The ratio of monomeric to aggregated forms of Aβ40 and Aβ42 is an important determinant of amyloid-β aggregation, fibrillogenesis, and toxicity

Aggregation and fibril formation of amyloid-beta (A beta) peptides A beta 40 and A beta 42 are central events in the pathogenesis of Alzheimer disease. Previous studies have established the ratio of A beta 40 to A beta 42 as an important factor in determining the fibrillogenesis, toxicity, and pathological distribution of A beta. To better understand the molecular basis underlying the pathologic consequences associated with alterations in the ratio of A beta 40 to A beta 42, we probed the concentration- and ratio-dependent interactions between well defined states of the two peptides at different stages of aggregation along the amyloid formation pathway. We report that monomeric A beta 40 alters the kinetic stability, solubility, and morphological properties of A beta 42 aggregates and prevents their conversion into mature fibrils. A beta 40, at approximately equimolar ratios (A beta 40/A beta 42 similar to 0.5-1), inhibits (> 50%) fibril formation by monomeric A beta 42, whereas inhibition of protofibrillar A beta 42 fibrillogenesis is achieved at lower, substoichiometric ratios (A beta 40/A beta 42 similar to 0.1). The inhibitory effect of A beta 40 on A beta 42 fibrillogenesis is reversed by the introduction of excess A beta 42 monomer. Additionally, monomeric A beta 42 and A beta 40 are constantly recycled and compete for binding to the ends of protofibrillar and fibrillar A beta aggregates. Whereas the fibrillogenesis of both monomeric species can be seeded by fibrils composed of either peptide, A beta 42 protofibrils selectively seed the fibrillogenesis of monomeric A beta 42 but not monomeric A beta 40. Finally, we also show that the amyloidogenic propensities of different individual and mixed A beta species correlates with their relative neuronal toxicities. These findings, which highlight specific points in the amyloid peptide equilibrium that are highly sensitive to the ratio of A beta 40 to A beta 42, carry important implications for the pathogenesis and current therapeutic strategies of Alzheimer disease.