Amyloid-beta peptide A beta p3-42 affects early aggregation of full-length A beta 1-42

The major amyloid-beta (A beta ) peptides found in the brain of familial and late onset Alzheimer's disease include the full-length A beta 1-42 and N-terminally truncated, pyroglutamylated peptides A beta p3-42 and A beta p11- 42. The biophysical properties of A beta 1-42 have been extensively studied, yet little is known about the other modified peptides. We investigated the aggregation kinetics of brain-specific A beta peptides to better understand their potential roles in plaque formation. Synthetic peptides were analyzed individually and in mixtures representing various ratios found in the brain. Spectrofluorometric analyses using Thioflavin-T showed that the aggregation of A beta 1-42 was faster compared to A beta p3-42; however, A beta p11-42 displayed similar kinetics. Surprisingly, mixtures of full-length A beta 1-42 and A beta p3-42 showed an initial delay in beta -sheet formation from both equimolar and non-equimolar samples. Electron microscopy of peptides individually and in mixtures further supported fluorescence data. These results indicate that A beta -A beta peptide interactions involving different forms may play a critical role in senile plaque formation and maintenance of the soluble A beta pool in the brain.