Synthetic post‐translationally modified human Aβ peptide exhibits a markedly increased tendency to form β‐pleated sheets in vitro

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Abstract
The \u3b2-amyloid peptide (A\u3b2) 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 \u3b2-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., Z\ufcrcher-Neely, H. A., Heinrikson, R. L., Ball, M. J. & Greenberg, B. D. (1993) J. Biol. Chem. 268, 3072\u20133083]. We used circular dichroism and Fourier-transform infrared spectroscopy to characterize the conformational changes on human A\u3b2 upon substitution of Asp1 and Asp7 to isoaspartic residues. We found that the intermolecular \u3b2-pleated-sheet content is markedly increased for the post-translationally modified peptide compared to that in the corresponding unmodified human or rodent A\u3b2 sequences both in aqueous solutions in the pH 7\u201312 range, and in membrane-mimicking solvents (such as aqueous octyl-\u3b2-d-glucoside or aqueous acetonitrile solutions). These findings underline the importance of the originally \u3b1-helical N-terminal regions of the unmodified A\u3b2 peptides in defining its secondary structure and may offer an explanation for the selective aggregation and retention of the isomerized A\u3b2 peptide in Alzheimer's-disease-affected brains.Peer reviewed: YesNRC publication: Ye

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