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The Inactive X Chromosome in Resilience Against Brain Aging and Cognitive Decline.

Record Type:	Language materials, manuscript : Monograph/item
Title/Author:	The Inactive X Chromosome in Resilience Against Brain Aging and Cognitive Decline./
Author:	Shaw, Cayce Katherine.
Description:	1 online resource (75 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 85-06, Section: B.
Contained By:	Dissertations Abstracts International85-06B.
Subject:	Neurosciences. -
Online resource:	click for full text (PQDT)
ISBN:	9798381183931

The Inactive X Chromosome in Resilience Against Brain Aging and Cognitive Decline.
Shaw, Cayce Katherine.

The Inactive X Chromosome in Resilience Against Brain Aging and Cognitive Decline. - 1 online resource (75 pages)

Source: Dissertations Abstracts International, Volume: 85-06, Section: B.

Thesis (Ph.D.)--University of California, San Francisco, 2023.

Includes bibliographical references

Sex biology influences vulnerability to brain aging and cognitive decline. Females show advantage in lifespan and cognitive deficits in aging human populations - while males are more vulnerable. Historically, female biology has been largely understudied - specifically it is unknown how sex chromosomes influence resilience to age-related cognitive decline. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because females (XX) show increased expression of select X factors. Both sexes (XX and XY) harbor one active X due to random X chromosome inactivation (XCI) in female cells. However, some genes, such as Kdm6a, transcriptionally escape silencing from the inactive X (Xi) during development - leading to higher transcript levels in females. Escapee gene Kdm6a, encodes a lysine demethylase, best known for interaction with tri-/di-methylated histone 3 lysine 27 (H3K27me3/2). Kdm6a contains additional functional domains and is linked with synaptic plasticity and cognition. Previous studies in our lab found that the second X in females promotes neuronal resilience against Alzheimer's disease (AD)-related toxicity partially through increased expression of Kdm6a.Here (Chapter 2), we used lentiviral-mediated overexpression of escapee Kdm6a - in a form without its demethylase function - to improve spatial learning and memory, in aging male mice, as measured using the Morris water-maze. Then (Chapter 3), we go onto further highlight the importance of the inactive X chromosome (Xi) by identifying and characterizing the transcriptional signatures of Xi during female brain aging using a mouse assay based on strain-specific detection of differing SNPs crossed with a well-established mouse line that contains an Xist deletion, leading to forced activation of the X chromosome. We found that aging preferentially changes female hippocampal gene expression on the X chromosome - which causes an increase in the transcription of several Xi genes: Plp1, Tspan7, Gpm6b, and Pck1n. Top Xi factor Plp1, encodes the myelin proteolipid protein and has increased expression in aging female hippocampal oligodendrocytes, possibly contributing to enhanced cognition. We used oligodendrocyte-specific adeno-associated virus (AAV)-mediated overexpression to increase Plp1 expression in aged XY and XX brains and tested male and female cognition using behavioral tasks. We found that increasing Plp1 - specifically in oligodendrocytes - improved hippocampal-dependent spatial working memory in both aging males and females, as measured using two-trial Y-maze. Plp1 additionally enhanced spatial learning in aging males, but not females, as tested in the Morris water-maze.These findings highlight a role of the inactive X, via baseline and age-induced transcriptional escape, in countering age-related cognitive decline. Understanding how the inactive X may confer female cognitive advantage, and specifically how it is regulated throughout the lifespan, may lead to novel therapeutic targets for age-related cognitive decline in both sexes.

Electronic reproduction.
Ann Arbor, Mich. :
ProQuest,
2024

Mode of access: World Wide Web

ISBN: 9798381183931Subjects--Topical Terms:

593561
Neurosciences.
Subjects--Index Terms:

Brain agingIndex Terms--Genre/Form:

554714
Electronic books.

The Inactive X Chromosome in Resilience Against Brain Aging and Cognitive Decline.
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504 $a Includes bibliographical references
520 $a Sex biology influences vulnerability to brain aging and cognitive decline. Females show advantage in lifespan and cognitive deficits in aging human populations - while males are more vulnerable. Historically, female biology has been largely understudied - specifically it is unknown how sex chromosomes influence resilience to age-related cognitive decline. In mammals, the X chromosome is enriched for neural genes and is a major source of biologic sex difference, in part, because females (XX) show increased expression of select X factors. Both sexes (XX and XY) harbor one active X due to random X chromosome inactivation (XCI) in female cells. However, some genes, such as Kdm6a, transcriptionally escape silencing from the inactive X (Xi) during development - leading to higher transcript levels in females. Escapee gene Kdm6a, encodes a lysine demethylase, best known for interaction with tri-/di-methylated histone 3 lysine 27 (H3K27me3/2). Kdm6a contains additional functional domains and is linked with synaptic plasticity and cognition. Previous studies in our lab found that the second X in females promotes neuronal resilience against Alzheimer's disease (AD)-related toxicity partially through increased expression of Kdm6a.Here (Chapter 2), we used lentiviral-mediated overexpression of escapee Kdm6a - in a form without its demethylase function - to improve spatial learning and memory, in aging male mice, as measured using the Morris water-maze. Then (Chapter 3), we go onto further highlight the importance of the inactive X chromosome (Xi) by identifying and characterizing the transcriptional signatures of Xi during female brain aging using a mouse assay based on strain-specific detection of differing SNPs crossed with a well-established mouse line that contains an Xist deletion, leading to forced activation of the X chromosome. We found that aging preferentially changes female hippocampal gene expression on the X chromosome - which causes an increase in the transcription of several Xi genes: Plp1, Tspan7, Gpm6b, and Pck1n. Top Xi factor Plp1, encodes the myelin proteolipid protein and has increased expression in aging female hippocampal oligodendrocytes, possibly contributing to enhanced cognition. We used oligodendrocyte-specific adeno-associated virus (AAV)-mediated overexpression to increase Plp1 expression in aged XY and XX brains and tested male and female cognition using behavioral tasks. We found that increasing Plp1 - specifically in oligodendrocytes - improved hippocampal-dependent spatial working memory in both aging males and females, as measured using two-trial Y-maze. Plp1 additionally enhanced spatial learning in aging males, but not females, as tested in the Morris water-maze.These findings highlight a role of the inactive X, via baseline and age-induced transcriptional escape, in countering age-related cognitive decline. Understanding how the inactive X may confer female cognitive advantage, and specifically how it is regulated throughout the lifespan, may lead to novel therapeutic targets for age-related cognitive decline in both sexes.
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