, PR China.
J Alzheimers Dis. 2017;59(3):851-869. doi: 10.3233/JAD-170246.
Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most frequent cause of progressive cognitive decline in the elderly population. To date, there is still no effective treatment for AD, requiring more underlying mechanisms. In the present study, we investigated the effects of Aβ42 on the inhibitory synaptic transmission in the cultured hippocampal neurons, and explored the possible mechanism. The frequency, but not amplitude, of miniature inhibitory post-synaptic currents was significantly suppressed by Aβ42, indicating that Aβ42 played its role in inhibitory transmitter release at the pre-synaptic sites. Aβ42 had no effect on miniature excitatory post-synaptic currents, suggesting GABAergic synapses are more susceptible to Aβ42 exposure. However, the number of GABAergic neurons or synapses was not influenced, suggesting the corresponding stage may be a preclinical one. The effect of Aβ42 can be mimicked by PD98059 (an inhibitor of ERK1/2) and blocked by curcumin (an activator of MEK), which reveals Aβ-involved influence is via the decreased phosphorylation of MAPK-ERK1/2. In addition, synaptophysin is confirmed to be a downstream protein of MAPK-ERK1/2 at the pre-synaptic site. At the same time, suppressed autophagy was observed after Aβ42 exposure, and the activation of autophagy increased pERK1/2 level and salvaged the disinhibition of hippocampal neurons. These data suggest that diminished GABAergic tone likely starts from the preclinical stage of AD, so some GABAergic stress test may be effective for identifying cognitively normal elder adults. Strategies against the dysfunction of autophagy should be adopted in the early stage of AD because of its initial effects.
阿尔茨海默病（AD）是一种进行性神经退行性疾病，也是老年人群中进行性认知衰退的最常见原因。迄今为止，AD仍无有效治疗方法，需要深入了解更多潜在机制。在本研究中，我们研究了Aβ42对培养的海马神经元抑制性突触传递的影响，并探讨了其可能机制。微小抑制性突触后电流的频率而非幅度受到Aβ42的显著抑制，表明Aβ42在突触前位点的抑制性递质释放中发挥作用。Aβ42对微小兴奋性突触后电流无影响，提示GABA能突触对Aβ42暴露更敏感。然而，GABA能神经元或突触的数量未受影响，提示相应阶段可能处于临床前期。PD98059（一种ERK1/2抑制剂）可模拟Aβ42的作用，姜黄素（一种MEK激活剂）可阻断其作用，这表明Aβ相关影响是通过降低MAPK-ERK1/2的磷酸化实现的。此外，突触素被证实是突触前位点MAPK-ERK1/2的下游蛋白。同时，Aβ42暴露后观察到自噬受到抑制，自噬激活可提高pERK1/2水平并挽救海马神经元的去抑制状态。这些数据表明，GABA能张力降低可能始于AD的临床前期，因此一些GABA能应激试验可能对识别认知正常的老年人有效。由于自噬功能障碍在AD早期就有影响，因此应在AD早期采取针对自噬功能障碍的策略。
