| First Author | Moskovitz J | Year | 2011 |
| Journal | Biochemistry | Volume | 50 |
| Issue | 49 | Pages | 10687-97 |
| PubMed ID | 22059533 | Mgi Jnum | J:178628 |
| Mgi Id | MGI:5299381 | Doi | 10.1021/bi201426b |
| Citation | Moskovitz J, et al. (2011) Induction of Methionine-Sulfoxide Reductases Protects Neurons from Amyloid beta-Protein Insults in Vitro and in Vivo. Biochemistry 50(49):10687-97 |
| abstractText | Self-assembly of amyloid beta-protein (Abeta) into toxic oligomers and fibrillar polymers is believed to cause Alzheimer's disease (AD). In the AD brain, a high percentage of Abeta contains Met-sulfoxide at position 35, though the role this modification plays in AD is not clear. Oxidation of Met(35) to sulfoxide has been reported to decrease the extent of Abeta assembly and neurotoxicity, whereas surprisingly, oxidation of Met(35) to sulfone yields a toxicity similar to that of unoxidized Abeta. We hypothesized that the lower toxicity of Abeta-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 Abeta-sulfoxide correlated with induction of Msr activity. In agreement with these observations, in MsrA(-/-) mice the difference in toxicity between native Abeta and Abeta-sulfoxide was essentially eliminated. Subsequently, we found that treatment with N-acetyl-Met-sulfoxide could induce Msr activity and protect neuronal cells from Abeta toxicity. In addition, we measured Msr activity in a double-transgenic mouse model of AD and found that it was increased significantly relative to that of nontransgenic mice. Immunization with a novel Met-sulfoxide-rich antigen for 6 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. |
