Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.
Asp23-to-Asn mutation within the coding sequence of beta-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Abeta40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Abeta40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10(-3) min(-1) and 1.07 x 10(-4) min(-1) for D23N-Abeta40 and the wild-type peptide WT-Abeta40, respectively) and without a lag phase. Electron microscopy shows that D23N-Abeta40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 A and a broad reflection at 9.4 A, which is notably smaller than the value for WT-Abeta40 fibrils (10.4 A). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Abeta40 fibrils containing the in-register, parallel beta-sheet structure commonly found in WT-Abeta40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through (13)C-(13)C and (15)N-(13)C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Abeta40 fibrils and the unusual vasculotropic clinical picture in these patients.
Tycko
Robert
R
Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-0520, USA.
Sciarretta
Kimberly L
KL
Orgel
Joseph P R O
JP
Meredith
Stephen C
SC
D000682:Amyloid / Q000737:chemistry* / Q000648:ultrastructure; D028227:Amyloid Neuropathies, Familial / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000235:genetics; D001224:Aspartic Acid / Q000737:chemistry; D052160:Benzothiazoles; D018698:Glutamic Acid / Q000737:chemistry; D006801:Humans; D007700:Kinetics; D007930:Leucine / Q000737:chemistry; D008239:Lysine / Q000737:chemistry; D046529:Microscopy, Electron, Transmission; D008958:Models, Molecular; D020125:Mutation, Missense; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics; D010649:Phenylalanine / Q000737:chemistry; D017433:Protein Structure, Secondary; D013050:Spectrometry, Fluorescence; D013844:Thiazoles / Q000737:chemistry; D014961:X-Ray Diffraction
D000682:Amyloid; D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C009462:thioflavin T; D001224:Aspartic Acid; D018698:Glutamic Acid; D010649:Phenylalanine; D007930:Leucine; D008239:Lysine