Furukawa K, Mattson M P
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
J Neurochem. 1995 Sep;65(3):1061-8. doi: 10.1046/j.1471-4159.1995.65031061.x.
Increasing data suggest that the amyloid beta-peptide (A beta), which accumulates in the brains of Alzheimer's victims, plays a role in promoting neuronal degeneration. Cell culture studies have shown that A beta can be neurotoxic and recent findings suggest that the mechanism involves destabilization of cellular calcium homeostasis. We now report that cytochalasin D, a compound that depolymerizes actin microfilaments selectively, protects cultured rat hippocampal neurons against A beta neurotoxicity. Cytochalasin D was effective at concentrations that depolymerized actin (10-100 nM). The elevation of [Ca2+]i induced by A beta, and the enhancement of [Ca2+]i responses to glutamate in neurons exposed to A beta, were markedly attenuated in neurons pretreated with cytochalasin D. The protective effect of cytochalasin D appeared to result from a specific effect on actin filaments and reduction in calcium influx, because cytochalasin E, another actin filament-disrupting agent, also protected neurons against A beta toxicity; the microtubule-disrupting agent colchicine was ineffective; cytochalasin D did not protect neurons against the toxicity of hydrogen peroxide. These findings suggest that actin filaments play a role in modulating [Ca2+]i responses to neurotoxic insults and that depolymerization of actin can protect neurons against insults relevant to the pathogenesis of Alzheimer's disease.
越来越多的数据表明，在阿尔茨海默病患者大脑中积累的β-淀粉样肽（Aβ）在促进神经元变性中起作用。细胞培养研究表明，Aβ具有神经毒性，最近的研究结果表明其机制涉及细胞钙稳态的破坏。我们现在报告，细胞松弛素D，一种能选择性地使肌动蛋白微丝解聚的化合物，可保护培养的大鼠海马神经元免受Aβ神经毒性的影响。细胞松弛素D在使肌动蛋白解聚的浓度（10-100 nM）下有效。在用细胞松弛素D预处理的神经元中，Aβ诱导的[Ca2+]i升高以及暴露于Aβ的神经元中[Ca2+]i对谷氨酸反应的增强均明显减弱。细胞松弛素D的保护作用似乎源于对肌动蛋白丝的特异性作用和钙内流的减少，因为另一种肌动蛋白丝破坏剂细胞松弛素E也能保护神经元免受Aβ毒性的影响；微管破坏剂秋水仙碱无效；细胞松弛素D不能保护神经元免受过氧化氢的毒性。这些发现表明，肌动蛋白丝在调节对神经毒性损伤的[Ca2+]i反应中起作用，并且肌动蛋白的解聚可以保护神经元免受与阿尔茨海默病发病机制相关的损伤。
