Journal
AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM
Volume 310, Issue 6, Pages E388-E393Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpendo.00453.2015
Keywords
posttranslational modification; Alzheimer's disease; mitochondria; oxidative stress
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Funding
- Hedwig Miller Fund for Aging Research
- Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health [P20 GM-103418]
- KU ADC [P30-AG-035982]
- Landon Center on Aging
- National Institute on Aging of the National Institutes of Health [R37AG037319]
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Accumulation of oxidized proteins, and especially beta-amyloid (A beta), 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 A beta through ablation of the methionine sulfoxide reductase A (MsrA) in a mouse model of AD, a mouse that overexpresses amyloid precursor protein (APP) and A beta 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 A beta. Indeed, the novel MsrA-deficient APP mice (APP(+)/MsrAKO) exhibited higher levels of soluble A beta 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 A beta solubility properties and causes mitochondrial dysfunction, and augmenting its activity may be beneficial in delaying AD progression.
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