title: The C-terminus of the beta protein is critical in amyloidogenesis.
abstract: The beta amyloid protein found in extracellular deposits in Alzheimer's disease (AD) is heterogeneous at its C-terminus; proteins ending at residues 40, 42, and 43 have been identified in neuritic deposits, while protein in vascular amyloid appears to end at residue 39 or 40. Studies of synthetic beta proteins (beta 1-39, beta 1-40, beta 1-42), and model peptides (beta 26-39, beta 26-40, beta 26-42, beta 26-43) demonstrate that amyloid formation is a nucleation-dependent phenomenon. Peptides ending at residues 39 or 40 were kinetically soluble for hours to days, while peptides ending at residues 42 or 43 aggregated immediately; all eventually reached similar thermodynamic solubility. The kinetically soluble variants could be seeded with the kinetically insoluble variants. The secondary structure of beta 26-39 fibrils was different from that of beta 26-42 fibrils, however, seeding beta 26-39 with beta 26-42 produces mixed fibrils with structure similar to beta 26-42. These results suggest that neuritic plaques may be seeded by their minor component; this may determine the structure and properties of amyloid in AD.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, Cambridge 02139.
authors.forename: J T
authors.initials: JT
authors.lastname: Jarrett
authors.forename: E P
authors.initials: EP
authors.lastname: Berger
authors.forename: P T
authors.initials: PT
authors.lastname: Lansbury
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000682:Amyloid / Q000096:biosynthesis* / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000378:metabolism
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments