Alzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor

The amyloid-␤ (A␤) peptide is neurotoxic and associated with the pathology of Alzheimer's disease (AD).We investigated the effect of A␤ peptides on insulin binding to the insulin receptor because it is known that (1) A␤ and insulin are both amyloidogenic peptides sharing a common sequence recognition motif, (2) A␤ and insulin are substrates for the same insulin degrading enzyme, and (3) impaired glucose metabolism is a characteristic event in the pathology of AD.We discovered that A␤ 1-40 and A␤ 1-42, the main physiological forms, reduced insulin binding and receptor autophosphorylation.The reduction in binding was caused by a decrease in the affinity of insulin binding to the insulin receptor.This reduction was independent of the receptor concentration.The reverse, control peptide A␤ 40-1 did not reduce insulin binding or insulin receptor autophosphorylation.These results demonstrate that A␤ is a direct competitive inhibitor of insulin binding and action.We speculate that the increased levels of A␤ in Alzheimer's disease may be linked to the associated insulin resistance that has been observed previously in this disease.