Figure 1. Involvement of Met-35 of Aβ(1-42) in lipid peroxidation.

The S-atom of Met-35 of the Aβ(1-42) peptide can undergo one-electron oxidation to form a sulfuranyl radical cation within the bilayer, which has the ability to abstract a labile, allylic H-atom from the unsaturated acyl chains of lipid molecules, leading to initiation of lipid peroxidation processes [13, 14]. Like most integral membrane proteins, α-helical Aβ(1-42) adheres to the i+4 rule, causing the backbone carbonyl oxygen of Ile-31 on Aβ(1-42) to draw the electron density of the Met-35 S-atom toward itself, making the S-atom more vulnerable to oxidation and subsequent formation of the sulfuranyl radical cation. The sulfuranyl radical can, in turn, abstract allylic H-atoms from neighboring fatty acyl chains within the bilayer, forming a fatty acid carbon-centered free radical that can immediately bind paramagnetic, non-polar oxygen (O₂) to form a peroxyl free radical. The peroxyl radical then abstracts another labile H-atom from nearby fatty acyl chains, perpetuating the catalytic chain reaction initiated by Met-35 of the Aβ(1-42) peptide. Because Met-35 is inevitably reduced back to its starting state, this reaction can begin again, amplifying the neurotoxic affects of the Aβ(1-42) peptide within the cell.