AMYLOID-BETA AGGREGATION - SELECTIVE-INHIBITION OF AGGREGATION IN MIXTURES OF AMYLOID WITH DIFFERENT CHAIN LENGTHS

One of the clinical manifestations of Alzheimer's disease is the depos ition of the 39-43 residue amyloid-beta (A beta) peptide in aggregated fibrils in senile plaques. Characterization of the aggregation behavi or of A beta is one of the critical issues in understanding the role o f A beta in the disease process. Using solution hydrodynamics, A beta was observed to form three types of species in phosphate-buffered sali ne: insoluble aggregates with sedimentation coefficients of similar to 50,000 S and molecular masses of similar to 10(9) Da, ''soluble aggre gates'' with sedimentation coefficients of similar to 30 S and masses of similar to 10(6) Da, and monomer. When starting from monomer, the a ggregation kinetics of A beta 1-40 (A beta 40) and A beta 1-42 (A beta 42), alone and in combination, reveal large differences in the tenden cy of these peptides to aggregate as a function of pH and other soluti on conditions. At pH 4.1 and 7.0-7.4, aggregation is significantly slo wer than at pH 5 and 6. Under all conditions, aggregation of the longe r A beta 42 was more rapid than A beta 40. Oxidation of Met-35 to the sulfoxide in A beta 40 enhances the aggregation rate over that of the nonoxidized peptide. Aggregation was found to be dependent upon temper ature and to be strongly dependent on peptide concentration and ionic strength, indicating that aggregation is driven by a hydrophobic effec t. When A beta 40 and A beta 42 are mixed together, A beta 40 retards the aggregation of A beta 42 in a concentration-dependent manner. Shor ter fragments have a decreasing ability to interfere with A beta 42 ag gregation. Conversely, the rate of aggregation of A beta 40 can be sig nificantly enhanced by seeding slow aggregating solutions with preform ed aggregates of A beta 42. Taken together, the inhibition of A beta 4 2 aggregation by A beta 40, the seeding of A beta 40 aggregation by A beta 42 aggregates, and the chemical oxidation of A beta 40 suggest th at the relative abundance and rates of production of different-length A beta and its exposure to radical damage may be factors in the accumu lation of A beta in plaques in vivo.