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

作者：Maiti Panchanan; Lomakin Aleksey; Benedek George B; Bitan Gal^*

来源：Journal of Neurochemistry, 2010, 113(5): 1252-1262.

DOI：10.1111/j.1471-4159.2010.06692.x

• Alzheimer's disease
• amyloid beta-protein
• oxidative stress
• neurotoxicity
• structure-activity relationship

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

• 出版日期2010-6