Researchers from the University of California, San Francisco (UCSF) say they have now found that when the brain cells of female mice express only a maternal X chromosome, the animals’ memory and cognitive skills deteriorate faster than in female mice that express both maternal and paternal X chromosomes. The discovery, the researchers suggest, could explain the variation in brain aging between the sexes—males inherit only a maternal X chromosome—as well as variation between individual women.
“These findings raise the possibility that some women who express more of their mom’s X chromosome just by pure chance may have more cognitive impairment with aging or an increased risk for diseases like Alzheimer’s,” said Dena Dubal, MD, PhD, a professor of neurology and the David A. Coulter Endowed Chair in Aging and Neurodegenerative Disease at UCSF. “Ultimately, it could also help us find constructive strategies for slowing brain aging in both sexes.”
Reporting on their findings in Nature, “The maternal X chromosome affects cognition and brain aging in female mice,” co-senior author Dubal and colleagues concluded, “Understanding how Xm impairs brain function could lead to an improved understanding of heterogeneity in cognitive health in female individuals and to X-chromosome-derived pathways that protect against cognitive deficits and brain aging.”
Previous research has hinted that the X chromosome is vital to brain health. Mutations in the X chromosome may cause intellectual disability, and women born with just one X chromosome (a diagnosis known as Turner syndrome) can have cognitive impairments, they further pointed out. “In the context of X chromosomal abnormalities, female individuals with Turner’s syndrome (45,XO) experience greater cognitive impairment when the X chromosome is maternally compared with paternally inherited, a finding also observed in mouse models of Turner’s syndrome.”
Inactivation of either the maternal or paternal X chromosome causes X mosaicism, and this varies between female individuals, the researchers explained, “… with some showing considerable or complete skew of the X chromosome that remains active … however, whether X skew or its mosaicism alters functions in female individuals is largely unknown.”
X chromosomes, some researchers hypothesize, could help explain sex differences in cognition, verbal memory, or brain disease risk. The authors noted, “In the brain, more genes are expressed from the X chromosome than from any single autosome, thus, the brain is probably more sensitive to alterations in X-chromosome-linked gene expression.”
Dubal and first author Samira Abdulai-Saiku, PhD, a UCSF postdoctoral fellow, were especially interested in whether the origin of the X chromosome—from mom or from dad— mattered to cells. They knew that when egg and sperm cells form, chemical tags are added to certain genes on the chromosomes. These marks differ depending on whether the chromosome is from the mother (egg) or father (sperm). The marks impact what genes are activated when each chromosome is used in cells.
Abdulai-Saiku stated, “Given the fact that the X chromosome is enriched for brain-related genes, it became very important for us to know what roles it might be playing in brain aging.”
Added Dubal: “Skewing of the X chromosome is common among humans, and there are certainly women who are walking around with much higher or lower levels of maternal X chromosomes than others, just by chance …There has been little research on the potential consequences of this.”
For their newly reported study, the team wanted to see whether a skew toward an active Xm chromosome impacts the brain and body, and also to evaluate “… unique features of Xm neurons and Xp neurons.”
To investigate this they bred female mice either to express only maternal X chromosomes, or a mixture of maternal and paternal X chromosomes. Their results showed that female mice with only an active maternal X chromosome showed poorer memory and learning abilities as they aged. In the brains of these mice, the maternal X chromosome sped up biological aging in the hippocampus—a brain area crucial for learning and memory.
“What we showed is that these animals’ brains were really aging faster than the brains of their genetically identical sisters who had both mom’s and dad’s X chromosomes turned on,” Dubal noted. In their paper, the team further wrote, “An active Xm chromosome impaired cognition in female mice throughout the lifespan and led to worsened cognition with age. Cognitive deficits were accompanied by Xm chromosome-mediated acceleration of biological or epigenetic aging of the hippocampus, a key center for learning and memory, in female mice.”
Carrying out detailed analyses of the brain cells the team was then able to identify certain genes that were completely silenced on maternal X chromosomes but not paternal ones. When the researchers used CRISPR gene editing technology to activate the silenced genes on maternal X chromosomes in female mice, these animals became smarter in their old age. “Several genes were imprinted on the Xm chromosome of hippocampal neurons, suggesting silenced cognitive loci,” they explained. “CRISPR-mediated activation of Xm-imprinted genes improved cognition in aging female mice.”
Abdulai-Saiku said, “Together, all these experiments suggested to us that the parental origin of an X chromosome can have a big impact on brain health.” The researchers concluded, “Our data suggest that female individuals with more skew toward an active Xm chromosome, even in the absence of mutations, could experience decreased cognitive functions—or could be at increased risk of neurodegenerative conditions such as Alzheimer’s disease—compared with those with more balanced X mosaicism in parent-of-X origin, particularly with age.”
While the new study was not designed to test exactly why the maternal X chromosome would accelerate brain aging compared to the paternal X chromosome, Dubal hypothesized that the genes silenced on the maternal chromosome could convey an advantage earlier in life. “It may be that this gene expression pattern is actually really beneficial to brain development, but then there is this tradeoff later in life.” Dubal hopes to continue studying the role of the X chromosome in brain aging, and whether it can explain people’s risk of brain diseases or memory loss. “The X chromosome you inherited from your mom is turning off genes, accelerating aging, and impairing cognition,” she said. “Can we reverse this?”
