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

J. Neurochem. (2010) 113 , 1252–1262. Abstract An important component of the pathologic process underlying Alzheimer’s disease is oxidative stress. Met 35 in amyloid β‐protein (Aβ) is prone to participating in redox reactions promoting oxidative stress, and therefore is believed to contribute significantly Aβ‐induced toxicity. Thus, substitution of Met 35 by residues that do not participate in redox chemistry would be expected to decrease Aβ toxicity. Indeed, substitution of Met 35 by norleucine (Nle) was reported to reduce Aβ toxicity. Surprisingly, however, substitution of Met 35 by Val was reported to increase toxicity. Aβ toxicity is known to be strongly related to its self‐assembly. However, neither substitution is predicted to affect Aβ assembly substantially. Thus, the effect of these substitutions on toxicity is difficult to explain. We revisited this issue and compared Aβ40 and Aβ42 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 Aβ assembly. Surprisingly, despite these effects, neither substitution changed Aβ neurotoxicity significantly in three different assays. These results suggest that the presence of Met 35 in Aβ is not important for Aβ toxicity, challenging to the prevailing paradigm, which suggests that redox reactions involving Met 35 contribute substantially to Aβ‐induced toxicity.