Structural evolution and membrane interaction of the 40-residue β amyloid peptides: differences in the initial proximity between peptides and the membrane bilayer studied by solid-state nuclear magnetic resonance spectroscopy.

Interactions between the β amyloid (Aβ) peptides and cellular membranes have severe consequences such as neuronal cell disruption and therefore may play important roles in Alzheimer's disease. Understanding the structural basis behind such interactions, however, is hindered by the complexity of the Aβ-membrane systems. In particular, because the Aβ peptides are partially incorporated in the membrane bilayer after enzymatic cleavage, there are multiple possibilities in terms of the initial proximity between the peptides and membranes. Structural studies using in vitro model systems with either externally added or preincorporated Aβ in membrane bilayers resulted in distinct evolution pathways. Previous work has shown that the externally added Aβ formed long and mature filaments, while preincorporated Aβ generated short and curvy fibrils. In this study, we perform detailed characterizations on the structural evolution and membrane interaction for these two pathways, using a combination of solid-state nuclear magnetic resonance spectroscopy and other techniques. For the externally added Aβ, we determined the residue-specific structural evolution during the fibrillation process. While the entire fibrillation process for the externally added Aβ was slow, the preincorporated Aβ generated Aβ-lipid complexes rapidly. Specific interactions between the lipids and peptides were observed, suggesting the colocalization of lipids and peptides within the complex. Formation of such a complex induced molecular-level changes in the lipid bilayer, which may serve as a possible mechanism of membrane disruption.