title: Amyloid beta-protein fibrillogenesis. Structure and biological activity of protofibrillar intermediates.
abstract: Alzheimer's disease is characterized by extensive cerebral amyloid deposition. Amyloid deposits associated with damaged neuropil and blood vessels contain abundant fibrils formed by the amyloid beta-protein (Abeta). Fibrils, both in vitro and in vivo, are neurotoxic. For this reason, substantial effort has been expended to develop therapeutic approaches to control Abeta production and amyloidogenesis. Achievement of the latter goal is facilitated by a rigorous mechanistic understanding of the fibrillogenesis process. Recently, we discovered a novel intermediate in the pathway of Abeta fibril formation, the amyloid protofibril (Walsh, D. M., Lomakin, A., Benedek, G. B., Condron, M. M., and Teplow, D. B. (1997) J. Biol. Chem. 272, 22364-22372). We report here results of studies of the assembly, structure, and biological activity of these polymers. We find that protofibrils: 1) are in equilibrium with low molecular weight Abeta (monomeric or dimeric); 2) have a secondary structure characteristic of amyloid fibrils; 3) appear as beaded chains in rotary shadowed preparations examined electron microscopically; 4) give rise to mature amyloid-like fibrils; and 5) affect the normal metabolism of cultured neurons. The implications of these results for the development of therapies for Alzheimer's disease and for our understanding of fibril assembly are discussed.
authors.affiliation: Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Walsh
authors.forename: D M
authors.initials: DM
authors.lastname: Hartley
authors.forename: Y
authors.initials: Y
authors.lastname: Kusumoto
authors.forename: Y
authors.initials: Y
authors.lastname: Fezoui
authors.forename: M M
authors.initials: MM
authors.lastname: Condron
authors.forename: A
authors.initials: A
authors.lastname: Lomakin
authors.forename: G B
authors.initials: GB
authors.lastname: Benedek
authors.forename: D J
authors.initials: DJ
authors.lastname: Selkoe
authors.forename: D B
authors.initials: DB
authors.lastname: Teplow
mesh_terms: D000544:Alzheimer Disease; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism / Q000648:ultrastructure; D019281:Dimerization; D006801:Humans; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D016229:Amyloid beta-Peptides