Seeding Specificity in Amyloid Growth Induced by Heterologous Fibrils

Over residues 15–36, which comprise the H-bonded core of the amyloid fibrils it forms, the Alzheimer's disease plaque peptide amyloid β (Aβ) possesses a very similar sequence to that of another short, amyloidogenic peptide, islet amyloid polypeptide (IAPP). Using elongation rates to quantify seeding efficiency, we inquired into the relationship between primary sequence similarity and seeding efficiency between Aβ-(1–40) and amyloid fibrils produced from IAPP as well as other proteins. In both a solution phase and a microtiter plate elongation assay, IAPP fibrils are poor seeds for Aβ-(1–40) elongation, exhibiting weight-normalized efficiencies of only 1–2% compared with Aβ-(1–40) fibrils. Amyloid fibrils of peptides with sequences completely unrelated to Aβ also exhibit poor to negligible seeding ability for Aβ elongation. Fibrils from a number of point mutants of Aβ-(1–40) exhibit intermediate seeding abilities for wild-type Aβ elongation, with differing efficiencies depending on whether or not the mutation is in the amyloid core region. The results suggest that amyloid fibrils from different proteins exhibit structural differences that control seeding efficiencies. Preliminary results also suggest that identical sequences can grow into different conformations of amyloid fibrils as detected by seeding efficiencies. The results have a number of implications for amyloid structure and biology.