title: C-Terminal Threonine Reduces Aβ43 Amyloidogenicity Compared with Aβ42.
abstract: Aβ43, a product of the proteolysis of the amyloid precursor protein APP, is related to Aβ42 by an additional Thr residue at the C-terminus. Aβ43 is typically generated at low levels compared with the predominant Aβ42 and Aβ40 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 Aβ42 and Aβ43 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, Aβ43 fibrils have fewer strong backbone H-bonds than Aβ42 fibrils, some of which are lost at the C-terminus. In contrast to previous reports, we found that Aβ43 spontaneously aggregates more slowly than Aβ42. In addition, Aβ43 fibrils are very inefficient at seeding Aβ42 amyloid formation, even though Aβ42 fibrils efficiently seed amyloid formation by Aβ43 monomers. Finally, mixtures of Aβ42 and Aβ43 aggregate more slowly than Aβ42 alone. Both in this Aβ42/Aβ43 co-aggregation reaction and in cross-seeding by Aβ42 fibrils, the structure of the Aβ43 in the product fibrils is influenced by the presence of Aβ42. 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 Aβ43 in the brain are unlikely to favorably impact the aggregation of Aβ42.
authors.affiliation: Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Saketh
authors.initials: S
authors.lastname: Chemuru
authors.affiliation: Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.affiliation: Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA. Electronic address: rwetzel@pitt.edu.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism*; D066263:Protein Aggregation, Pathological; D011489:Protein Denaturation; D055503:Protein Multimerization; D013912:Threonine / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D013912:Threonine
keywords: amyloid; cross-seeding; hydrogen–deuterium exchange; polymorphism; weight-normalized ThT