Familial Alzheimer's disease Osaka mutant (ΔE22) β-barrels suggest an explanation for the different Aβ1-40/42 preferred conformational states observed by experiment.

An unusual ΔE693 mutation in the amyloid precursor protein (APP) producing a β-amyloid (Aβ) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (ΔE22). Previously, several point mutations in the Aβ peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer’s disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families affected by the disease. To see whether this aggregation-prone Aβ mutant could directly relate to the Aβ ion channel-mediated mechanism as observed for the wild type (WT) Aβ peptide in AD pathology, we modeled Osaka mutant β-barrels in a lipid bilayer. Using molecular dynamics (MD) simulations, two conformer ΔE22 barrels with the U-shaped monomer conformation derived from NMR-based WT Aβ fibrils were simulated in explicit lipid environment. Here, we show that the ΔE22 barrels obtain the lipid-relaxed β-sheet channel...