UCSF

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.