Park Daehun, Na Myeongsu, Kim Jung Ah, Lee Unghwi, Cho Eunji, Jang Mirye, Chang Sunghoe
Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul 110-799, South Korea.
Neuroscience Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea.
Sci Signal. 2017 Jul 11;10(487):eaam8661. doi: 10.1126/scisignal.aam8661.
The prefibrillar form of soluble amyloid-β (sAβ) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sAβ led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. We found that sAβ prevented new synapse formation induced by chemical long-term potentiation (cLTP). In cultured rat hippocampal neurons, nanomolar amounts of sAβ impaired Ca clearance from presynaptic terminals and increased the basal Ca concentration. This caused an increase in the phosphorylation of Ca/calmodulin-dependent protein kinase IV (CaMKIV) and its substrate synapsin, which markedly inhibited SV trafficking along axons between synapses. Neurons derived from a transgenic AD mouse model had similar defects, which were prevented by an inhibitor of CaMK kinase (CaMKK; which activates CaMKIV), by antibodies against Aβ, or by expression a phosphodeficient synapsin mutant. The CaMKK inhibitor also abolished the defects in activity-dependent synaptogenesis caused by sAβ Our results suggest that by disrupting SV reallocation between synapses, sAβ prevents neurons from forming new synapses or adjusting strength and activity among neighboring synapses. Targeting this mechanism might prevent synaptic dysfunction in AD patients.
可溶性淀粉样前体蛋白β（sAβ）的原纤维形式会损害突触功能，并与阿尔茨海默病（AD）的早期阶段相关。我们使用基于量子点的单粒子追踪方法来监测沿轴突的突触小泡（SV）运输，以研究sAβ如何导致突触前缺陷。我们发现，sAβ可阻止化学性长期增强（cLTP）诱导的新突触形成。在培养的大鼠海马神经元中，纳摩尔量的sAβ会损害突触前终末的钙清除，并增加基础钙浓度。这导致钙/钙调蛋白依赖性蛋白激酶IV（CaMKIV）及其底物突触素的磷酸化增加，从而显著抑制突触间轴突上的SV运输。源自转基因AD小鼠模型的神经元也有类似缺陷，而CaMK激酶（CaMKK；激活CaMKIV）的抑制剂、抗Aβ抗体或表达磷酸化缺陷的突触素突变体可预防这些缺陷。CaMKK抑制剂还消除了sAβ引起的活性依赖性突触形成缺陷。我们的结果表明，sAβ通过破坏突触间的SV重新分配，阻止神经元形成新突触或调节相邻突触之间的强度和活性。针对这一机制可能预防AD患者的突触功能障碍。
