Redox modulation of long-term potentiation in the hippocampus via regulation of the glycogen synthase kinase-3β pathway
Redox modulation of long-term potentiation in the hippocampus via regulation of the glycogen synthase kinase-3β pathway
复制标题
通过调节糖原合酶激酶-3β 途径对海马长时程增强进行氧化还原调节。
DOI：
10.1016/j.freeradbiomed.2008.06.014
复制
发表时间：
2008-10-01
影响因子：
7.4
通讯作者：
Chen, Jian-Guo
中科院分区：
文献类型：
--
作者：
Cai, Fei;Wang, Fang;Chen, Jian-Guo
阿尔茨海默病是一种与年龄相关的神经退行性疾病。许多观察表明，AD合并突触衰竭与氧化还原调节受损有关。本研究的目的是研究氧化还原激动剂在大鼠海马片CA1区长时程增强(LTP)中的作用，并阐明导致这些变化的分子序列。结果表明，膜透性氧化剂氯胺-T(CH-T)抑制LTP的诱导，而膜透性还原剂二硫苏糖醇(DTT)则增强LTP的诱导。而膜不透性氧化剂5，5‘-二硫代双(2-硝基苯甲酸)(DTNB)和膜不透性还原剂三(2-羧乙基)膦(TCEP)均不影响LTP的诱导。DTT对LTP的抑制作用可被DTT恢复，但TCEP不能恢复；而DTT对LTP的增强作用可被CH-T逆转，但不能被DTNB逆转。我们还提供了证据表明，CH-T对LTP的抑制是通过激活糖原合成酶激酶-3β(GSK-3β)来实现的，而对LTP的增强作用则是通过失活GSK-3β来实现的。这些发现将有助于理解氧化还原在突触可塑性和AD发病机制中的作用。
Alzheimer disease (AD) is an age-related neurodegenerative disorder. Many observations indicate that impaired redox regulation is implicated in AD with synaptic failure. The aim of the current investigation was to characterize the role of redox-active agents on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices and to elucidate the molecular sequence of events leading to these changes. The results presented here indicate that the membrane-permeable oxidizing agent chloramine-T (CH-T) inhibits the induction of LTP, whereas the membrane-permeable reducing agent dithiothreitol (DTT) enhances the induction of LTP. In contrast, neither the membrane-impermeable oxidizing agent 5,5′-dithio-bis-(2-nitrobenzoic acid) (DTNB) nor the membrane-impermeable reducing agent tris-(2-carboxyethyl) phosphine (TCEP) can affect the induction of LTP. The inhibition of LTP by CH-T can be restored by pretreatment with DTT but not with TCEP, whereas the enhancement of LTP by DTT can be reversed by pretreatment with CH-T but not with DTNB. We also provide evidence that the CH-T-evoked inhibition of LTP is mediated via activation of glycogen synthase kinase-3β (GSK-3β), whereas the DTT-evoked enhancement of LTP is mediated via inactivation of GSK-3β. These findings will benefit the understanding of the redox contribution to the mechanisms underlying synaptic plasticity and AD pathogenesis.