Structural conversion of neurotoxic amyloid-beta(1-42) oligomers to fibrils.
The amyloid-beta(1-42) (Abeta42) peptide rapidly aggregates to form oligomers, protofibils and fibrils en route to the deposition of amyloid plaques associated with Alzheimer's disease. We show that low-temperature and low-salt conditions can stabilize disc-shaped oligomers (pentamers) that are substantially more toxic to mouse cortical neurons than protofibrils and fibrils. We find that these neurotoxic oligomers do not have the beta-sheet structure characteristic of fibrils. Rather, the oligomers are composed of loosely aggregated strands whose C termini are protected from solvent exchange and which have a turn conformation, placing Phe19 in contact with Leu34. On the basis of NMR spectroscopy, we show that the structural conversion of Abeta42 oligomers to fibrils involves the association of these loosely aggregated strands into beta-sheets whose individual beta-strands polymerize in a parallel, in-register orientation and are staggered at an intermonomer contact between Gln15 and Gly37.
Ahmed
Mahiuddin
M
Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, New York, USA.
Davis
Judianne
J
Aucoin
Darryl
D
Sato
Takeshi
T
Ahuja
Shivani
S
Aimoto
Saburo
S
Elliott
James I
JI
Van Nostrand
William E
WE
Smith
Steven O
SO
D000544:Alzheimer Disease / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival; D002478:Cells, Cultured; D003080:Cold Temperature; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D012492:Salts / Q000737:chemistry
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D012492:Salts; C075222:amyloid beta-protein (1-42)
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