title: Induction of methionine-sulfoxide reductases protects neurons from amyloid β-protein insults in vitro and in vivo.
abstract: Self-assembly of amyloid β-protein (Aβ) 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 Met(35) to sulfoxide has been reported to decrease the extent of Aβ assembly and neurotoxicity, whereas surprisingly, oxidation of Met(35) to sulfone yields a toxicity similar to that of 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 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.
authors: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas 66045, United States.
authors: Jackob
authors: J
authors: Moskovitz
authors: Panchanan
authors: P
authors: Maiti
authors: Dahabada H J
authors: DH
authors: Lopes
authors: Derek B
authors: DB
authors: Oien
authors: Aida
authors: A
authors: Attar
authors: Tingyu
authors: T
authors: Liu
authors: Shivina
authors: S
authors: Mittal
authors: Jane
authors: J
authors: Hayes
authors: Gal
authors: G
authors: Bitan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology; D051150:Methionine Sulfoxide Reductases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; C035120:N-acetylmethionine sulfoxide; D008715:Methionine; D051150:Methionine Sulfoxide Reductases; C013111:methionine sulfoxide