Amyloid β-protein oligomerization: Prenucleation interactions revealed by photo-induced cross-linking of unmodified proteins
- Author(s): Bitan, G
- Lomakin, A
- Teplow, DB
- et al.
Published Web Locationhttps://doi.org/10.1074/jbc.M102223200
Assembly of the amyloid β-protein (Aβ) into neurotoxic oligomers and fibrils is a seminal event in Alzheimer's disease. Understanding the earliest phases of Aβ assembly, including prenucleation and nucleation, is essential for the development of rational therapeutic strategies. We have applied a powerful new method, photoinduced cross-linking of unmodified proteins (PI-CUP), to the study of Aβ oligomerization. Significant advantages of this method include an extremely short reaction time, enabling the identification and quantification of short lived metastable assemblies, and the fact that no pre facto structural modification of the native peptide is required. Using PICUP, the distribution of Aβ oligomers existing prior to assembly was defined. A rapid equilibrium was observed involving monomer, dimer, trimer, and tetramer. A similar distribution was seen in studies of an unrelated amyloidogenic peptide, whereas nonamyloidogenic peptides yielded distributions indicative of a lack of monomer preassociation. These results suggest that simple nucleation-dependent polymerization models are insufficient to describe the dynamic equilibria associated with prenucleation phases of Aβ assembly.
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