W0232: SANS and NMR Investigation of the Aggregation of Beta-Amyloid Peptides

W0232

SANS and NMR Investigation of Aggregation of [beta]-Amyloid Peptides. P. Thiyagarajan, T.L.S. Benzinger³, T.S. Burkoth⁴, D. M. Gregory², R.E. Botto², D.G. Lynn⁴ and S.C. Meredith³, IPNS and ²Chemistry Divisions, Argonne National Laboratory, Argonne, IL 60439 USA and ³Departments of Pathology and ⁴Chemistry, University of Chicago, Chicago, IL 60637 USA

Alzheimer's disease is manifested by dense extracellular proteinaceous lesions called amyloid plaques, composed mainly of the [beta]-amyloid peptide (A[beta]). The model of the disease process is that A[beta] peptides first undergo secondary structural changes followed by self-aggregation which lead to the formation of amyloid plaques. In order to understand the mechanism of plaque formation we have used NMR and SANS on solutions of A[beta] peptides as a function of pH. Solution NMR studies of the peptides covalently modified by the attachment of polyethylene glycol (PEG) have shown that the monomers are in a conformation indistinguishable from the native peptide, but the fibrils of the modified peptides remain in solution for much longer times. Hence, we carried out similar studies on the PEG modified peptides. NMR studies provided information on both the conformational aspects of individual peptides and the contacts between neighboring peptides. SANS experiments revealed that at low pH, the A[beta] peptides associate to form rod-shaped particles with a constant radius, but their length and mass per unit length increase with time. Thus, the density of the fibrils formed at low pH increases with time. At physiological pH, however, the aggregation levels of similar rod-like particles are much higher. The aggregation behavior of PEG-peptides resembles that of native peptides at low pH, but the rod-like particles have a larger radius than that of the native fibrils. These studies reveal that the A[beta] peptides aggregate through end-to-end association and PEG molecules are arranged radially on the surface of the rod.

Work supported by U.S. Department of Energy, BES, contract No. W-31-109-ENG-38.