Livingstone Rhys W, Elder Megan K, Barrett Maya C, Westlake Courteney M, Peppercorn Katie, Tate Warren P, Abraham Wickliffe C, Williams Joanna M
Department of Anatomy, Brain Health Research Centre, Brain Research New Zealand, Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand.
Department of Biochemistry, Brain Health Research Centre, Brain Research New Zealand, Rangahau Roro Aotearoa, University of Otago, Dunedin, New Zealand.
Front Mol Neurosci. 2019 Aug 14;12:198. doi: 10.3389/fnmol.2019.00198. eCollection 2019.
Secreted amyloid precursor protein-α (sAPPα) is a neuroprotective and memory-enhancing molecule, however, the mechanisms through which sAPPα promotes these effects are not well understood. Recently, we have shown that sAPPα enhances cell-surface expression of glutamate receptors. Activity-related cytoskeletal-associated protein Arc (Arg3.1) is an immediate early gene capable of modulating long-term potentiation, long-term depression and homeostatic plasticity through regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor localization. Accordingly, we hypothesized that sAPPα may enhance synaptic plasticity, in part, by the synthesis of Arc. Using primary cortical and hippocampal neuronal cultures we found that sAPPα (1 nM, 2 h) enhances levels of mRNA and protein. Arc protein levels were increased in both the neuronal somata and dendrites in a Ca/calmodulin-dependent protein kinase II-dependent manner. Additionally, dendritic Arc expression was dependent upon activation of mitogen-activated protein kinase and protein kinase G. The enhancement of dendritic Arc protein was significantly reduced by antagonism of -methyl-D-aspartate (NMDA) and nicotinic acetylcholine (α7nACh) receptors, and fully eliminated by dual application of these antagonists. This effect was further corroborated in area CA1 of acute hippocampal slices. These data suggest sAPPα-regulated plasticity within hippocampal neurons is mediated by cooperation of NMDA and α7nACh receptors to engage a cascade of signal transduction molecules to enhance the transcription and translation of Arc.
分泌型淀粉样前体蛋白-α（sAPPα）是一种具有神经保护作用且能增强记忆的分子，然而，sAPPα发挥这些作用的机制尚不清楚。最近，我们发现sAPPα可增强谷氨酸受体的细胞表面表达。活性相关细胞骨架相关蛋白Arc（Arg3.1）是一种即刻早期基因，能够通过调节α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的定位来调控长时程增强、长时程抑制和稳态可塑性。因此，我们推测sAPPα可能部分通过Arc的合成来增强突触可塑性。利用原代皮质和海马神经元培养物，我们发现sAPPα（1 nM，2小时）可提高mRNA和蛋白质水平。Arc蛋白水平在神经元胞体和树突中均以钙/钙调蛋白依赖性蛋白激酶II依赖的方式增加。此外，树突状Arc的表达依赖于丝裂原活化蛋白激酶和蛋白激酶G的激活。通过拮抗N-甲基-D-天冬氨酸（NMDA）和烟碱型乙酰胆碱（α7nACh）受体，树突状Arc蛋白的增强作用显著降低，同时应用这两种拮抗剂则可完全消除这种作用。在急性海马切片的CA1区进一步证实了这一效应。这些数据表明，sAPPα调节的海马神经元可塑性是由NMDA和α7nACh受体协同作用介导的，通过一系列信号转导分子来增强Arc的转录和翻译。
