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BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1

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Abstract

Brain-derived neurotrophic factor (BDNF) promotes the survival and growth of neurons during brain development and mediates activity-dependent synaptic plasticity and associated learning and memory in the adult. BDNF levels are reduced in brain regions affected in Alzheimer’s, Parkinson’s, and Huntington’s diseases, and elevation of BDNF levels can ameliorate neuronal dysfunction and degeneration in experimental models of these diseases. Because neurons accumulate oxidative lesions in their DNA during normal activity and in neurodegenerative disorders, we determined whether and how BDNF affects the ability of neurons to cope with oxidative DNA damage. We found that BDNF protects cerebral cortical neurons against oxidative DNA damage-induced death by a mechanism involving enhanced DNA repair. BDNF stimulates DNA repair by activating cyclic AMP response element-binding protein (CREB), which, in turn, induces the expression of apurinic/apyrimidinic endonuclease 1 (APE1), a key enzyme in the base excision DNA repair pathway. Suppression of either APE1 or TrkB by RNA interference abolishes the ability of BDNF to protect neurons against oxidized DNA damage-induced death. The ability of BDNF to activate CREB and upregulate APE1 expression is abolished by shRNA of TrkB as well as inhibitors of TrkB, PI3 kinase, and Akt kinase. Voluntary running wheel exercise significantly increases levels of BDNF, activates CREB, and upregulates APE1 in the cerebral cortex and hippocampus of mice, suggesting a novel mechanism whereby exercise may protect neurons from oxidative DNA damage. Our findings reveal a previously unknown ability of BDNF to enhance DNA repair by inducing the expression of the DNA repair enzyme APE1.

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Acknowledgments

This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health, Chang Gung Medical Foundation Grant No. CLRPG871342, CMRPG8A0781, CRPG8B0051, and research grants NSC 101-2320-B-182A-007- and NSC 102-2320-B-182A-012- from National Science Council Taiwan.

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The authors declare that they have no conflicts of interest to report.

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Authors and Affiliations

  1. Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA

    Jenq-Lin Yang & Mark P. Mattson

  2. Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD, 21224, USA

    Jenq-Lin Yang & Vilhelm A. Bohr

  3. Center for Translation Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, 83301, Taiwan

    Jenq-Lin Yang & Yu-Ting Lin

  4. Department of Medical Research, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung, 83301, Taiwan

    Pei-Chin Chuang

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  1. Jenq-Lin Yang
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  2. Yu-Ting Lin
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  4. Vilhelm A. Bohr
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Correspondence to Mark P. Mattson.

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Vilhelm A. Bohr and Mark P. Mattson are senior authors and have contributed equally to this work.

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Yang, JL., Lin, YT., Chuang, PC. et al. BDNF and Exercise Enhance Neuronal DNA Repair by Stimulating CREB-Mediated Production of Apurinic/Apyrimidinic Endonuclease 1. Neuromol Med 16, 161–174 (2014). https://doi.org/10.1007/s12017-013-8270-x

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