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Induction of methionine-sulfoxide reductases protects neurons from amyloid β-protein insults in vitro and in vivo
Moskovitz, Jackob Maiti, Panchanan Lopes, Dahabada H. J. Oien, Derek B. Attar, Aida Liu, Tingyu Mittal, Shivina Hayes, Jane Bitan, Gal
Moskovitz, Jackob
Maiti, Panchanan
Lopes, Dahabada H. J.
Oien, Derek B.
Attar, Aida
Liu, Tingyu
Mittal, Shivina
Hayes, Jane
Bitan, Gal
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Abstract
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.
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2011-12-13
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ACS
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Moskovitz, J., Maiti, P., Lopes, D. H. J., Oien, D. B., Attar, A., Liu, T., … Bitan, G. (2011). Induction of methionine-sulfoxide reductases protects neurons from amyloid β-protein insults in vitro and in vivo. Biochemistry, 50(49), 10687–10697. http://doi.org/10.1021/bi201426b