H-1-NMR OF A-BETA AMYLOID PEPTIDE CONGENERS IN WATER SOLUTION - CONFORMATIONAL-CHANGES CORRELATE WITH PLAQUE COMPETENCE

To begin to examine the structural basis for the deposition of soluble A beta amyloid peptide onto senile plaques in Alzheimer's disease, we have prepared A beta congeners and measured their activity in an in v itro plaque growth assay. The N-terminal fragment, A beta(1-28)-OH, wa s inactive at all pH values tested. While the central fragment, A beta (10-35)-NH2, and the full length peptide, A beta(1-40)-OH, were inacti ve below pH 4, both were active (plaque competent) between pH 5 and 9. The active and inactive fragments were studied by nuclear magnetic re sonance spectroscopy in water at submillimolar concentrations at pH 2. 1 and 5.6. Changes in chemical shifts, coupling constants, and nuclear Overhauser enhancements indicate a pH dependent folding transition in A beta(10-35)-NH2 as it becomes active. The conformation of the activ e fragment is not helical, and preliminary data indicate the presence of several turns and at least two short strands. In contrast, the inac tive fragment A beta(1-28)-OH did not undergo a similar folding transi tion. Earlier nuclear magnetic resonance studies of amyloid peptides i n fluorinated alcohols or detergent micelles at low pH described a hel ical conformation and proposed a helix to sheet transition in plaque f ormation; the present study demonstrates that no such conformations ar e present in water under conditions where the peptides can adhere to a uthentic amyloid plaques.