Janciauskiene S, Wright H T, Lindgren S
Gastroenterology-Hepatology Division, Department of Medicine, University Hospital, Malmö, Sweden.
Neuropeptides. 1999 Dec;33(6):510-6. doi: 10.1054/npep.1999.0771.
Amyloid forming peptides are known to disturb vital cellular functions and induce cell death. However, the mechanisms by which fibrillogenic peptides induce cytotoxic effects in various cells has not been established. In this study the effects on low density lipoprotein binding and uptake of fibrils of the Alzheimer's amyloid beta-peptide (Abeta(1-42)), which is known to play a central role in the pathogenesis of Alzheimer's disease, were investigated in pheochromocytoma PC12 cells. Fibrillar Abeta(1-42) at micromol concentrations increased low-density lipoprotein (LDL) binding and cell association by 460% and 200% respectively, and LDL degradation by about 62%. Approximately 49% and 34% of Abeta fibril stimulated LDL cell association and degradation was inhibited by anti-LDL receptor antibodies. The soluble form of Abeta had no effect on any of these measures of LDL metabolism. The observed increased glutathione reductase activity, DNA fragmentation (TUNEL assay) and decreased DNA synthesis ([(3)H] thymidine incorporation assay) in cells treated with Abeta(1-42) fibrils alone or together with LDL relative to controls, suggests that the interaction of fibrils with LDL receptors might be one possible pathway which contributes to fibril cytotoxicity.
已知形成淀粉样蛋白的肽会干扰重要的细胞功能并诱导细胞死亡。然而，原纤维形成肽在各种细胞中诱导细胞毒性作用的机制尚未明确。在本研究中，我们在嗜铬细胞瘤PC12细胞中研究了阿尔茨海默病淀粉样β肽（Abeta(1-42)）的原纤维对低密度脂蛋白结合和摄取的影响，该肽在阿尔茨海默病发病机制中起核心作用。微摩尔浓度的原纤维状Abeta(1-42)分别使低密度脂蛋白（LDL）结合和细胞结合增加了460%和200%，并使LDL降解增加了约62%。抗LDL受体抗体抑制了约49%和34%的Abeta原纤维刺激的LDL细胞结合和降解。Abeta的可溶形式对这些LDL代谢指标均无影响。相对于对照组，单独用Abeta(1-42)原纤维或与LDL一起处理的细胞中观察到谷胱甘肽还原酶活性增加（TUNEL检测）、DNA片段化增加以及DNA合成减少（[³H]胸苷掺入检测），这表明原纤维与LDL受体之间的相互作用可能是导致原纤维细胞毒性的一种可能途径。
