Structural and functional alterations in amyloid-β precursor protein induced by amyloid-β peptides.

作者: Clare Peters Libeu , Karen S. Poksay , Varghese John , Dale E. Bredesen

DOI: 10.3233/JAD-2011-101938

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摘要: Alzheimer's disease-associated amyloid-β (Aβ) peptide is neurotoxic as an oligomer, but not a monomer, by unknown mechanism. We showed previously that Aβ interacts with the precursor protein (AβPP), leading to caspase cleavage and cell death induction. To characterize this structure interaction further, we purified extracellular domain of AβPP695 (eAβPP) its complex oligomers (AβOs) varying sizes, then performed small angle X-ray scattering (SAXS). In absence any Aβ, eAβPP was compact homodimer tight association between E1 E2 domains. Dimeric induced monomerization while larger also bound preserved homodimer. Efficient binding correlated presence prefibrillar oligomers, suggesting limited conformational subset oligomers. Both forms at Aβ-cognate region dissociation Our data provide first structural evidence for Aβ-AβPP suggest mechanism differential modulation AβPP processing signaling dimers versus conformationally-specific

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