Enhanced Phosphorylation of Bax and Its Translocation into Mitochondria in the Brains of Individuals Affiliated with Alzheimer’s Disease
L.E. Henderson1, M.A. Abdelmegeed1, S.H. Yoo1, S.G. Rhee2, X. Zhu3, M.A. Smith3, R.Q. Nguyen4, G. Perry4, *, B.J. Song1, *
1 Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9410, USA
2 Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul, Korea
3 Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
4 Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA
Despite increased neuronal death, senile plaques, and neurofibrillary tangles observed in patients suffering from Alzheimer’s disease (AD), the detailed mechanism of cell death in AD is still poorly understood.
We hypothesized that p38 kinase activates and then phosphorylates Bax, leading to its translocation to mitochondria in AD brains compared to controls. The aim of this study was to investigate the role of p38 kinase in phosphorylation and sub-cellular localization of pro-apoptotic Bax in the frontal cortex of the brains from AD and control subjects. Increased oxidative stress in AD individuals compared to control was evaluated by measuring the levels of carbonylated proteins and oxidized peroxiredoxin, an antioxidant enzyme. The relative amounts of p38 kinase and phospho-Bax in mitochondria in AD brains and controls were determined by immunoblot analysis using the respective antibody against each protein following immunoprecipitation.
Our results showed that the levels of oxidized peroxiredoxin-SO3 and carbonylated proteins are significantly elevated in AD brains compared to controls, demonstrating the increased oxidative stress.
The amount of phospho-p38 kinase is increased in AD brains and the activated p38 kinase appears to phosphorylate Thr residue(s) of Bax, which leads to its mitochondrial translocation, contributing to apoptosis and ultimately, neurodegeneration.
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* Address correspondence to this author at the Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-9410, USA; Tel: +1-82-2-2740-8360; Fax: +1-301-594-3113; E-mail: firstname.lastname@example.org; Department of Biology, College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA; Tel: +12104584450; Fax: +12104584445; E-mail: email@example.com