Exercise-induced DNA damage response and memory formation in mice

Ricciardi, N. R.; McCartan, R.; Laverde Paz, J.; Cao, H.; Borja, C.; Cherry, A.; Baranov, A.; Locklear, C.; Wojcikowska, O.; Zeier, Z.; Kapranov, P.; Wahlestedt, C.; Volmar, C.-H.

doi:10.1101/2025.09.26.678909

bioRxiv · 10.1101/2025.09.26.678909

Exercise-induced DNA damage response and memory formation in mice

Ricciardi, N. R.·McCartan, R.·Laverde Paz, J.·Cao, H.·Borja, C.·Cherry, A.·Baranov, A.·Locklear, C.·Wojcikowska, O.·Zeier, Z.·Kapranov, P.·Wahlestedt, C.·Volmar, C.-H.

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Abstract

This study reveals that acute aerobic exercise enhances memory formation through a controlled DNA damage mechanism, offering crucial insights into Alzheimers disease (AD) prevention. This work challenges the traditional view that DNA damage is inherently harmful, demonstrating that minor, reversible DNA single-strand breaks (SSBs) induced by exercise serve as necessary primers for memory consolidation - a mechanism that may be impaired in AD pathogenesis. AD affects 1 in 9 adults over 65, with ~95% being late-onset cases where up to 40% of risk factors are modifiable through lifestyle interventions like exercise. While exercise demonstrably lowers AD risk, underlying mechanisms remain unclear. This study provides a missing mechanistic link by showing how exercise-induced DNA damage repair systems could counteract the DNA damage accumulation and repair dysregulation that are established hallmarks of brain aging and AD. In data presented herein, young mice showed significantly higher SSB rates in active genomic regions compared to aged mice, suggesting the decline of a protective mechanism (i.e., hormesis) with aging - potentially explaining increased AD susceptibility in older adults. The present study also suggests that exercise-induced SSBs are not random cellular damage but precisely targeted events that occur at genes essential for neuroplasticity, synaptic function, and memory formation. These breaks activate PARP1 (Poly ADP ribose polymerase 1), a crucial DNA damage sensor that simultaneously initiates repair processes while facilitating transcriptional programs necessary for memory consolidation. This mechanism may represent how exercise "primes" the brain against the pathological DNA damage accumulation seen in AD. In support of this, in behavioral experiments, a single exercise bout converted sub-threshold learning into robust long-term memory formation. This memory enhancement correlated with upregulation of both neurotrophic genes (BDNF, Fos) and DNA repair enzymes (PARP1, PARP2), demonstrating coordinated damage-repair processes that appear compromised in AD. We identify HPF1 as a critical cofactor enabling PARP1 to perform trans-ADP-ribosylation of histones, linking DNA damage sensing to epigenetic chromatin remodeling required for memory-related gene expression. This pathway represents a novel therapeutic target for AD, as restoring efficient DNA repair mechanisms might slow or prevent memory loss.

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Ricciardi, N. R., McCartan, R., Laverde Paz, J., Cao, H., Borja, C., Cherry, A., Baranov, A., Locklear, C., Wojcikowska, O., Zeier, Z., Kapranov, P., Wahlestedt, C., Volmar, C.-H.. 2025-09-28. Exercise-induced DNA damage response and memory formation in mice. https://doi.org/10.1101/2025.09.26.678909

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