Editors' ChoiceAlzheimer’s Disease

Mental Break(down) in the Nucleus

See allHide authors and affiliations

Science Translational Medicine  10 Jul 2013:
Vol. 5, Issue 193, pp. 193ec114
DOI: 10.1126/scitranslmed.3006921

DNA damage is a potentially dangerous consequence of cellular stress and aging and is closely associated with the development of cellular malignancies. In the brain, double-stranded breaks in the DNA have been associated with the development of age-related neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease.

An exciting study by Suberbielle et al. now challenges our understanding of gene expression regulation in healthy neurons by suggesting that active DNA damage and repair mechanisms are an integral part of normal brain activity. Furthermore, the study provides evidence suggesting that aberrant functioning of this process in a mouse model of Alzheimer’s disease may contribute to the development of this disorder.

In an elegant set of experiments, Suberbielle et al. show that normal brain activity, such as that initiated by the exploration of a new environment, can cause a transient (<24 hours) increase in the recruitment of the DNA double-strand break (DSB) markers γ-H2AX and 53BP1 in neurons of young adult wild-type mice. The authors provide extensive evidence that the observed increase in potential DSBs occurred as a direct result of physiological neuronal activation and appeared most abundant in the brain regions affected by the specific behavior, including the hippocampus, which is involved in learning and memory. The authors then turned to the J20 mouse model of Alzheimer’s disease, which expresses the human precursor protein of amyloid ß (hAPP) at high levels and displays several characteristic features of the disease, including impaired learning and memory. In comparison with wild-type neurons in which DNA damage induced by neuronal activity was resolved within 24 hours, hAPP mice as young as 1 month of age displayed increased and persistent DNA damage both at baseline and 24 hours after exploration of a new environment. These results suggest that high concentrations of amyloid in the brains of these mice might interfere with the normal process by either causing exacerbated neuronal activity or preventing consecutive DNA repair. Indeed, supporting the former, suppression of aberrant neuronal network activity in hAPP mice—either by genetic deletion of the tau protein or treatment with the antiepileptic drug levetiracetam—normalized the occurrence of DSB foci in neurons. Readily available drugs that suppress excessive neuronal activity or aberrant network function might therefore help to protect neurons against some of the nuclear damage induced in Alzheimer’s disease.

The authors use three well-established readouts of DSB formation (γ-H2AX, 53BP1 colocalization, and the comet assay), but the final proof that the observed changes indeed represent DSBs (as opposed to changes in neuronal chromatin flexibility or an attempt by neurons to reenter the cell cycle) is still missing. Although many questions remain to be answered, the study by Suberbielle et al. suggests that our neurons are playing a “Russian roulette” between a high degree of activity-induced gene expression regulation and potentially lethal damage to neuronal DNA.

E. Suberbielle et al., Physiologic brain activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-β. Nat. Neurosci. 16, 613–621 (2013). [Abstract]

Stay Connected to Science Translational Medicine

Navigate This Article