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

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    Moskovitz_ACS_2011.pdf (1.673Mb)
    Issue Date
    2011-12-13
    Author
    Moskovitz, Jackob
    Maiti, Panchanan
    Lopes, Dahabada H. J.
    Oien, Derek B.
    Attar, Aida
    Liu, Tingyu
    Mittal, Shivina
    Hayes, Jane
    Bitan, Gal
    Publisher
    ACS
    Type
    Article
    Article Version
    Scholarly/refereed, author accepted manuscript
    Rights
    Copyright © 2011 American Chemical Society
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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.
    URI
    http://hdl.handle.net/1808/23690
    DOI
    https://doi.org/10.1021/bi201426b
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    • Pharmacy Scholarly Works [280]
    Citation
    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

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    KU Libraries
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    Contact KU ScholarWorks
    785-864-8983
    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    785-864-8983

    KU Libraries
    1425 Jayhawk Blvd
    Lawrence, KS 66045
    Image Credits
     

     

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