Open AccessSynthetic post‐translationally modified human Aβ peptide exhibits a markedly increased tendency to form β‐pleated sheets in vitro
Author(s) -
FABIAN Heinz,
SZENDREI Gyorgyi I.,
MANTSCH Henry H.,
GREENBERG Barry D.,
ÖTVÖS Laszlo
Publication year - 1994
Publication title -
european journal of biochemistry
Language(s) - English
Resource type - Journals
eISSN - 1432-1033
pISSN - 0014-2956
DOI - 10.1111/j.1432-1033.1994.tb18811.x
Subject(s) - peptide , circular dichroism , chemistry , aqueous solution , senile plaques , in vitro , amyloid (mycology) , biophysics , beta sheet , beta (programming language) , parenchyma , amyloid beta , stereochemistry , protein secondary structure , alzheimer's disease , biochemistry , biology , pathology , organic chemistry , medicine , disease , inorganic chemistry , programming language , computer science
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.