Inhibition of Amyloid β Protein Aggregation and Neurotoxicity by Rifampicin 论文

摘要

Aggregation of physiologically produced soluble amyloid beta protein (Abeta) to insoluble, neurotoxic fibrils is a crucial step in the pathogenesis of Alzheimer's disease. Aggregation studies with synthetic Abeta1-40 peptide by the thioflavin T fluorescence assay and electron microscopy and cytotoxicity assays using rat pheochromocytoma PC12 cells showed that an antibiotic, rifampicin, and its derivatives, which possess a naphthohydroquinone or naphthoquinone structure, inhibited Abeta1-40 aggregation and neurotoxicity in a concentration-dependent manner. Hydroquinone, p-benzoquinone, and 1,4dihydroxynaphthalene, which represent partial structures of the aromatic chromophore of rifampicin derivatives, also inhibited A beta1 40 aggregation and neurotoxicity at comparable molar concentrations to rifampicin. Electron spin resonance spectrometric analysis revealed that the inhibitory activities of those agents correlated with their radical-scavenging ability on hydroxyl free radical, which was shown to be generated in cell-free incubation of Abeta1-40 peptide. These results suggest that at least one mechanism of rifampicin-mediated inhibition of A beta aggregation and neurotoxicity involves scavenging of free radicals and that rifampicin and/or appropriate hydroxyl radical scavengers may have therapeutic potential for Alzheimer's disease.