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"MUSIC map shows that some brain cells age faster
Last reviewed: 02.07.2025
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Engineers at the University of California, San Diego, have discovered that some brain cells age faster than others, and they are disproportionately abundant in people with Alzheimer's disease. The researchers also observed differences in the aging process of certain brain cells depending on gender: The cerebral cortex of women has a higher proportion of "old" oligodendrocytes compared to "old" neurons compared to the cortex of men.
These discoveries were made possible by a new technique called MUSIC (mapping of nucleic acid interactions in single cells), which allows researchers to peer inside individual brain cells and map the interactions between chromatin — the tightly coiled form of DNA — and RNA. The technique makes it possible to visualize these interactions at the level of individual cells and study how they affect gene expression.
"MUSIC is a powerful tool that allows us to gain deeper insight into the complex aspects of Alzheimer's disease," said senior study author Sheng Zhong, a professor in the Shu Chien-Gen Lai Department of Bioengineering in the Jacobs School of Engineering at the University of California, San Diego.
"This technology has the potential to uncover new molecular mechanisms underlying Alzheimer's disease pathology, which could pave the way for more targeted therapeutic interventions and improved outcomes for patients."
The human brain contains a complex network of cells that communicate and interact in complex ways. Within each of these cells, genetic components, including chromatin and RNA, interact dynamically to determine critical cellular functions. As brain cells grow and age, these interactions between chromatin and RNA change. And these complexes can vary greatly from cell to cell, especially in mature cells. Unraveling the intricacies of these interactions, however, has remained a challenge.
To the rescue came a technique called MUSIC, which provides a window into the inner workings of individual brain cells. Using MUSIC, Zhong’s team analyzed postmortem brain samples, specifically human frontal cortex tissue, from 14 donors aged 59 and older, some with Alzheimer’s disease and some without.
They found that different types of brain cells exhibited different patterns of interactions between chromatin and RNA. Interestingly, cells with fewer short chromatin interactions tended to show signs of aging and Alzheimer's disease.
“By using this transformative technology to analyze individual cells, we found that some brain cells are older than others,” Zhong said. He explained that people with Alzheimer’s had a higher number of these older brain cells than healthy people.
Researchers believe the discovery could help develop new treatments for Alzheimer's disease.
"If we can identify dysregulated genes in these old cells and understand their functions in the local chromatin structure, we may also be able to identify new potential therapeutic targets," said first author of the study Xingzhao Wen, a bioinformatics PhD candidate in Zhong's lab.
The study also found sex differences in how brain cells age. In the cerebral cortex of women, the researchers found a higher ratio of old oligodendrocytes to old neurons. Oligodendrocytes are a type of brain cell that form a protective layer around neurons. Given their critical role in maintaining normal brain function, increased numbers of old oligodendrocytes may exacerbate cognitive decline.
"The disproportionate presence of senescent oligodendrocytes in the cerebral cortex of women may shed new light on the increased risks of neurodegenerative and psychiatric disorders observed in women," Wen said.
The next step for the researchers will be to further optimize MUSIC so that it can be used to identify factors—such as regulatory genes and genetic circuits—that are responsible for accelerated aging in certain brain cells.
"We will then develop strategies to suppress the activity of these genes or circuits, hoping to slow down brain aging," Zhong said.
The results of the work are described in detail in an article published in the journal Nature.