Amyloid beta-protein fibrillogenesis - Structure and biological activity of protofibrillar intermediates

Alzheimer's disease is characterized by extensive cerebral amyloid depositi on. Amyloid deposits associated with damaged neuropil and blood vessels con tain abundant fibrils formed by the amyloid beta-protein (A beta). Fibrils, both in vitro and in vivo, are neurotoxic. For this reason, substantial ef fort has been expended to develop therapeutic approaches to control A beta production and amyloidogenesis. Achievement of the latter goal is facilitat ed by a rigorous mechanistic understanding of the fibrillogenesis process. Recently, we discovered a novel intermediate in the pathway of A beta fibri l formation, the amyloid protofibril (Walsh, D, RI,, Lomakin, A., Benedek, G. B., Condron, RI. Ri,, and Teplow, D. B. (1997) J. Biol. Chem. 272-, 2236 4-22372). We report here results of studies of the assembly, structure, and biological activity of these polymers. We find that protofibrils: 1) are i n equilibrium with low molecular weight A beta (monomeric or dimeric); 2) h ave a secondary structure characteristic of amyloid fibrils; 3) appear as b eaded chains in rotary shadowed preparations examined electron microscopica lly; 4) give rise to mature amyloid-like fibrils; and 5) affect the normal metabolism of cultured neurons. The implications of these results for the d evelopment of therapies for Alzheimer's disease and for our understanding o f fibril assembly are discussed.