Amyloidogenicity of rodent and human beta A4 sequences

Previously we have shown that aggregation of the C-terminal 100 residues (A4CT) of the beta A4 amyloid protein precursor (APP) and also of beta A4 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 beta A4 induced by radical generation systems involves oxidation of histidine, tyrosine and methionine residues. The rodent beta A4 sequence lacking the single tyrosine and one of the three histidine residues of human beta A4 and a beta A4 variant in which the tyrosine and the three histidine residues were replaced showed a reduced tendency for aggregation. Thus our results may explain why beta A4 amyloid deposits could so far not been detected in the rodent brain.