ALUMINUM, IRON, AND ZINC IONS PROMOTE AGGREGATION OF PHYSIOLOGICAL CONCENTRATIONS OF BETA-AMYLOID PEPTIDE

A major pathological feature of Alzheimer's disease (AD) is the presen ce of a high density of amyloid plaques in the brain tissue of patient s. The plaques are predominantly composed of human beta-amyloid peptid e betaA4, a 40-mer whose neurotoxicity is related to its aggregation. Certain metals have been proposed as risk factors for AD, but the mech anism by which the metals may exert their effects is unclear. Radioiod inated human betaA4 has been used to assess the effects of various met als on the aggregation of the peptide in dilute solution (1 0(-10) M). In physiological buffers, 10(-3) M calcium, cobalt, copper, manganese , magnesium, sodium, or potassium had no effect on the rate of betaA4 aggregation. In sharp contrast, aluminum, iron, and zinc under the sam e conditions strongly promoted aggregation (rate enhancement of 1 00-1 ,000-fold). The aggregation of betaA4 induced by aluminum and iron is distinguishable from that induced by zinc in terms of rate, extent, pH and temperature dependence. These results suggest that high concentra tions of certain metals may play a role in the pathogenesis of AD by p romoting aggregation of betaA4.