HN Summary
• Researchers identified brain cells that may contribute to age-related cognitive decline when they become dysfunctional.
• Lower levels of the protein NRF2 were linked to greater cognitive decline, suggesting cell function may matter more than cell numbers.
• Existing multiple sclerosis drugs targeting NRF2 could potentially be repurposed, opening a new avenue for treating cognitive decline.
A study led by St. Michael’s Hospital researchers found that specialized brain cells that produce myelin can become dysfunctional and actively contribute to cognitive decline during aging. The study, published Tuesday in Nature Medicine, looked at oligodendrocytes, cells that help to speed communication between brain regions supporting learning and memory.
What they found
• Researchers found that oligodendrocytes, long believed to play a largely supportive role in brain health, can become dysfunctional and actively contribute to cognitive decline.
• Researchers also identified that people with severe cognitive decline had lower levels of the protein NRF2 in oligodendrocytes. NRF2 helps cells respond to stress and maintain healthy cellular function.
• Because several existing drugs that activate NRF2 are used in multiple sclerosis, they could potentially be repurposed to treat age-related cognitive decline.
• People experiencing greater cognitive decline also showed significant changes in the brain’s nerve fibers, including thicker-than-normal myelin, the coating that wraps around nerve fibers in the brain and spinal cord.
• Experiments in mice validated those findings and showed blunted improvements in cognitive performance as they aged.
How they did it
The study authors investigated the health of white matter in the brain as it relates to cognitive decline by examining samples from the longest running study of human cognition called the Lothian Birth Cohort. Those studied in this cohort were born in 1936 in Scotland and their IQs were tested at age 11, again at 70, and approximately every three years until passing. Almost all those over age 70 exhibited cognitive decline as they aged.
The researchers identified the cellular, structural and molecular changes in the white matter of the brain that are associated with age-related cognitive decline.
Building on the human cohort findings, the researchers leveraged a mechanistic mouse model to determine whether oligodendrocyte dysfunction alone could cause the white matter abnormalities that contribute to cognitive impairment during aging.
Why it matters
The findings indicate that treatment strategies focused on increasing oligodendrocytes may not be the most effective way to address cognitive decline in humans.
In fact, these therapeutic strategies could be potentially detrimental to human health. Based on the study’s findings, those with cognitive decline had higher numbers of oligodendrocytes which suggests that oligodendrocyte function, as opposed to abundance, may be critical for maintaining cognitive health.
The NRF2 pathway that underlies the oligodendrocyte dysfunction, is already targeted by several existing therapies seen in the treatment of multiple sclerosis. There could be potential in rapidly repurposing these drugs for age-related cognitive decline.
What’s next
As cognitive decline becomes increasingly common in aging populations, these findings open new avenues for developing treatments that target oligodendrocyte dysfunction and the NRF2 pathway.
Veronique Miron – is the John David Eaton Chair in Multiple Sclerosis Research at the Barlo MS Centre and the Keenan Research Centre for Biomedical Science at St. Michael’s Hospital, part of Unity Health Toronto. Georgina Craig – is a postdoctoral fellow at the Miron lab at St. Michael’s Hospital, part of Unity Health Toronto.