P4-289: Normal healthy donors possess plasma IgG reactive to a neutralizing epitope for toxic and amyloid-seeding beta-amyloid oligomers

Computational chemistry methods have been applied to investigate the observed decrease in affinity.Results:As expected, the Swedishmutation peptide showed the highest maximum velocity, while the KM value was comparable to that for the wild-type substrate. The A673T mutation substrate yielded a Vmax value in the same range as the wild-type, but the KM value was increased by 50 fold. These results suggest the turnover rate of the enzyme-peptide complex is not affected by the mutation on the peptide. However, interpreting KM as a surrogate for affinity, the mutation reduces the affinity of the substrate for the enzyme. Preliminary modelingresults indicate that suboptimal interaction between BACE and the T673 hydroxyl group, which do not offset its increase desolvation, might be one of the reasons affecting the free energy of binding of the mutant. We also confirmed previous observations that in cells overexpressing APPA673T, soluble APP beta (sAPPb) secretion, primary product of BACE1 cleavage, is reduced by 50% compared to cells overexpressing the wild type construct. Conclusions: Taken together, this data suggest that a reduction of BACE affinity for this mutated APP explains how it may protect against Alzheimer’s disease. Thus providing strong evidence that reducing BACE activity by inhibitors may be beneficial for the treatment of AD.