N-terminal lipid conjugation of amyloid β(1-40) leads to the formation of highly ordered N-terminally extended fibrils.

Fibril formation of amyloid β(1-40) (Aβ(1-40)) peptides N-terminally lipid modified with saturated octanoyl or palmitoyl lipid chains was investigated. Lipid modification of Aβ(1-40) significantly accelerates the fibrillation kinetics of the Aβ peptides as revealed by ThT fluorescence. Electron microscopy and X-ray diffraction results indicate a heterogeneous cross-β structure of the fibrils formed by the lipid-conjugated peptides. Solid-state NMR was used to investigate structural features of these fibrils. The lipid moieties form dynamic and loosely structured heterogeneous lipid assemblies as inferred from H NMR of the deuterated lipid chains. C NMR studies of selected isotopic labels reveals that in addition to Phe and Val, which are part of the canonical cross-β structure, also N-terminal residues (Ala, Phe, Val) are found in β-strand conformation. This suggests that the increased hydrophobicity induced by the lipid modification, alters the energy landscape rendering an N-terminal extension of the β-sheet structure favorable. Furthermore, the fibrils formed by the Aβ-lipid hybrids are much more rigid than wildtype Aβ fibrils as inferred from NMR order parameter measurements. Taken together, increasing the local hydrophobicity of the Aβ N-terminus results in highly ordered but heterogeneous amyloid fibrils with extended N-terminal β-sheet structure.