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DNA Damage, Brain Function, and Neurodegeneration

03/26/2013
Jesse Jenkins

What is the role of DNA damage in healthy brain function and neurodegenerative disease? A new study delves into the relationship between double-strand DNA breaks and brain network activity. Learn more...

Progressive neuronal DNA damage in aging brains has been closely linked with the onset of neurodegenerative disorders such as Alzheimer’s disease. However, a new study suggests that one type of neuronal damage, double-strand DNA breaks (DSBs), might also be a regular part of healthy learning and memory functions.

“The most surprising to me is the ability of normal brain activity to increase DNA breaks and the very rapid repair,” said Dr. Lennart Mucke, Director and Senior Investigator at Gladstone Institutes, who led the study. “That suggests this dynamic of breaking and repairing DNA is part and parcel of normal brain activity, and we’re dying to find out what its meaning is.”

In a paper published in Nature Neuroscience, Mucke’s team also reported the effects of two separate treatments for the accumulation of neuronal DSB damage related to the brain’s overproduction of the amyloid-ß protein–a protein thought to be a significant cause of Alzheimer’s.

“We demonstrated for the first time that blocking the abnormal brain network activity that amyloid proteins cause can totally prevent the DNA breaks,” said Mucke.

In the study, Mucke’s team observed two groups of mice–transgenic Alzheimer’s model mice with increased levels of amyloid proteins and healthy controls. The mice were introduced to new environments with different types of visual stimulation for 2 hours and then placed back into their home cages to rest for 24 hours.

Mucke and colleagues carefully analyzed nerve cells in different brain regions that showed evidence for DSBs. By microscopy, the team was able to count the number of neurons that had markers of DNA breaks. The results showed that the mice’s activities led to an increase in DSBs, especially in the dentate gyrus, a brain region that is involved in learning and memory. Within 24 hours, the breaks were found to be repaired in the healthy mice but not in the mice with elevated levels of amyloid proteins.

“The amyloid proteins seemed to not only increase the number of breaks at baseline by changing the activity pattern in the brain, but they also seem to delay the repair when there had been an exploration-related increase in the breakage,” said Mucke. “And over time that could of course lead to the accumulation of DNA damage.”

During their investigation, the group also found that they could prevent accumulation of the DNA damage caused by the amyloid proteins through two different strategies. First, they were able to improve neuronal connectivity in the Alzheimer’s-type mice using an FDA approved anti-epileptic drug called Levetiracetam. Second, the team was able to regulate the tau protein, which has been shown to cooperate with amyloid proteins in increasing DSB levels.

According to Mucke, both methods may offer a solution to preventing the increase in DNA breaks caused by the amyloid proteins. “[It’s] exciting because it means that one can probably protect the DNA inside nerve cells from at least some of the amyloid-related damage by changing the activity of neuronal networks, which we achieved by these two different strategies,” Mucke explained.

Mucke says that the findings could lead to future research into the role of DSBs in neuroplasticity–the ability of the nervous system to adapt to changes in the environment

But for now, Mucke and his lab are investigating whether these DSBs might occur randomly in chromosomes or if they actually take place at very specific sites involved in learning and memory.

“That’s a very interesting endeavor in an effort to better understand what role [DSBs] might play,” said Mucke.

1. Suberbielle, E., A.V. Kravitz, X. Wang, K. Ho, K. Eilertson, N. Devidze, A.C. Kreitzer, and L. Mucke, Physiologic neuron activity causes DNA double-strand breaks in neurons, with exacerbation by amyloid-ß. Nature Neuroscience, doi:10.1038/nn3356, 2013.