title: Rapid α-oligomer formation mediated by the Aβ C terminus initiates an amyloid assembly pathway.
abstract: Since early oligomeric intermediates in amyloid assembly are often transient and difficult to distinguish, characterize and quantify, the mechanistic basis of the initiation of spontaneous amyloid growth is often opaque. We describe here an approach to the analysis of the Aβ aggregation mechanism that uses Aβ-polyglutamine hybrid peptides designed to retard amyloid maturation and an adjusted thioflavin intensity scale that reveals structural features of aggregation intermediates. The results support an aggregation initiation mechanism for Aβ-polyQ hybrids, and by extension for full-length Aβ peptides, in which a modular Aβ C-terminal segment mediates rapid, non-nucleated formation of α-helical oligomers. The resulting high local concentration of tethered amyloidogenic segments within these α-oligomers facilitates transition to a β-oligomer population that, via further remodelling and/or elongation steps, ultimately generates mature amyloid. Consistent with this mechanism, an engineered Aβ C-terminal fragment delays aggregation onset by Aβ-polyglutamine peptides and redirects assembly of Aβ42 fibrils.
authors.affiliation: Structural Biology Department, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh 15260, Pennsylvania, USA.
authors.forename: Pinaki
authors.initials: P
authors.lastname: Misra
authors.affiliation: Structural Biology Department, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh 15260, Pennsylvania, USA.
authors.forename: Ravindra
authors.initials: R
authors.lastname: Kodali
authors.affiliation: Structural Biology Department, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh 15260, Pennsylvania, USA.
authors.forename: Saketh
authors.initials: S
authors.lastname: Chemuru
authors.affiliation: Structural Biology Department, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh 15260, Pennsylvania, USA.
authors.forename: Karunakar
authors.identifier: 0000-0001-7047-6539
authors.initials: K
authors.lastname: Kar
authors.affiliation: Structural Biology Department, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.|Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh 15260, Pennsylvania, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
mesh_terms: D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D052160:Benzothiazoles; D002942:Circular Dichroism; D005456:Fluorescent Dyes / Q000737:chemistry; D006801:Humans; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D066263:Protein Aggregation, Pathological / Q000473:pathology*; D015202:Protein Engineering; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D013057:Spectrum Analysis / Q000379:methods; D013844:Thiazoles / Q000737:chemistry; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D005456:Fluorescent Dyes; D010446:Peptide Fragments; D010455:Peptides; D013844:Thiazoles; C075222:amyloid beta-protein (1-42); C009462:thioflavin T; C097188:polyglutamine