Dynamics and Cleavability at the α-Cleavage Site of APP(684-726) in Different Lipid Environments

The occurrence of late-onset Alzheimer's disease has been related to the lipid homeostasis. We tested whether the membrane lipid environment affects the dynamics and cleavability of a model peptide corresponding to the amino acid sequence 684–726 of the amyloid precursor protein APP reconstituted in liposomes. Solid-state NMR with 2H-Ala 713, which is located within the putative transmembrane domain, suggested that the peptide observes less rotational motion in egg phosphatidylcholine (PhC) membranes than in dimyristoyl-phosphatidylcholine (DMPC) bilayers above the main phase transition temperature T c. The residue 15N-Ala 692, which is in the vicinity of the α-cleavage site, i.e., Lys 687, showed less motion after reconstitution in distearoyl-phosphatidylcholine liposomes < T c than in PhC, DMPC, or sphingomyelin vesicles. In all tested liposomal systems the α-cleavage site was accessible for hydrolysis by trypsin. However, the catalytic rate constant was higher in the PhC and DMPC than in the sphingomyelin and distearoyl-phosphatidylcholine systems. In conclusion, the dynamics of APP(684–726) on the transmembrane level as well as the motion of the α-cleavage site and its hydrolysis by a model enzyme are dependent on the bilayer characteristics. This could be relevant for the processing of APP in vivo.