Conformational Changes Induced by the A21G Flemish Mutation in the Amyloid Precursor Protein Lead to Increased Aβ Production

• The extracellular region of β-CTF of APP folds into β sheet
• The β sheet structure in the β CTF inhibits processing of APP to the Aβ peptides
• The familial A21G mutation reduces β sheet in the adjacent, inhibitory LVFF motif
• Cholesterol enhances the effects of the A21G mutation

SummaryProteolysis of the β C-terminal fragment (β-CTF) of the amyloid precursor protein generates the Aβ peptides associated with Alzheimer’s disease. Familial mutations in the β-CTF, such as the A21G Flemish mutation, can increase Aβ secretion. We establish how the Flemish mutation alters the structure of C55, the first 55 residues of the β-CTF, using FTIR and solid-state NMR spectroscopy. We show that the A21G mutation reduces β sheet structure of C55 from Leu17 to Ala21, an inhibitory region near the site of the mutation, and increases α-helical structure from Gly25 to Gly29, in a region near the membrane surface and thought to interact with cholesterol. Cholesterol also increases Aβ peptide secretion, and we show that the incorporation of cholesterol into model membranes enhances the structural changes induced by the Flemish mutant, suggesting a common link between familial mutations and the cellular environment.