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Senescent cells linked to brain disease in mice

Illustration of cells in the brain, including neurons (yellow), astrocytes (orange), and microglia (white). The researchers found that astrocytes and microglia became senescent in a mouse model of neurodegenerative disease. selvanegra/iStock /Getty Images Plus

In neurodegenerative diseases, deposits of certain abnormal proteins accumulate in the brain. These deposits are thought to damage healthy nerve cells, causing them to stop working and die.

Previous studies have suggested that senescent cells might also play a role in certain neurodegenerative diseases. Senescent cells are old or damaged cells that have stopped dividing to produce new cells. Over time, senescent cells can build up in the body and contribute to disease.

A research team led by Dr. Darren J. Baker of the Mayo Clinic set out to determine whether senescent cells play a role in neurodegenerative diseases. Their work was funded in part by NIH’s National Institute on Aging (NIA). The study results were published in Nature on September 19, 2018.

The team used a mouse model of neurodegenerative disease called MAPT^P301SPS19 (or "PS19"). They genetically modified the model so that senescent cells would be eliminated when the mice received injections of a specific compound. The mice were treated from 3 weeks of age until 6 months old.

The researchers confirmed that the treated PS19 mice did not have senescent cells in their brains. These mice also had reduced markers of brain disease, such as tau protein tangles and abnormal structural changes. The team closely examined untreated PS19 mice and found that the senescent cells in their brains were astrocytes and microglia, the cells that hold nerve cells in place and help them work the way they should.

Next, the researchers tested short-term memory with scented candle and visual cue tests. PS19 mice that were treated to eliminate senescent cells performed better on the short-term memory tests. These results suggest that senescent cells lead to neurodegenerative disease and memory problems in this mouse model.

The team tried to reproduce their findings using a research drug called ABT263, which selectively kills senescent cells. They treated PS19 mice with ABT263 from 3 weeks to 6 months old. The drug prevented or reduced tau protein tangles and signs of senescence and inflammation in the brain. This finding suggests that a drug may be able to help prevent neurodegenerative disease if given before senescent cells develop.

“Senescent cells are known to accumulate with advancing natural age and at sites related to diseases of aging, including osteoarthritis; atherosclerosis; and neurodegenerative diseases, such as Alzheimer's and Parkinson’s,” Baker says. “We had no idea whether senescent cells actively contributed to disease pathology in the brain, and to find that it's the astrocytes and microglia that are prone to senescence is somewhat of a surprise, as well.”

The research team is now working to discover the specific molecular changes in senescent cells that may contribute to neurodegenerative disease. More research is needed to determine whether these findings might apply to people.

—by Geri Piazza