title: BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1.
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.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA; Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA; Center for Translation Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung 83301, Taiwan.
authors.forename: Jenq-Lin
authors.initials: JL
authors.lastname: Yang
authors.affiliation: Center for Translation Research in Biomedical Sciences, Kaohsiung Chang Gung Memorial Hospital, 123 Ta Pei Road, Kaohsiung 83301, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Lin
authors.affiliation: Department of Medical Research, Kaohsiung Chang Gung, Memorial Hospital, 123 Ta Pei Road, Kaohsiung 83301, Taiwan.
authors.forename: Pei-Chin
authors.initials: PC
authors.lastname: Chuang
authors.affiliation: Laboratory of Molecular Gerontology, National Institute on Aging Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Vilhelm A
authors.initials: VA
authors.lastname: Bohr
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, 251 Bayview Boulevard, Baltimore, MD 21224, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology / Q000502:physiology*; D002540:Cerebral Cortex / Q000166:cytology; D017362:Cyclic AMP Response Element-Binding Protein / Q000037:antagonists & inhibitors / Q000502:physiology*; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020813:Receptor, trkB / Q000037:antagonists & inhibitors / Q000502:physiology; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; C508137:Creb1 protein, rat; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D024483:Vitamin K 3; D020813:Receptor, trkB; C514862:Akt1 protein, mouse; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; C486216:Apex1 protein, mouse; C470319:Apex1 protein, rat; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase