NeuroMolecular Medicine

, Volume 16, Issue 1, pp 161–174 | Cite as

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

  • Jenq-Lin Yang
  • Yu-Ting Lin
  • Pei-Chin Chuang
  • Vilhelm A. Bohr
  • Mark P. Mattson
Original Paper

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.

Keywords

Running Base excision repair Exercise Alzheimer Oxidative stress Akt kinase Synaptic plasticity Comet assay 

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Copyright information

© Springer Science+Business Media New York (outside the USA) 2013

Authors and Affiliations

  • Jenq-Lin Yang
    • 1
    • 2
    • 3
  • Yu-Ting Lin
    • 3
  • Pei-Chin Chuang
    • 4
  • Vilhelm A. Bohr
    • 2
  • Mark P. Mattson
    • 1
  1. 1.Laboratory of NeurosciencesNational Institute on Aging Intramural Research ProgramBaltimoreUSA
  2. 2.Laboratory of Molecular GerontologyNational Institute on Aging Intramural Research ProgramBaltimoreUSA
  3. 3.Center for Translation Research in Biomedical SciencesKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
  4. 4.Department of Medical ResearchKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan

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