Grant: Project Grant

Alzheimer's disease (AD) is a neurodegenerative condition characterized by progressive memory decline that is propagated by impaired regulation of gene expression. We recently identified histone variants as novel regulators of neuronal gene expression and memory formation, but their role in AD and other dementias has never been studied. We found that levels of the histone variant macroH2A1 (mH2A1) are altered in the hippocampus of AD patients, a brain region critical for memory, indicating that changes in mH2A1 levels may contribute to AD pathology and memory deficits. mH2A1 is alternatively spliced to produce two mH2A1.1 and mH2A1.2, which differ only in their ability to bind poly-ADP-ribose (PAR), a post-translational modification that accumulates in AD to propagate neurodegeneration. To assess the role of mH2A1 isoforms in AD, we will first characterize the binding of mH2A1.1 and mH2A1.2 in chromatin of human AD patients and AD model mice and investigate their role in dysregulated transcription and impaired memory in AD. The cause of altered mH2A1 binding in AD is unknown, but age-related loss of estrogen and testosterone is associated with increased risk for the disease, whereas hormone replacement reduces AD risk in both men and women. Our preliminary data indicate that mH2A1 is a potent regulator of mH2A1 binding in chromatin, which suggests that sex hormones may contribute to dysregulated mH2A1 binding in AD. We will test this hypothesis by removing gonadal hormones and assessing effects of hormone loss and replacement on mH2A1 binding, memory, and pathology in mouse models of AD. Finally, we will test if loss of mH2A1.1 contributes to AD-related increase in PAR, a post-translational modification whose accumulation impairs neuronal function and promotes cell death. mH2A1.1 is a potent inhibitor of PAR in model cell lines, indicating that changes in mH2A1.1 levels in AD can promote neurodegeneration by increasing PAR levels in the brain.