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Study reveals how nerve cells recruit brain’s immune cells to repair their damaged DNA 

Study reveals how nerve cells recruit brain’s immune cells to repair their damaged DNA 

A recent study from MIT found that nerve cells team up with microglia to clear damaged DNA strands – opens avenues to explore targeted therapy for neurodegenerative disorders.
Representational image | Shutterstock

A just-published study in Science Advances (on September 28) reveals that when nerve cells in the brain cannot repair their damaged DNA, they seek help from the brain’s resident immune cells called microglia.  

This DNA damage in neurons is a precursor to various neurodegenerative disorders such as Alzheimer’s. 

“This is a novel concept in neuroscience. The general idea was that neurons have a more passive relationship with microglia with age-associated neuroinflammation,” said Gwyneth Welch, the study’s lead author from the Picower Institute of Learning and Memory, MIT, in a statement. 

The human DNA is a double helical structure; damage can happen to it when either or both strands break. In neurons, such DNA breaks can affect synapses leading to neurodegeneration. Synapses are non-contact regions between nerve cells through which they communicate with each other.  

The team found that when the DNA strand breaks accumulate, the neurons first try to clear out the damaged parts through their internal repair mechanisms. However, when they fail, they seek help from microglia cells in the brain. The researchers deciphered the steps in this communication and found that a gene-activating protein called Nuclear Factor KappaB (NFkappaB) and two cytokines facilitated this communication.  

In response, the microglia induce intense inflammation in the neurons to clear the DNA strand breaks. However, this process affects the neuron’s synapses, leading to some neurons losing their function.  

The researchers hypothesised that the build-up of DNA strand breaks could lead to Alzheimer’s. “We previously observed profound DNA damage in neurons in the early stages of neurodegeneration,” said Prof Li Huei Tsai, the senior author in the statement.  

The team further investigated the signalling process by performing experiments on two groups of mice — one with an Alzheimer-like disease and the other without. In the non-diseased group, they induced double-strand breaks to compare the roles of the genes in both groups. They found that both mouse groups had similar genes involved in the process, confirming that accumulating DNA breaks were responsible for neurodegeneration. Also, the team looked at the brain tissues of deceased people with Alzheimer’s and DNA breaks.  

They found similar patterns where, in the brain tissue with Alzheimer’s, the microglial gene activity was more, suggesting that this type of DNA damage activated the brain’s immune system in disease-associated neuroinflammation. Even in mice, parts of the brain with more DNA damage had a relatively high amount of microglia in an inflammatory state.  

In further experiments, the researchers disrupted the cytokines and NFkappaB activity to reduce the inflammation in neurons. They found that targeting cytokines was more effective in preserving nerve cell activity and cognitive function than NFkappaB, which has other crucial cell functions.   

“It’s more a proof of principle that if you turn off a major switch for inflammation, that will change how microglia and neurons interact,” Welch said. “If your goal is to target inflammatory pathways, focussing on specific signalling molecules might be the more precise way to intervene,” she added.  

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