Induction of methionine-sulfoxide reductases protects neurons from amyloid β-protein insults in vitro and in vivo

Amyloid β-protein (Aβ) self-assembly into toxic oligomers and fibrillar polymers is believed to cause Alzheimer’s disease (AD). In the AD brain, a high percentage of Aβ contains Met-sulfoxide at position 35, though the role this modification plays in AD is not clear. Oxidation of Met35 to sulfoxide has been reported to decrease Aβ assembly and neurotoxicity, whereas surprisingly, Met35 oxidation to sulfone yields similar toxicity to unoxidized Aβ. We hypothesized that the lower toxicity of Aβ-sulfoxide might result not only from structural alteration of the C-terminal region, but also from activation of methionine-sulfoxide reductase (Msr), an important component of the cellular antioxidant system. Supporting this hypothesis, we found that the low toxicity of Aβ-sulfoxide correlated with induction of Msr activity. In agreement with these observations, in MsrA−/− mice the difference in toxicity between native Aβ and Aβ-sulfoxide was essentially eliminated. Subsequently, we found that treatment with N-acetyl-Met-sulfoxide could induce Msr activity and protect neuronal cells from Aβ toxicity. In addition, we measured Msr activity in a double-transgenic mouse model of AD and found that it was increased significantly relative to non-transgenic mice. Immunization with a novel methionine sulfoxide-rich antigen for six months led to antibody production, decreased Msr activity, and lowered hippocampal plaque burden. The data suggest an important neuroprotective role for the Msr system in the AD brain, which may lead to development of new therapeutic approaches for AD

Tranilast Binds to Aβ Monomers and Promotes Aβ Fibrillation

The antiallergy and potential anticancer drug tranilast has been patented for treating Alzheimer’s disease (AD), in which amyloid β-protein (Aβ) plays a key pathogenic role. We used solution NMR to determine that tranilast binds to Aβ40 monomers with ∼300 μM affinity. Remarkably, tranilast increases Aβ40 fibrillation more than 20-fold in the thioflavin T assay at a 1:1 molar ratio, as well as significantly reducing the lag time. Tranilast likely promotes fibrillation by shifting Aβ monomer conformations to those capable of seed formation and fibril elongation. Molecular docking results qualitatively agree with NMR chemical shift perturbation, which together indicate that hydrophobic interactions are the major driving force of the Aβ–tranilast interaction. These data suggest that AD may be a potential complication for tranilast usage in elderly patients