Involvement of p75NTR in the effects of Aβ on L-type Ca2+ channel in cultured neuronal networks
Involvement of p75NTR in the effects of Aβ on L-type Ca2+ channel in cultured neuronal networks
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p75NTR 参与 Aβ 对培养神经元网络中 L 型 Ca2 通道的影响
DOI：
10.1016/j.lfs.2020.117293
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发表时间：
2020
期刊：
影响因子：
6.1
通讯作者：
Chongdong Jian
中科院分区：
文献类型：
--
作者：
Yifan Wang;Haidan Tang;Chengmin Yang;Hucheng Zhao;Chongdong Jian
神经元中的Ca 2+超载与阿尔茨海默病（AD）有关。已知通过L-型Ca 2+通道上调的Ca 2+参与了AD中淀粉样β（Aβ）肽诱导的神经变性。然而，关于L型Ca 2+通道电流上调与Aβ诱导的神经元毒性相关的机制知之甚少。在本研究中，我们发现转基因AD小鼠（Tg 2576）神经元中的L型Ca 2+电流大于野生型（WT）神经元，并且这种Ca 2+通道电流变化在Tg 2576/p75 NTR +/−（p75神经营养因子受体）神经元中被挽救。我们进一步检测了Aβ42处理后L-型钙通道门控的变化，结果表明Aβ42处理显著增加WT海马神经元L-型钙通道电流。阻断或降低p75 NTR的表达可消除Aβ42对WT海马神经元L型钙通道电流的影响。我们还评估了Aβ42如何影响培养WT神经元中L型Ca 2+通道的电压依赖性激活和失活。结果表明，Aβ42处理后，神经元的半最大激活电压（V1/2）左移，半失活电压（V1/2）右移。降低p75 NTR的表达可消除Aβ42对L型Ca 2+通道电压依赖性激活和失活的影响。这些结果表明，Aβ42通过调节通道的激活和失活动力学来改变L型Ca 2+通道电流，而降低p75 NTR表达可以消除这种作用。
Ca2+overload in neurons has been implicated in Alzheimer's Disease (AD). Upregulation of Ca2+through L-type Ca2+channels was known to be involved in the neurodegeneration induced by amyloid-β (Aβ) peptides in AD. However, little is known about the mechanism by which upregulation of L-type Ca2+channel currents is linked to Aβ-induced neuronal toxicity. In the present study, we found that the L-type Ca2+current in transgenic AD mice (Tg2576) neurons is greater than in wild-type (WT) neurons, and this Ca2+channel current change were rescued in Tg2576/p75NTR+/−(p75 neurotrophin receptor) neurons. We further examined the changes in the gating of L-type Ca2+channels following Aβ42 treatment, and the results showed that the L-type Ca2+channel current was significantly increased by Aβ42 treatment in WT hippocampal neurons. Blocking or decreasing the expression of p75NTR eliminated the influence of Aβ42 on the L-type Ca2+channel current in WT hippocampal neurons. We also evaluated how Aβ42 affected the voltage-dependent activation and inactivation of L-type Ca2+channels in cultured WT neurons. The results indicated that the half-maximal activation voltage (V1/2) was left shifted, and the half-inactivation voltage (V1/2) displayed a right shift in neuron treated by Aβ42. Decreasing the expression of p75NTR eliminated the effect of Aβ42 on voltage-dependent activation and inactivation of the L-type Ca2+channel. These results indicate that Aβ42 changes L-type Ca2+channel currents by modulating the channel's activation and inactivation dynamics, while decreasing p75NTR expression can remove this effect.