AMYLOIDOGENICITY OF RODENT AND HUMAN BETA-A4 SEQUENCES

Previously we have shown that aggregation of the C-terminal 100 residues (A4CT) of the betaA4 amyloid protein precursor (APP) and also of betaA4 itself depends on the presence of metal-catalyzed oxidation systems [T. Dyrks et al. (1988) EMBO J. 7, 949-957]. We showed that aggregation of the amyloidogenic peptides induced by radical generation systems requires amino acid oxidation and protein cross-linking. Here we report that aggregation of A4CT and betaA4 induced by radical generation systems involves oxidation of histidine, tyrosine and methionine residues. The rodent betaA4 sequence lacking the single tyrosine and one of the three histidine residues of human betaA4 and a betaA4 variant in which the tyrosine and the three histidine residues were replaced showed a reduced tendency for aggregation. Thus our results may explain why betaA4 amyloid deposits could so far not been detected in the rodent brain.