Induction of Methionine-Sulfoxide Reductases Protects Neurons from Amyloid 尾-Protein Insults in Vitro and in Vivo

详细信息    查看全文

• 作者：Jackob Moskovitz ; Panchanan Maiti ; Dahabada H. J. Lopes ; Derek B. Oien ; Aida Attar ; Tingyu Liu ; Shivina Mittal ; Jane Hayes ; Gal Bitan
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：December 13, 2011
• 年：2011
• 卷：50
• 期：49
• 页码：10687-10697
• 全文大小：368K
• 年卷期：v.50,no.49(December 13, 2011)
• ISSN：1520-4995

文摘

Self-assembly of amyloid 尾-protein (A尾) into toxic oligomers and fibrillar polymers is believed to cause Alzheimer鈥檚 disease (AD). In the AD brain, a high percentage of A尾 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 the extent of A尾 assembly and neurotoxicity, whereas surprisingly, oxidation of Met³⁵ to sulfone yields a toxicity similar to that of unoxidized A尾. We hypothesized that the lower toxicity of A尾-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 A尾-sulfoxide correlated with induction of Msr activity. In agreement with these observations, in MsrA^{鈥?/i>/鈥?/i>} mice the difference in toxicity between native A尾 and A尾-sulfoxide was essentially eliminated. Subsequently, we found that treatment with N-acetyl-Met-sulfoxide could induce Msr activity and protect neuronal cells from A尾 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.