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首页> 外文期刊>Science Signaling >Activation of CaMKIV by soluble amyloid-p1_42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis
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Activation of CaMKIV by soluble amyloid-p1_42 impedes trafficking of axonal vesicles and impairs activity-dependent synaptogenesis

机译：通过可溶性淀粉样蛋白-P1_42激活Camkiv阻碍了轴突囊泡的运输并损害活性依赖性突触发生

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摘要

The prefibrillar form of soluble amyloid-p (sApn_42) impairs synaptic function and is associated with the early phase of Alzheimer's disease (AD). We investigated how sApn_42 led to presynaptic defects using a quantum dot-based, single particle-tracking method to monitor synaptic vesicle (SV) trafficking along axons. We found that sApn_42 prevented new synapse formation induced by chemical long-term potentiation (cLTP). In cultured rat hippocampal neurons, nanomolar amounts of sApn_42 impaired Ca2+ clearance from presynaptic terminals and increased the basal Ca2+ concentration. This caused an increase in the phosphorylation of Ca2+/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 Apn_42, or by expression a phosphodeficient synapsin mutant. The CaMKK inhibitor also abolished the defects in activity-dependent synaptogenesis caused by sApn_42. Our results suggest that by disrupting SV reallocation between synapses, sApn_42 prevents neurons from forming new synapses or adjusting strength and activity among neighboring synapses. Targeting this mechanism might prevent synaptic dysfunction in AD patients.
机译：可溶性淀粉样蛋白-P（SAPN_42）的前纤毛形式损害突触函数，与阿尔茨海默病的早期相比（AD）有关。我们研究了SAPN_42如何使用量子点的单粒跟踪方法导致突触缺陷，以监测沿着轴突的突触囊泡（SV）。我们发现SAPN_42阻止了化学长期增强（CLTP）引起的新突触形成。在培养的大鼠海马神经元中，纳米摩尔量的SaPN_42从突触前末端的Ca2 +间隙受损，增加了基础Ca2 +浓度。这导致Ca2 + /钙调蛋白依赖性蛋白激酶IV（Camkiv）及其基材Synapsin的磷酸化增加，其显着抑制了突触之间的轴突的SV贩运。衍生自转基因AD小鼠模型的神经元具有类似的缺陷，其通过凸起激酶（CAMKK;其激活CAMKIV）的抑制剂，通过针对APN_42的抗体，或通过表达磷酸二磷纤维蛋白突变体。 Camkk抑制剂还废除了SAPN_42引起的活性依赖性突触突变中的缺陷。我们的结果表明，通过中断突触之间的SV重新分配，SAPN_42可防止神经元在相邻突触中形成新的突触或调整强度和活动。靶向这种机制可能会阻止AD患者的突触功能障碍。

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  • 来源
    《Science Signaling》 |2017年第487期|共11页
  • 作者

    Daehun Park; Myeongsu Na; Jung Ah Kim; Unghwi Lee; Eunji Cho; Mirye Jang; Sunghoe Chang;

  • 作者单位

    Department of Physiology and Biomedical Sciences Seoul National University College of Medicine Seoul 110-799 South Korea;

    Department of Physiology and Biomedical Sciences Seoul National University College of Medicine Seoul 110-799 South Korea;

    Department of Physiology and Biomedical Sciences Seoul National University College of Medicine Seoul 110-799 South Korea;

    Department of Physiology and Biomedical Sciences Seoul National University College of Medicine Seoul 110-799 South Korea;

    Department of Physiology and Biomedical Sciences Seoul National University College of Medicine Seoul 110-799 South Korea;

    Department of Physiology and Biomedical Sciences Seoul National University College of Medicine Seoul 110-799 South Korea;

    Department of Physiology and Biomedical Sciences Seoul National University College of Medicine Seoul 110-799 South Korea;

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  • 正文语种 eng
  • 中图分类 细胞生物学;
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