Year: 2024
Type: dissertation
Abstract: Alzheimer’s Disease (AD) is a debilitating neurodegenerative disorder affecting 50 million people worldwide, but effective treatments are lacking. We recently identified the histone variant H2A.Z as an epigenetic memory suppressor whose levels increase in the aging mouse hippocampus, generating the hypothesis that aberrant H2A.Z dysregulation may promote memory decline in AD. Consistent with this hypothesis, we found that mRNA expression of H2AZ1 (formerly H2AFZ), a gene encoding the histone variant H2A.Z, is elevated in the post-mortem hippocampus of female, but not male AD patients. We confirmed that a similar sex difference occurs in 5xFAD mouse model of AD, whereby female 5xFAD mice show greater dysregulation of H2A.Z binding in chromatin compared to male AD model mice. To test the functional relevance of this dysregulation, we depleted H2A.Z.1 in area CA1 of the mouse hippocampus at 2.5 months of age and tested their object location memory monthly until 8 months of age. H2A.Z.1 depletion enhanced memory only in female mice at every age tested, suggesting that H2A.Z.1 depletion has sex-specific benefits for AD-related memory decline. Enhanced memory was associated with reduced levels of AD pathology markers, including amyloid β 42 (Aβ42) and phosphorylated tau 217 (pTau217) in female, but not male mice with H2A.Z.1 depletion. In addition, RNA sequencing revealed reduced expression of the CTSE gene, which encodes a protease responsible for Aβ production, suggesting that H2A.Z.1 depletion may reduce amyloid pathology by reducing Aβ production. Moreover, H2A.Z.1 depletion produced largely distinct transcriptional profiles in wt mice and 5xFAD mice, suggesting H2A.Z.1 regulates distinct genes in AD. 5xFAD mice also showed a different pattern of learning-induced gene expression compared to wt mice and these changes were partially rescued with H2A.Z.1 depletion, suggesting that H2A.Z.1 dysregulation may contribute to impaired learning-induced gene expression in AD. Finally, we conducted single nuclei RNA sequencing to determine which cells were most strongly affected by H2A.Z.1 depletion in female mice. These data showed that excitatory neurons were most strongly impacted by H2A.Z.1 depletion, which resulted in altered expression of synaptic genes in 5xFAD mice and metabolic genes in wt mice, indicating that H2A.Z.1 regulates AD pathology and memory through unique gene targets. Overall, this study is the first implicate histone variants in regulating memory formation and disease progression in AD, and to show that these mechanisms are sex specific.
Source: TSpace (University of Toronto)
Author: Luo, Jian Qi
Institution: University of Toronto
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7133100930