BDNF and exercise enhance neuronal DNA repair by stimulating CREB-mediated production of apurinic/apyrimidinic endonuclease 1
Open accessAbstract
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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BDNF promotes DNA repair by activating the transcription factor CREB and the base excision repair enzyme APE1.
“BDNF promotes DNA repair by activating the transcription factor cAMP responsive element binding protein 1 (CREB) and the base excision repair enzyme apurinic/apyrimidinic endonuclease 1 (APE1) (37).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [37]
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“…including exercise and intermittent fasting, which were previously reported to enhance autophagy and stimulate CREB signaling (Altarejos and Montminy 2011; Mattson 2012; Jamart et al. 2013; Yang et al. 2014), even though DNP has the specific effect to enhance energy (a) (b) (c) (d) (e) Fig.”
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- Authors
- Yang, J.-L., Lin, Y.-T., Chuang, P.-C., Bohr, V. A., & Mattson, M. P.
- Affiliations
- Kaohsiung Chang Gung Memorial Hospital (TW)
- National Institutes of Health (US)
- National Institute on Aging (US)
- Corresponding author
- Mattson, Mark P.
- Venue
- NeuroMolecular Medicine
- Published
- 2013-10-10
- Volume
- 16
- Issue
- 1
- Pages
- 161-174
- ISSN
- 1535-1084 (ISSN-L)
- 1559-1174
- PMC
- PMC3948322
- OpenAlex
- W2028791716
- Cited by
- 159
- References
- 51
- Citations by year
- 2026: 7 · 2025: 13 · 2024: 9 · 2023: 13 · 2022: 13 · 2021: 16 · 2020: 17 · 2019: 11 · 2018: 12 · 2017: 10 · 2016: 12 · 2015: 12 · 2014: 13 · 2013: 1
- FWCI
- 6.22
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- NeuroMolecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Institute on Aging (ZIAAG000313, ZIAAG000314, ZIAAG000331)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nerve injury and regeneration
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- brain-derived neurotrophic factor, physical activity, oxidative DNA damage, DNA repair, APE1, CREB, TrkB, base excision repair, neuronal survival, neuroprotection, neurodegenerative diseases, PI3K/Akt signaling, voluntary running, cerebral cortex, hippocampus
- MeSH terms
- Animals, Cerebral Cortex, DNA Repair, Enzyme Induction, Hippocampus, Male, Mice, Inbred C57BL, Nerve Tissue Proteins, Neurons, Physical Conditioning, Animal, Random Allocation, Rats, Sprague-Dawley, Cyclic AMP Response Element-Binding Protein, Brain-Derived Neurotrophic Factor, Receptor, trkB, Vitamin K 3, RNA Interference, RNA, Small Interfering, DNA-(Apurinic or Apyrimidinic Site) Lyase, Proto-Oncogene Proteins c-akt, Mice, Rats
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