Evidence for Novel β-Sheet Structures in Iowa Mutant β-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-A beta 40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-A beta 40 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-A beta 40 and the wild-type peptide WT-A beta 40, respectively) and without a lag phase. Electron microscopy shows that D23N-A beta 40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 angstrom and a broad reflection at 9.4 angstrom, which is notably smaller than the value for WT-A beta 40 fibrils (10.4 angstrom). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-A beta 40 fibrils containing the in-register, parallel P-sheet structure commonly found in WT-A beta 40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through C-13-C-13 and N-15-C-13 dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-A beta 40 fibrils and the unusual vasculotropic clinical picture in these patients.