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首页> 外文学位 >Activity-dependent regulation of amyloid precursor protein (APP) by Polo-like kinase 2 (Plk2): Novel roles in synaptic plasticity.
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Activity-dependent regulation of amyloid precursor protein (APP) by Polo-like kinase 2 (Plk2): Novel roles in synaptic plasticity.

机译：Polo样激酶2（Plk2）对淀粉样前体蛋白（APP）的活性依赖性调节：在突触可塑性中的新作用。

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摘要

The brain uses a special feature, synaptic plasticity, for learning and memory. As forms of synaptic plasticity, associative plasticity, long-term potentiation (LTP) and long-term depression (LTD), is a positive feedback mechanism for memory encoding, whereas homeostatic plasticity (HSP) is a tuning process to stabilize neural networks. The synaptic plasticity is impaired in neurodegenerative disorders, including Alzheimer disease (AD). AD demonstrates pathological hallmarks, neurofibrillary tangles and amyloid plaques. The plaques are formed by aggregation and accumulation of amyloid beta (Abeta) which is a proteolytic fragment of the amyloid precursor protein (APP). While APP expression facilitates synaptic formation and transmission, APP processing by synaptic activity and APP knock-out contribute to synaptic depression, suggesting APP involvement in synaptic plasticity. However, the physiological roles of APP and APP processing are not well understood.;Herein, we identify novel functions of APP and APP processing in synaptic plasticity and suggest their contribution to memory and AD pathogenesis. In heightened synaptic activity, Polo-like kinase 2 (Plk2), a homeostatic repressor of overexcitation, phosphorylates T668 and S675 of APP and promotes APP beta-processing. Plk2 levels in brains of AD mouse models and patients are elevated in both a spatial and temporal manner. Genetic blockade of Plk2 kinase function prevents plaque deposits and activity-dependent Abeta production, and pharmacological inhibition hinders Abeta formation, synapse loss, and memory decline in AD mouse models. Furthermore, APP phosphorylation at T668 and S675 by Plk2 promotes GluA2 endocytosis in HSP. On the other hand, blocking phosphorylation of S655 and T686 inhibits GluA2 internalization in NMDAR-LTD. The synaptic connection between APP and GluA2 appears to occur via N-ethylmaleimide-sensitive factor (NSF).;Overall, Plk2-mediated Abeta production links synaptic overactivity to APP beta-processing and synaptic depression; this process supports a physiological role for Plk2 as a homeostatic modulator. Pathological conditions in AD, however, disturb this homeostatic balance and increase Abeta production by Plk2. Moreover, regulation of GluA2-containing AMPAR trafficking by exclusive dual phosphosites of APP in HSP and LTD implicates a role for APP in the cellular mechanisms underlying learning and memory. Thus, alterations in APP phosphorylation or related kinases may have effects on cognitive processes in the brains.
机译：大脑利用特殊功能突触可塑性来学习和记忆。作为突触可塑性的形式，联想可塑性，长期增强（LTP）和长期抑郁（LTD）是记忆编码的正反馈机制，而稳态可塑性（HSP）是稳定神经网络的调节过程。在包括阿尔茨海默氏病（AD）在内的神经退行性疾病中，突触可塑性受到损害。 AD表现出病理学特征，神经原纤维缠结和淀粉样斑块。斑块是由淀粉样蛋白β（Abeta）的聚集和积累形成的，后者是淀粉样蛋白前体蛋白（APP）的蛋白水解片段。虽然APP表达促进突触的形成和传递，但通过突触活性和APP敲除进行的APP处理会导致突触抑制，提示APP参与突触可塑性。然而，APP和APP加工的生理作用还没有被很好地理解。在这里，我们确定APP和APP加工在突触可塑性中的新功能，并暗示它们对记忆和AD发病机理的贡献。在增强的突触活性中，过度激发的稳态抑制剂Polo样激酶2（Plk2）使APP的T668和S675磷酸化，并促进APP的β加工。 AD小鼠模型和患者大脑中的Plk2水平以时空方式升高。对Plk2激酶功能的遗传封锁可防止斑块沉积和活性依赖性Abeta产生，并且药理学抑制作用可阻止AD小鼠模型中Abeta的形成，突触损失和记忆力下降。此外，Plk2在T668和S675处的APP磷酸化促进了HSP中GluA2的内吞作用。另一方面，阻断S655和T686的磷酸化可抑制NMDAR-LTD中的GluA2内在化。 APP和GluA2之间的突触连接似乎是通过N-乙基马来酰亚胺敏感因子（NSF）发生的。总体而言，Plk2介导的Abeta产生将突触过度活性与APP beta加工和突触抑制联系在一起；这个过程支持Plk2作为稳态调节剂的生理作用。然而，AD的病理状况干扰了体内平衡，并通过Plk2增加了Abeta的产生。此外，HSP和LTD中APP的排他性双重磷酸位点对含GluA2的AMPAR转运的调控，也暗示了APP在基础学习和记忆的细胞机制中的作用。因此，APP磷酸化或相关激酶的改变可能会影响大脑的认知过程。

著录项

  • 作者

    Lee, Ji Soo.;

  • 作者单位

    Georgetown University.;

  • 授予单位 Georgetown University.;
  • 学科 Neurosciences.;Medicine.;Molecular biology.
  • 学位 Ph.D.
  • 年度 2016
  • 页码 110 p.
  • 总页数 110
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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