Neuroprotection induced by Navβ2-knockdown in APP/PS1 transgenic neurons is associated with NEP regulation
Neuroprotection induced by Navβ2-knockdown in APP/PS1 transgenic neurons is associated with NEP regulation
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DOI：
10.3892/mmr.2019.10406
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发表时间：
2019-08-01
影响因子：
3.4
通讯作者：
Xiyang, Yan-Bin
中科院分区：
文献类型：
--
作者：
Hu, Tao;Li, Shan-Shan;Xiyang, Yan-Bin
电压门控钠通道β 2 （Nav β 2）作为β位点淀粉样蛋白前体切割酶1的非常规底物，参与调控钠通道的神经元表面表达。先前的研究表明，在APP/早老素1 （PS1）转基因老年小鼠中，敲低Nav β 2通过部分减少淀粉样前体蛋白（APP）的病理淀粉样变性加工来保护神经元并诱导空间认知改善。本研究旨在探讨Nav β 2敲低是否通过调节A β降解酶neprilysin （NEP）改变APP代谢。采用携带Nav β 2敲低突变（APP/PS1/Nav β 2-kd）或不携带Nav β 2敲低突变（APP/PS1）的APPswe/PS1 Delta E9小鼠（具有C57BL/6J遗传背景的APP/PS1转基因小鼠）进行细胞培养和进一步分析。目前的研究结果表明，在APP/PS1小鼠来源的神经元中，Nav β 2敲低部分逆转了病理性APP切割的减少，以及神经突延伸和神经元面积的恢复。此外，Nav β 2敲除增加NEP活性和水平，以及细胞内结构域片段与NEP启动子结合的水平。目前的研究结果表明，Nav β 2的敲低可以通过调节NEP逆转APP/PS1突变诱导的淀粉样蛋白降解缺陷。
Voltage-gated sodium channel beta 2 (Nav beta 2), as an unconventional substrate of beta-site amyloid precursor protein cleaving enzyme 1, is involved in regulating the neuronal surface expression of sodium channels. A previous study demonstrated that knockdown of Nav beta 2 protected neurons and induced spatial cognition improvement by partially reducing pathological amyloidogenic processing of amyloid precursor protein (APP) in aged APP/presenilin 1 (PS1) transgenic mice. The present study aimed to investigate whether Nav beta 2 knockdown altered APP metabolism via regulation of the A beta-degrading enzyme neprilysin (NEP). APPswe/PS1 Delta E9 mice (APP/PS1 transgenic mice with a C57BL/6J genetic background) carrying a Nav beta 2-knockdown mutation (APP/PS1/Nav beta 2-kd) or without Nav beta 2 knockdown (APP/PS1) were used for cell culture and further analysis. The present results demonstrated that in APP/PS1 mouse-derived neurons, Nav beta 2 knockdown partially reversed the reduction in pathological APP cleavage, and the recovery of neurite extension and neuron area. Additionally, Nav beta 2 knockdown increased NEP activity and levels, and the levels of intracellular domain fragment binding to the NEP promoter. The present findings suggested that knockdown of Nav beta 2 reversed the APP/PS1 mutation-induced deficiency in amyloid beta degradation by regulating NEP.