Despite its role in assembly, methionine 35 is not necessary for amyloid β‐protein toxicity

An important component of the pathologic process underlying Alzheimer's disease is oxidative stress. Met(35) in amyloid beta-protein (A beta) is prone to participating in redox reactions promoting oxidative stress, and therefore is believed to contribute significantly A beta-induced toxicity. Thus, substitution of Met(35) by residues that do not participate in redox chemistry would be expected to decrease A beta toxicity. Indeed, substitution of Met(35) by norleucine (Nle) was reported to reduce A beta toxicity. Surprisingly, however, substitution of Met(35) by Val was reported to increase toxicity. A beta toxicity is known to be strongly related to its self-assembly. However, neither substitution is predicted to affect A beta assembly substantially. Thus, the effect of these substitutions on toxicity is difficult to explain. We revisited this issue and compared A beta 40 and A beta 42 with analogs containing Met(35)-->Nle or Met(35)-->Val substitutions using multiple biophysical and toxicity assays. We found that substitution of Met(35) by Nle or Val had moderate effects on A beta assembly. Surprisingly, despite these effects, neither substitution changed A beta neurotoxicity significantly in three different assays. These results suggest that the presence of Met(35) in A beta is not important for A beta toxicity, challenging to the prevailing paradigm, which suggests that redox reactions involving Met(35) contribute substantially to A beta-induced toxicity.