The Ratio of Monomeric to Aggregated Forms of A 40 and A 42 Is an Important Determinant of Amyloid- Aggregation, Fibrillogenesis, and Toxicity*

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