Hertel C, Hauser N, Schubenel R, Seilheimer B, Kemp J A
Preclinical Research, Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
J Neurochem. 1996 Jul;67(1):272-6. doi: 10.1046/j.1471-4159.1996.67010272.x.
In an attempt to understand the cause of neurodegeneration in Alzheimer's disease, the toxic effects of beta-amyloid (Abeta) peptides have been widely studied. At high micromolar concentrations Abeta peptides have been demonstrated to be acutely toxic to various cell types. At submicromolar concentrations, Abeta peptides have been suggested to inhibit cellular metabolic activity, due to their inhibition of the ability of cells to metabolize the oxidoreductase substrate 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). Here we show, first, that MTT reduction surprisingly leads to a breakdown in PC12 cell membrane integrity and cell death, presumably through the formation of a crystalline formazan product, and, second, that pretreatment of PC12 cells with nanomolar concentrations of Abeta peptide, rather than inhibiting their metabolic activity, increases the susceptibility of these cells to the secondary toxic effect of formazan crystal formation. These results suggest that low nanomolar concentrations of Abeta render membranes more susceptible to damage by a secondary insult, in this case, MTT reduction. It is plausible that such an effect, when combined with additional risk factors, could contribute to the neurodegeneration that occurs in Alzheimer's disease.
为了试图理解阿尔茨海默病中神经退行性变的病因，β-淀粉样蛋白（Aβ）肽的毒性作用已得到广泛研究。在高微摩尔浓度下，Aβ肽已被证明对多种细胞类型具有急性毒性。在亚微摩尔浓度下，由于Aβ肽抑制细胞代谢氧化还原酶底物3-(4,5-二甲基噻唑-2-基)-2,5-二苯基四氮唑溴盐（MTT）的能力，有人提出其可抑制细胞代谢活性。在此我们首先表明，MTT还原令人惊讶地导致PC12细胞膜完整性破坏和细胞死亡，推测是通过形成结晶状甲臜产物；其次，用纳摩尔浓度的Aβ肽预处理PC12细胞，非但不抑制其代谢活性，反而增加了这些细胞对甲臜晶体形成的继发性毒性作用的敏感性。这些结果表明，低纳摩尔浓度的Aβ使细胞膜更容易受到继发性损伤的破坏，在这种情况下，即MTT还原。当这种效应与其他风险因素相结合时，有可能导致阿尔茨海默病中发生的神经退行性变。
