Effects of the mutations Glu22 to Gln and Ala21 to Gly on the aggregation of a synthetic fragment of the Alzheimer's amyloid beta/A4 peptide.
We assessed the fibrillogenic properties of synthetic peptides corresponding to residues 13-26 of beta/A4 amyloid, containing either the normal sequence (beta 13 26) or the mutations Glu22 to Gln (beta 13-26Q22) and Ala21 to Gly (beta 13-26G21). The kinetics of aggregation were monitored at 37 degrees C and pH 7.4 by measuring the amount of peptide remaining in solution, using reverse-phase high performance liquid chromatography. Negative stain electron microscopy revealed that all of the peptides formed fibrils. However, beta 13-26Q22 showed greatly accelerated fibril formation compared to the other two. The results suggest that the Q22 mutation confers increased amyloidogenic properties on the beta/A4 peptide, whereas the G21 mutation acts by a different pathogenic mechanism.
Clements
A
A
Division of Biochemistry, School of Biology and Biochemistry, Queen's University of Belfast, UK.
Walsh
D M
DM
Williams
C H
CH
Allsop
D
D
D000409:Alanine / Q000235:genetics; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000682:Amyloid / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics*; D005971:Glutamates / Q000235:genetics; D018698:Glutamic Acid; D005998:Glycine / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation
D000682:Amyloid; D016229:Amyloid beta-Peptides; D005971:Glutamates; D018698:Glutamic Acid; D000409:Alanine; D005998:Glycine