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

Abstract

An important component of the pathologic process underlying Alzheimer’s disease is oxidative stress. Met[superscript 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[superscript 35] by residues that do not participate in redox chemistry would be expected to decrease Aβ toxicity. Indeed, substitution of Met[superscript 35] by norleucine (Nle) was reported to reduce Aβ toxicity. Surprisingly, however, substitution of Met[superscript 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[superscript 35]→Nle or Met[superscript 35]→Val substitutions using multiple biophysical and toxicity assays. We found that substitution of Met[superscript 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[superscript 35] in Aβ is not important for Aβ toxicity, challenging to the prevailing paradigm, which suggests that redox reactions involving Met35 contribute substantially to Aβ-induced toxicity.