| Abstract | The β-amyloid peptide (Aβ) 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 β-amyloid peptide, which contains isoaspartatic 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 Aβ upon substitution of Asp1 and Asp7 to isoaspartic residues. We found that the intermolecular β-pleated-sheet content is markedly increased for the post-translationally modified peptide compared to that in the corresponding unmodified human or rodent Aβ sequences both in aqueous solutions in the pH 7–12 range, and in membrane-mimicking solvents (such as aqueous octyl-β-d-glucoside or aqueous acetonitrile solutions). These findings underline the importance of the originally α-helical N-terminal regions of the unmodified Aβ peptides in defining its secondary structure and may offer an explanation for the selective aggregation and retention of the isomerized Aβ peptide in Alzheimer's-disease-affected brains. |
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