Mechanochemical mechanism for peptidyl free radical generation by amyloid fibrils.
beta-Amyloid peptides (A beta) form the core of Alzheimer's disease (AD) senile plaques, and are implicated in AD neurotoxicity. A beta and some derivatives generate free radicals upon fibrilogenesis. A mechanism for free radical generation is proposed, based upon fibril cross beta-sheet structure: (1) During fibrilogenesis there is a small probability of mispacking of A beta monomers, resulting in abnormal fibril packing. (2) Continued fibrilogenesis traps a packing defect within the beta-sheet. Surrounding beta-sheet resists distortion, and the abnormally packed polypeptide(s) is strained. (3) Thermal processes cause homolytic bond scission and radical production from strained polypeptide through mechanically activated thermal decomposition. (4) Reaction with oxygen produces peroxy radicals, prevents unproductive radical recombination, 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 production, and may be relevant to cytotoxicity in prion and other amyloidoses.
Kay
C J
CJ
Department of Biochemistry and Molecular Biology, University of South Florida College of Medicine, Tampa 33612, USA. ckay@com 1.med.usf.edu
D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity; D005349:Fibroins / Q000737:chemistry; D005609:Free Radicals; D008956:Models, Chemical; D008958:Models, Molecular; D010100:Oxygen / Q000378:metabolism; D010455:Peptides / Q000378:metabolism* / Q000633:toxicity; D011489:Protein Denaturation; D017433:Protein Structure, Secondary; D013314:Stress, Mechanical
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D010455:Peptides; D005349:Fibroins; D010100:Oxygen