MECHANOCHEMICAL MECHANISM FOR PEPTIDYL FREE-RADICAL GENERATION BY AMYLOID FIBRILS

beta-Amyloid peptides (A beta) form the core of Alzheimer's disease (A D) senile plaques, and are implicated in AD neurotoxicity. A beta and some derivatives generate free radicals upon fibrilogenesis. A mechani sm for free radical generation is proposed, based upon fibril cross be ta-sheet structure: (1) During fibrilogenesis there is a small probabi lity of mispacking of A beta monomers, resulting in abnormal fibril pa cking, (2) Continued fibrilogenesis traps a packing defect within the beta-sheet, Surrounding beta-sheet resists distortion, and the abnorma lly packed polypeptide(s) is strained, (3) Thermal processes cause hom olytic bond scission and radical production from strained polypeptide through mechanically activated thermal decomposition, (4) Reaction wit h oxygen produces peroxy radicals, prevents unproductive radical recom bination, and promotes observed cross-linking, production of reactive oxygen species and peptide fragmentation, Adiabatic mapping suggested significant strain would be generated by beta-sheet misalignment. The mechanism relates the common structure of fibrils to radical productio n, and may be relevant to cytotoxicity in prion and other amyloidoses. (C) 1997 Federation of European Biochemical Societies.