The solvent protection of Alzheimer amyloid-β-(1-42) fibrils as determined by solution NMR spectroscopy

Alzheimer disease is a neurodegenerative disorder that is tightly linked to the self- assembly and amyloid formation of the 39 - 43residue- long amyloid-beta(A beta) peptide. Considerable evidence suggests a correlation between Alzheimer disease development and the longer variants of the peptide, A beta-(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 beta-(1-42) fibrils under physiological conditions, using solution NMR spectroscopy. The obtained residue-specific and quantitative map of the solvent protection within the A beta-(1-42) fibril shows that there are two protected core regions, Glu(11)-Gly(25) and Lys(28)-Ala(42), and that the residues in between, Ser(26) and Asn(27), as well as those in the N terminus, Asp(1)- Tyr(10), are solvent- accessible. This result reveals considerable discrepancies when compared with a previous investigation on A beta- (1-40) fibrils and suggests that the additional residues in A beta-(1-42), Ile(41) and Ala(42), significantly increase the solvent protection and stability of the C-terminal region Lys(28)Ala(42). Consequently, our findings provide a molecular explanation for the increased amyloidogenicity and toxicity of A beta-(1-42) compared with shorter A beta variants found in vivo.