C-Terminal Threonine Reduces Aβ43 Amyloidogenicity Compared with Aβ42

Abstract Aβ 43 , a product of the proteolysis of the amyloid precursor protein APP, is related to Aβ 42 by an additional Thr residue at the C-terminus. Aβ 43 is typically generated at low levels compared with the predominant Aβ 42 and Aβ 40 forms, but it has been suggested that this longer peptide might have an impact on amyloid-β aggregation and Alzheimer's disease that is out of proportion to its brain content. Here, we report that both Aβ 42 and Aβ 43 spontaneously aggregate into mature amyloid fibrils via sequential appearance of the same series of oligomeric and protofibrillar intermediates, the earliest of which appears to lack β-structure. In spite of the additional β-branched amino acid at the C-terminus, Aβ 43 fibrils have fewer strong backbone H-bonds than Aβ 42 fibrils, some of which are lost at the C-terminus. In contrast to previous reports, we found that Aβ 43 spontaneously aggregates more slowly than Aβ 42 . In addition, Aβ 43 fibrils are very inefficient at seeding Aβ 42 amyloid formation, even though Aβ 42 fibrils efficiently seed amyloid formation by Aβ 43 monomers. Finally, mixtures of Aβ 42 and Aβ 43 aggregate more slowly than Aβ 42 alone. Both in this Aβ 42 /Aβ 43 co-aggregation reaction and in cross-seeding by Aβ 42 fibrils, the structure of the Aβ 43 in the product fibrils is influenced by the presence of Aβ 42 . The results provide new details of amyloid structure and assembly pathways, an example of structural plasticity in prion-like replication, and data showing that low levels of Aβ 43 in the brain are unlikely to favorably impact the aggregation of Aβ 42 .