THE CARBOXY TERMINUS OF THE BETA-AMYLOID PROTEIN IS CRITICAL FOR THE SEEDING OF AMYLOID FORMATION - IMPLICATIONS FOR THE PATHOGENESIS OF ALZHEIMERS-DISEASE

Several variants of the beta amyloid protein, differing only at their carboxy terminus (beta1-39, beta1-40, beta1-42, and beta1-43), have been identified as the major components of the cerebral amyloid deposits which are characteristic of Alzheimer's disease. Kinetic studies of aggregation by three naturally occurring beta protein variants (beta1-39, beta1-40, beta1-42) and four model peptides (beta26-39, beta26-40, beta26-42, beta26-43) demonstrate that amyloid formation, like crystallization, is a nucleation-dependent phenomenon. This discovery has practical consequences for studies of the beta amyloid protein. The length of the C-terminus is a critical determinant of the rate of amyloid formation (''kinetic solubility'') but has only a minor effect on the thermodynamic solubility. Amyloid formation by the kinetically soluble peptides (e.g., beta1-39, beta1-40, beta26-39, beta26-40) can be nucleated, or ''seeded'', by peptides which include the critical C-terminal residues (beta1-42,beta26-42,beta26-43,beta34-42). These results suggest that nucleation may be the rate-determining step of in vivo amyloidogenesis and that beta1-42 and/or beta1-43, rather than beta1-40, may be the pathogenic protein(s) in AD.