The Ca2+ channel inhibitor 2-APB reverses β-amyloid-induced LTP deficit in hippocampus by blocking BAX and caspase-3 hyperactivation
The Ca2+ channel inhibitor 2-APB reverses β-amyloid-induced LTP deficit in hippocampus by blocking BAX and caspase-3 hyperactivation
复制标题
Ca2 通道抑制剂 2-APB 通过阻断 BAX 和 caspase-3 过度激活来逆转海马中 β-淀粉样蛋白诱导的 LTP 缺陷
DOI：
10.1111/bph.13048
复制
发表时间：
2015-05-01
影响因子：
7.3
通讯作者：
Xiao, Zhi-Cheng
中科院分区：
文献类型：
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作者：
Hu, Wei-Yan;He, Zhi-Yong;Xiao, Zhi-Cheng
背景和目的在阿尔茨海默病(AD)的早期阶段，淀粉样蛋白(A)寡聚体的积聚扰乱了细胞内钙稳态，破坏了脑神经元的突触可塑性。预防A诱导的突触衰竭仍然是AD治疗中尚未解决的问题。在这里，我们探讨了2-氨基乙氧基二苯硼酸酯(2-APB)对A诱导的突触长时程增强(LTP)缺陷的影响及其可能的分子机制。研究方法包括电生理记录、膜蛋白提取、Western印迹分析和钙离子成像。关键结果：10M处的2-APB能有效逆转LTP寡聚体A(1-42)(500 Nm)对海马脑片LTP的抑制作用。2-APB还恢复了A处理的海马片中谷氨酸受体亚单位GluA1的磷酸化和转运，支持其对突触功能的保护作用。2-APB可阻断A介导的异常神经元[Ca~(2+)](I)对线粒体凋亡蛋白Bax、caspase-3和糖原合成酶-3的升高和过度激活。此外，APP(Swe)/PS1(E9)基因突变小鼠海马片的长时程增强缺陷可在10M时被2-APB挽救。结论和意义2-APB是一种潜在的保护突触可塑性的化学物质，可对抗A对AD的神经毒性作用。
Background and PurposeAt the early stage of Alzheimer's disease (AD), the accumulation of -amyloid (A) oligomers disturbs intracellular Ca2+ homeostasis and disrupts synaptic plasticity of brain neurons. Prevention of A-induced synaptic failure remains an unsolved problem for the treatment of AD. Here, the effects of 2-aminoethoxydiphenyl borate (2-APB), a non-specific, but moderately potent Ca2+ channel inhibitor, on A-induced deficit of synaptic long-term potentiation (LTP) and the underlying molecular mechanisms were explored.Experimental ApproachWe used hippocampal slices and primary cultures of hippocampal neurons from C57BL/6 mice. Methods applied in our study included electrophysiological recording, membrane protein extraction, Western blot assay and Ca2+ imaging.Key Results2-APB at 10M effectively reversed suppression by oligomeric A(1-42) (500nM) of LTP in hippocampal slices. 2-APB also restored phosphorylation and trafficking of the glutamate receptor subunit GluA1 in A-treated hippocampal slices, supporting its protective action on synaptic function. A-mediated abnormal neuronal [Ca2+](i) elevation and hyperactivation of the mitochondrial apoptotic proteins BAX, caspase-3, and glycogen synthase kinase-3, were blocked by 2-APB pretreatment. Moreover, the defict in long term potentiation deficit in hippocampal slices from APP(swe)/PS1(E9) gene mutant mice was rescued by 2-APB at 10M.Conclusions and ImplicationThese data demonstrate that 2-APB is a potentially useful chemical to protect synaptic plasticity against neurotoxic effects of A in AD.