Alzheimer disease is a neurodegenerative disorder that is tightly linked to the self-assembly and amyloid formation of the 39 -43-residue-long amyloid- (A) peptide. Considerable evidence suggests a correlation between Alzheimer disease development and the longer variants of the peptide, A-(1-42/43). Currently, a molecular understanding for this behavior is lacking. In the present study, we have investigated the hydrogen/deuterium exchange of A-(1-42) fibrils under physiological conditions, using solution NMR spectroscopy. Protein assemblies in the form of amyloid fibrils are today linked to a group of ϳ20 different syndromes, of which Alzheimer disease (AD), 2 as well as various forms of prion disorders, are among the most well known. Amyloids, in general, are composed of predominantly -sheet structures, where the -strands are arranged perpendicular to the fibrillar axis into a common so-called cross- pattern (1-4). AD is a neurological disorder presenting itself as progressive dementia. The pathology is tightly linked to the aggregation of a 39 -43-residue-long peptide fragment denoted amyloid- (A) derived as a result of proteolytic processing of the considerably larger amyloid precursor protein. Aggregated A peptides are found in AD brains in the form of diffuse and senile plaques as well as in cerebrovascular tissues. Considerable experimental evidence suggests an important role of A-(1-42/43) in the progress of AD, because it represents the main constituent of the first deposits found in the course of disease development (5, 6) and if overproduced may result in early onset AD (7, 8) (for a recent review, see Ref.9). The mechanisms by which a cytotoxic effect is exerted in vivo and the reasons why a pathologic self-aggregation is induced in certain individuals are complex and at present not completely understood. Prevention of A assembly therefore constitutes a considerable therapeutic challenge, where an increased understanding regarding the properties of amyloid, and the pathways leading to its formation, is of utmost importance.Because of the generic quaternary structure and the large size of amyloid structures, elucidation of their architecture provides a complicated problem, where traditional methods, such as crystal diffraction and solution NMR, are not readily applicable. However, two recent crystallographic studies on fibrous micro-crystals, grown from peptides with either seven or twelve residues, have revealed many interesting structural details about the cross- spine of fibrils (10, 11). Solid-state NMR performed on dried fibrils provides an alternative to the above mentioned techniques and has been used extensively to investigate the structure of A amyloid. Studies on A-(10 -35), A-(1-40), and A-(1-42) suggest an arrangement where fibrils are formed by extended parallel -strands arranged into two sheets (12-14). The results suggest a fibrillar core involving residues Val 12 -Val 24 and Ala 30 -Ala 42 and a loop spanning between residues Val 24 -Ala 30 (15). The structural restrai...
