title: Methionine sulfoxide reductase A affects β-amyloid solubility and mitochondrial function in a mouse model of Alzheimer's disease.
abstract: Accumulation of oxidized proteins, and especially β-amyloid (Aβ), is thought to be one of the common causes of Alzheimer's disease (AD). The current studies determine the effect of an in vivo methionine sulfoxidation of Aβ through ablation of the methionine sulfoxide reductase A (MsrA) in a mouse model of AD, a mouse that overexpresses amyloid precursor protein (APP) and Aβ in neurons. Lack of MsrA fosters the formation of methionine sulfoxide in proteins, and thus its ablation in the AD-mouse model will increase the formation of methionine sulfoxide in Aβ. Indeed, the novel MsrA-deficient APP mice (APP(+)/MsrAKO) exhibited higher levels of soluble Aβ in brain compared with APP(+) mice. Furthermore, mitochondrial respiration and the activity of cytochrome c oxidase were compromised in the APP(+)/MsrAKO compared with control mice. These results suggest that lower MsrA activity modifies Aβ solubility properties and causes mitochondrial dysfunction, and augmenting its activity may be beneficial in delaying AD progression.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas moskovij@ku.edu.
authors.forename: Jackob
authors.initials: J
authors.lastname: Moskovitz
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas.
authors.forename: Fang
authors.initials: F
authors.lastname: Du
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas.
authors.forename: Connor F
authors.initials: CF
authors.lastname: Bowman
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, Kansas.
authors.forename: Shirley S
authors.initials: SS
authors.lastname: Yan
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000378:metabolism*; D019069:Cell Respiration / Q000235:genetics; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D055879:Gene Knock-In Techniques; D008715:Methionine / Q000031:analogs & derivatives* / Q000378:metabolism; D051150:Methionine Sulfoxide Reductases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism*; D012995:Solubility
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D008715:Methionine; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; D003576:Electron Transport Complex IV; C013111:methionine sulfoxide
keywords: Alzheimer's disease; mitochondria; oxidative stress; posttranslational modification