Calcium signals induced by amylold β peptide and their consequences in neurons and astrocytes in culture
Calcium signals induced by amylold β peptide and their consequences in neurons and astrocytes in culture
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DOI：
10.1016/j.bbamcr.2004.09.006
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发表时间：
2004-12-06
影响因子：
5.1
通讯作者：
Duchen, MR
中科院分区：
文献类型：
--
作者：
Abramov, AY;Canevari, L;Duchen, MR
在阿尔茨海默病中，淀粉样β蛋白(Abeta)多肽沉积在大脑的神经炎斑块中。Abeta多肽1-42或片段2535具有神经毒性。在此，我们回顾了我们最近在海马区培养的Abeta毒性机制方面的探索。Abeta对神经细胞内钙离子无影响，但引起邻近星形胶质细胞的显着变化。[Ca(2+)]_2信号类似于Aβ作用后5-15分钟开始，由零星的[Ca~(2+)](C)脉冲组成。这些钙离子完全依赖于胞外Ca(2+)，而不依赖于内质网钙(2+)的储存，可能是通过Abeta诱导的膜通道引起的。Ca(2+)信号与一过性、间歇性酸化密切相关，这种酸化可能反映质子从结合部位移位或Ca(2+)/2H(+)交换。Abeta导致活性氧物种(ROS)的生成率增加，在星形胶质细胞中也可以看到，但在神经元中没有。增加的ROS生成被NADPH氧化酶的抑制剂所阻断，这强烈地表明这种通常与免疫细胞相关的酶在星形胶质细胞中表达。ROS的产生也是依赖于Ca(2+)的，这表明酶的Abeta激活可能次于[Ca(2+)](C)的增加。Abeta导致迟发性神经元死亡，尽管所有的反应都只在星形胶质细胞中看到。谷氨酸受体拮抗剂不能保护神经元，但可以通过抑制NADPH氧化酶、抗氧化剂和增加谷胱甘肽来拯救神经元。这些数据表明，Abeta通过激活星形细胞中的NADPH氧化酶导致钙依赖的氧化应激，神经元死亡是由于抗氧化剂支持的失败。(C)2004爱思唯尔B.V.保留所有权利。
In Alzheimer's disease, amyloid beta (Abeta) peptide is deposited in neuritic plaques in the brain. The Abeta peptide 1-42 or the fragment 2535 are neurotoxic. We here review our recent explorations of the mechanisms of Abeta toxicity in hippocampal cultures. Abeta had no effect on intracellular calcium in neurons but caused striking changes in nearby astrocytes. The [Ca(2+)], signals started similar to5-15 min after Abeta application and consisted of sporadic [Ca(2+)](c) pulses. These were entirely dependent on extracellular Ca(2+), independent of ER Ca(2+) stores and resulted from Ca(2+) influx, probably through Abeta-induced membrane channels. The Ca(2+) signals were closely associated with transient, episodic acidification which may reflect displacement of protons from binding sites or Ca(2+)/2H(+) exchange. Abeta caused all increased rate of generation of reactive oxygen species (ROS), also seen in astrocytes and not in neurons. The increased ROS generation was blocked by inhibitors of the NADPH oxidase, strongly Suggesting that this enzyme, normally associated with immune cells, is expressed in astrocytes. ROS generation was also Ca(2+)-dependent, Suggesting that Abeta activation of the enzyme may be secondary to the increase in [Ca(2+)](c). Abeta caused delayed neuronal death despite the fact that all responses were seen only in astrocytes. Neurons could not be protected by glutamate receptor antagonists, but were rescued by inhibition of the NADPH oxidase, by antioxidants and by increasing glutathione. These data suggest that Abeta causes Ca(2+)-dependent oxidative stress by activating an astrocytic NADPH oxidase, and that neuronal death follows through a failure of antioxidant support. (C) 2004 Elsevier B.V. All rights reserved.