Biological activity associated with a high molecular weight form of beta-amyloid

The pathogenesis of Alzheimer's disease is associated with the deposition o f aggregates or fibrils of beta-amyloid peptide in vulnerable areas of the brain. The precise identification of the form or forms of the peptide invol ved in this neurodegeneration is unclear. In this present report we have ch aracterized a biologically active form of the peptide by a number of assay systems designed to monitor the ability of the peptide to form fibrils. Uti lising the pH-dependent differences in the fibrillization profile, it has b een demonstrated that only peptide which is allowed to fibrillize at a pH c lose to 7.4 is biologically active. Although fibrillized material could be detected following incubation at a pH of 5.5 or 6.8, no biological activity was noted with these preparations. beta-amyloid, which had been fibrillize d at pH 7.4, was further analysed by gel electrophoresis and shown uniquely to contain a high molecular weight species of >250 kDa. Compounds such as hemin or daunomycin, which inhibit the fibrillization-dependent effects on biological activity, also prevent the production of this high molecular wei ght species. Thus, the neuronal cell loss observed in Alzheimer's disease m ay be associated with the formation and deposition of a large multimeric fo rm of the peptide.