Mitochondrial methionine sulfoxide reductase B2 links oxidative stress to Alzheimer's disease-like pathology.

Affiliation

Department of Neurology, the First Affiliated Hospital of Chongqing Medical University, Chongqing Key Laboratory of Neurology, 1 Youyi Road, Chongqing 400016, China. Electronic address: [Email]

Abstract

Methionine sulfoxide reductase B2 (MSRB2) is a mitochondrial protein that protects cell from oxidative stress. The antioxidant activity suggests that MSRB2 may play a role in the pathophysiology of Alzheimer's disease (AD). Here, we report that in APP/PS1 mice, an animal model of AD, MSRB2 protein levels were decreased in the hippocampus at both young (6 mon) and old (18 mon) age, and in the cortex only at an old age, respectively. In HEK293 cells that stably express human full-length β-amyloid precursor protein (APP, HEK/APP), MSRB2 reduced the protein and mRNA levels of APP and β-amyloid converting enzyme 1 (BACE1), and the consequent amyloid beta peptide (Aβ) 1-40 and Aβ1-42 levels. MSRB2 overexpression or knockdown also oppositely affected Tau phosphorylation at selective sites, with the concomitant alteration of the phosphorylated extracellular signal regulated kinase (p-ERK) and AMP-activated protein kinase (p-AMPK) levels. Moreover, in cells treated with long-term (24 h) hydrogen peroxide, the alterations of APP processing and Tau phosphorylation were reversed by MSRB2 overexpression. We further found that MSRB2-mediated regulation of APP transcription involved JNK and ERK signaling, as MSRB2 also reduced the levels of phosphorylated JNK (p-JNK), and JNK or ERK inhibitor attenuated the effect of MSRB2 on APP proteins and transcripts. Finally, MSRB2 reduced apoptosis-related proteins Bax and caspase3 and enhanced the anti-apoptotic protein Bcl2. These results indicated that the role for MSRB2 in AD-like pathology was closely associated with its antioxidant activity. By attenuating both amyloidogenesis and Tau phosphorylation, MSRB2 may serve as a potential therapeutic target for AD.

Keywords

APP,APP/PS1 mice,JNK,Methionine sulfoxide reductase B2,Oxidative stress,Phosphorylation,Tau,Transcription,

OUR Recent Articles