Abstract
Alzheimer disease is a neurodegenerative disorder that is tightly linked to the self-assembly and amyloid formation of the 39-43-residue-long amyloid-beta (Abeta) peptide. Considerable evidence suggests a correlation between Alzheimer disease development and the longer variants of the peptide, Abeta-(1-42/43). Currently, a molecular understanding for this behavior is lacking. In the present study, we have investigated the hydrogen/deuterium exchange of Abeta-(1-42) fibrils under physiological conditions, using solution NMR spectroscopy. The obtained residue-specific and quantitative map of the solvent protection within the Abeta-(1-42) fibril shows that there are two protected core regions, Glu11-Gly25 and Lys28-Ala42, and that the residues in between, Ser26 and Asn27, as well as those in the N terminus, Asp1-Tyr10, are solvent-accessible. This result reveals considerable discrepancies when compared with a previous investigation on Abeta-(1-40) fibrils and suggests that the additional residues in Abeta-(1-42), Ile41 and Ala42, significantly increase the solvent protection and stability of the C-terminal region Lys28-Ala42. Consequently, our findings provide a molecular explanation for the increased amyloidogenicity and toxicity of Abeta-(1-42) compared with shorter Abeta variants found in vivo.
Highlights
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
We found that a mixture of 80% HFIP/20% water (v/v) at pH 3 had the capability of rapid dissolution of A-(1– 42) fibrils
The A peptide is the main protein component of plaques found in patients with the neurodegenerative disorder Alzheimer disease
Summary
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. This result reveals considerable discrepancies when compared with a previous investigation on A-(1– 40) fibrils and suggests that the additional residues in A-(1– 42), Ile[41] and Ala[42], significantly increase the solvent protection and stability of the C-terminal region Lys28Ala[42].
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