Attenuation of beta-amyloid neurotoxicity in vitro by potassium-induced depolarization.
Attenuation of beta-amyloid neurotoxicity in vitro by potassium-induced depolarization.
复制标题
通过钾诱导的去极化在体外减弱β-淀粉样蛋白神经毒性。
DOI：
10.1046/j.1471-4159.1996.67041774.x
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发表时间：
1996
影响因子：
4.7
通讯作者：
Cotman,CW
中科院分区：
文献类型：
--
作者：
Pike,CJ;Balázs,R;Cotman,CW
由β-淀粉样多肽引发的培养神经元的细胞死亡已经被理论上模拟了至少部分与阿尔茨海默病相关的神经退行性变。为了研究在体外阻断β-淀粉样蛋白神经毒性的可能策略，我们研究了钾诱导的膜去极化的影响；这是一种先前证明可以减少培养神经元发育相关的细胞凋亡的治疗方法。我们在这里报道，培养的大鼠海马神经元用30mMKCI预处理几个小时后，对聚集的β-淀粉样多肽的易感性显著降低。用电压依赖性钙通道阻断剂r(+)-Bay K8644和钙/钙调素依赖性蛋白激酶II抑制剂KN-62减弱钾离子介导的神经保护作用。蛋白质合成抑制剂放线菌酮也可减轻β-淀粉样蛋白的神经毒性。30mMKCI后加入放线菌酮显著增加了膜去极化的保护作用，而在膜去极化时加入放线菌亚胺则阻断了这种保护作用。这些数据表明，抑制β-淀粉样蛋白诱导的神经元死亡的一种细胞途径是通过电压敏感通道的钙内流，然后刺激钙/钙调蛋白依赖的蛋白激酶活性和新蛋白质的合成(S)。
The cell death of cultured neurons triggered by β‐amyloid peptides has been theorized to model, at least in part, the neurodegeneration associated with Alzheimer's disease. To investigate potential strategies to interrupt β‐amyloid neurotoxicity in vitro, we examined the effects of potassium‐induced membrane depolarization; a treatment previously demonstrated to reduce development‐related apoptosis in cultured neurons. We report here that cultured rat hippocampal neurons pretreated for several hours with 30 mMKCI exhibit significantly reduced vulnerability to aggregated β‐amyloid peptides. The potassium‐mediated neuroprotection was mimicked by activation of voltage‐sensitive calcium channels usingS(−)‐Bay K 8644 and was attenuated byR(+)‐Bay K 8644, a blocker of voltage‐dependent calcium channels, and KN‐62, an inhibitor of calcium/calmodulin‐dependent protein kinase II. The protein synthesis inhibitor cycloheximide also attenuated β‐amyloid neurotoxicity. Addition of cycloheximide following 30 mMKCI significantly increased protection offered by membrane depolarization, whereas cycloheximide addition during membrane depolarization blocked the protective effect. These data suggest that one cellular pathway that can inhibit neuronal death induced by β‐amyloid involves calcium influx through voltage‐sensitive channels followed by stimulation of calcium/calmodulin‐dependent protein kinase activity and synthesis of new protein(s).