Resistance to the apoptotic effect of aggregated amyloid-beta peptide in several different cell types including neuronal- and hepatoma-derived cell lines.
Resistance to the apoptotic effect of aggregated amyloid-beta peptide in several different cell types including neuronal- and hepatoma-derived cell lines.
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DOI：
10.1042/bj3320517
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发表时间：
1998-06
期刊：
影响因子：
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通讯作者：
M. Mazziotti;D. Perlmutter
中科院分区：
文献类型：
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作者：
M. Mazziotti;D. Perlmutter
有大量文献表明聚集的淀粉样β肽（Abeta）对神经元有毒，并表明这种神经毒性代表阿尔茨海默病中神经元变性的最终共同途径。先前的研究已经表明，如果亲本细胞系在聚集的A β肽存在下生长许多代，则大鼠神经元细胞系PC 12的亚克隆的生长对聚集的A β肽的毒性作用具有抗性[Behl，Davis，Lesley和Schubert（1994）Cell 77，817-827; Boland，Behrens，Choi，Manias和Perlmutter（1996）J.Biol.Chem.271，18032-18044]。为了开始表征PC 12细胞对Abeta肽的凋亡作用产生抗性的机制，在本研究中，我们检查了抗性是否特异于聚集的肽、特异于细胞死亡的凋亡形式和特异于细胞类型，或者是可以在不同细胞类型中引起的对细胞死亡的一般抗性。结果表明，抗性特异于通过产生羟基自由基或H2 O2具有凋亡作用的化合物，包括聚集的Abeta-（25-35）、Abeta-（1-40）、Abeta-（1-42）、Abeta-（1-43）、胰淀素、6-羟基多巴胺和H2 O2本身。PC 12的抗性亚克隆对其他形式的凋亡性细胞死亡或坏死性细胞死亡没有抗性。当人肝癌细胞系HepG 2在存在聚集的Abeta-（25-35）的情况下生长几代时，也在该细胞系中鉴定出抗性状态，这表明导致该抗性的机制或分子不限于神经元细胞，并且可能与其他细胞类型中的氧化损伤的病理生物学相关。
There is a large body of literature indicating that aggregated amyloid-beta peptide (Abeta) is toxic to neurons and suggesting that this neurotoxicity represents the final common pathway for neuronal degeneration in Alzheimer's disease. Previous studies have shown the outgrowth of a subclone of the rat neuronal cell line PC12 that is resistant to the toxic effect of aggregated Abeta peptide if the parent cell line is grown in the presence of aggregated Abeta peptide for a number of passages [Behl, Davis, Lesley and Schubert (1994) Cell 77, 817-827; Boland, Behrens, Choi, Manias and Perlmutter (1996) J. Biol. Chem. 271, 18032-18044]. To begin to characterize the mechanism by which PC12 cells become resistant to the apoptotic effect of Abeta peptide, in the present study we examined whether the resistance was specific to aggregated peptides, specific to an apoptotic form of cell death, and specific in cell type or was a general resistance to cell death that could be elicited in diverse cell types. The results show that the resistance is specific to compounds that have apoptotic effects through the generation of hydroxyl radical or H2O2, including aggregated Abeta-(25-35), Abeta-(1-40), Abeta-(1-42), Abeta-(1-43), amylin, 6-hydroxydopamine and H2O2 itself. The resistant subclones of PC12 were not resistant to other forms of apoptotic cell death or to necrotic cell death. The resistant state was also identified in a human hepatoma cell line, HepG2, when it was grown in the presence of aggregated Abeta-(25-35) for several passages, indicating that the mechanism(s) or molecule(s) responsible for this resistance are not restricted to neuronal cells and may be relevant to the pathobiology of oxidative injury in other cell types.