Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: Involvement of endoplasmic reticulum calcium release in oligomer-induced cell death
Neurotoxic effect of oligomeric and fibrillar species of amyloid-beta peptide 1-42: Involvement of endoplasmic reticulum calcium release in oligomer-induced cell death
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DOI：
10.1016/j.neuroscience.2008.06.036
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发表时间：
2008-08-26
期刊：
影响因子：
3.3
通讯作者：
De Oliveira, C. Resende
中科院分区：
文献类型：
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作者：
Resende, R.;Ferreiro, E.;De Oliveira, C. Resende
参与早期阿尔茨海默病 (AD) 病理学的淀粉样β肽 (Aβ) 的毒性形式的性质以及对神经元最有害的是纤维肽还是寡聚肽仍然存在争议。这项工作旨在比较不同淀粉样蛋白-β 肽 1-42 (A beta 1-42) 组装体的神经毒性，使用分别富含寡聚体和原纤维种类的新鲜和陈化样品，以及分离的寡聚体和原纤维。用新鲜和老化的 A beta 1-42 制剂获得的结果表明，寡聚物种类对培养物中的皮质神经元的毒性比纤维形式更大，这一点通过使用分离的寡聚物和原纤维得到证实。为了进一步阐明可溶性 Aβ 毒性的机制，评估了内质网 (ER) 钙 (Ca2+) 释放在寡聚物诱导的细胞凋亡中的作用。我们观察到寡聚 A beta 1-42 会消耗 ER Ca2+ 水平，导致细胞内 Ca2+ 稳态失调，涉及磷脂酶 C 激活。此外，在丹曲林（一种通过兰尼定受体释放 ER Ca2+ 的抑制剂）存在的情况下，寡聚体诱导的细胞凋亡被阻止，这证明了 ER Ca2+ 释放的参与。 (C) 2008 国际广播组织。由爱思唯尔有限公司出版。保留所有权利。
The nature of the toxic form of amyloid-beta peptide (A beta) involved in early Alzheimer's disease (AD) pathology and whether it is the fibrillar or the oligomeric peptide that is the most deleterious to neurons remain controversial. This work aimed to compare the neurotoxicity of different amyloid-beta peptide 1-42 (A beta 1-42) assemblies, using fresh and aged samples enriched in oligomeric and fibrillar species, respectively, and also isolated oligomers and fibrils. The results obtained with fresh and aged A beta 1-42 preparations suggested that oligomeric species are more toxic to cortical neurons in culture than fibrillar forms, which was confirmed by using isolated oligomers and fibrils. In order to further elucidate the mechanisms involved in soluble A beta toxicity, the involvement of endoplasmic reticulum (ER) calcium (Ca2+) release in oligomer-induced apoptosis was evaluated. We observed that oligomeric A beta 1-42 depletes ER Ca2+ levels leading to intracellular Ca2+ dyshomeostasis involving phospholipase C activation. Moreover, in the presence of dantrolene, an inhibitor of ER Ca2+ release through ryanodine receptors, the oligomer-induced apoptosis was prevented demonstrating the involvement of ER Ca2+ release. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.