title: Structural and functional alterations in amyloid-β precursor protein induced by amyloid-β peptides.
abstract: Alzheimer's disease-associated amyloid-β (Aβ) peptide is neurotoxic as an oligomer, but not as a monomer, by an unknown mechanism. We showed previously that Aβ interacts with the amyloid-β precursor protein (AβPP), leading to caspase cleavage and cell death induction. To characterize this structure and interaction further, we purified the extracellular domain of AβPP695 (eAβPP) and its complex with Aβ oligomers (AβOs) of varying sizes, and then performed small angle X-ray scattering (SAXS). In the absence of any Aβ, eAβPP was a compact homodimer with a tight association between the E1 and E2 domains. Dimeric Aβ oligomers induced monomerization of eAβPP while larger oligomers also bound eAβPP but preserved the homodimer. Efficient binding of the larger oligomers correlated with the presence of prefibrillar oligomers, suggesting that the eAβPP binding is limited to a conformational subset of Aβ oligomers. Both forms of Aβ bound to eAβPP at the Aβ-cognate region and induced dissociation of the E1 and E2 domains. Our data provide the first structural evidence for Aβ-AβPP binding and suggest a mechanism for differential modulation of AβPP processing and cell death signaling by Aβ dimers versus conformationally-specific larger oligomers.
authors.affiliation: Buck Institute for Age Research, Novato, CA 94945, USA.
authors.forename: Clare Peters
authors.initials: CP
authors.lastname: Libeu
authors.forename: Karen S
authors.initials: KS
authors.lastname: Poksay
authors.forename: Varghese
authors.initials: V
authors.lastname: John
authors.forename: Dale E
authors.initials: DE
authors.lastname: Bredesen
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008970:Molecular Weight; D010446:Peptide Fragments; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments