Maternal X Chromosome Influences Cognitive Decline

The X chromosome you got from mom might impair cognition as you age." Researchers find maternal X can accelerate brain aging—but understanding this could unlock treatments for Alzheimer’s.

One X chromosome is inherited from each parent and two are present in women at birth. However, only one X chromosome is required in each of their body cells, therefore the other is inactivated at random. Only the maternal X chromosome is used by some cells, whereas the paternal X is used by others.

The memory and cognitive abilities of female mice that express only a maternal X chromosome decline more quickly than those of female mice that express both maternal and paternal X chromosomes, according to a study from UC San Francisco ().

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‘Did you know the X chromosome from your mom might speed up brain aging? Women with more active maternal Xs may face greater risks of cognitive decline, including Alzheimer’s. #science #brainhealth #medindia’

Professor of Neurology said, "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." Finally, it might also aid in the development of beneficial methods for delaying the aging of the brain in both sexes.

X Marks the Brain

Prior studies have suggested that the X chromosome, which most men have one of and most women have two, is essential for brain function.

Women born with only one X chromosome (a condition known as Turner Syndrome) may have cognitive deficits, and X chromosome mutations frequently result in intellectual disability. X chromosomes may contribute to the explanation of gender variations in verbal memory, brain illness risk, or cognitive abilities.

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“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,” said Samira Abdulai-Saiku, PhD, a UCSF postdoctoral fellow and first author of the new work.

Dubal and Abdulai-Saiku were especially interested in whether the origin of the X chromosome – from mom or 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.

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In the new study, the research team bred female mice either to express only maternal X chromosomes or a mixture of maternal and paternal X chromosomes.

“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,” said Dubal. “There has been little research on the potential consequences of this.”

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Effect of Maternal Chromosomes

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 aging faster than the brains of their genetically identical sisters who had both mom’s and dad’s X chromosomes turned on,” explained Dubal.

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, they became smarter in their old age.

“Together, all these experiments suggested to us that the parental origin of an X chromosome can have a big impact on brain health,” Abdulai-Saiku said.

The new study was not designed to test exactly why the maternal X chromosome would accelerate brain aging compared to the paternal X chromosome. However, 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 beneficial to brain development, but then there is this tradeoff later in life,” she said.

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.

Reference:

The maternal X chromosome affects cognition and brain ageing in female mice - (https://www.nature.com/articles/s41586-024-08457-y)

Source-Eurekalert