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.

中文翻译：

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p75NTR参与Aβ对培养的神经元网络中L型Ca2 +通道的影响。

神经元中的Ca2 +超负荷与阿尔茨海默氏病（AD）有关。已知通过L型Ca2 +通道对Ca2 +的上调与AD中淀粉样蛋白-β（Aβ）肽诱导的神经变性有关。然而，关于L型Ca2 +通道电流的上调与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（Tg2576）神经元中的L型Ca2 +电流大于野生型（WT）神经元中的L型Ca2 +电流，并且在Tg2576 / p75NTR +/-（p75神经营养蛋白受体）神经元。我们进一步检查了Aβ42处理后L型Ca2 +通道门控的变化，结果表明，Aβ42处理可显着增加野生型海马神经元的L型Ca2 +通道电流。阻断或降低p75NTR的表达消除了Aβ42对野生型海马神经元L型Ca2 +通道电流的影响。我们还评估了Aβ42如何影响培养的WT神经元中L型Ca2 +通道的电压依赖性激活和失活。结果表明，在用Aβ42处理的神经元中，最大激活电压（V1 / 2）向左移动一半，而最大灭活电压（V1 / 2）向右移动。减少p75NTR的表达消除了Aβ42对电压依赖性激活和L型Ca2 +通道失活的影响。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Ca2 +通道电流，而降低p75NTR表达可以消除这种影响。