Synthetic post-translationally modified human A beta peptide exhibits a markedly increased tendency to form beta-pleated sheets in vitro.
The beta-amyloid peptide (A beta) is the major constituent of senile plaques, one of the hallmark neuropathological lesions of Alzheimer's disease. Recently a post-translationally modified analogue of the human beta-amyloid peptide, which contains isoaspartic residues in positions 1 and 7, was isolated from parenchyma and leptomeningeal microvasculature of Alzheimer's disease patients [Roher, A. E., Lowenson, JD., Clarke, S., Wolkow, C., Wang, R., Cotter, R. J., Reardon, I. M., Zürcher-Neely, H. A., Heinrikson, R. L., Ball, M. J. & Greenberg, B. D. (1993) J. Biol. Chem. 268, 3072-3083]. We used circular dichroism and Fourier-transform infrared spectroscopy to characterize the conformational changes on human A beta upon substitution of Asp1 and Asp7 to isoaspartic residues. We found that the intermolecular beta-pleated-sheet content is markedly increased for the post-translationally modified peptide compared to that in the corresponding unmodified human or rodent A beta sequences both in aqueous solutions in the pH 7-12 range, and in membrane-mimicking solvents (such as aqueous octyl-beta-D-glucoside or aqueous acetonitrile solutions). These findings underline the importance of the originally alpha-helical N-terminal regions of the unmodified A beta peptides in defining its secondary structure and may offer an explanation for the selective aggregation and retention of the isomerized A beta peptide in Alzheimer's-disease-affected brains.
Fabian
H
H
Institute for Biodiagnostics, National Research Council Canada, Winnipeg.
Szendrei
G I
GI
Mantsch
H H
HH
Greenberg
B D
BD
Otvös
L
L
D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism; D001216:Asparagine / Q000737:chemistry; D001224:Aspartic Acid / Q000737:chemistry; D002942:Circular Dichroism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008969:Molecular Sequence Data; D011499:Protein Processing, Post-Translational; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared; D013237:Stereoisomerism
D016229:Amyloid beta-Peptides; D001224:Aspartic Acid; D001216:Asparagine