Cell Type-Specific Epitranscriptomic Regulation in the Brain in Aging and Alzheimer's Disease - Project Summary Alzheimer’s Disease (AD) is a progressive neurodegenerative disorder which currently affects nearly 7 million people nationwide. Although the causes of AD are still not completely understood, it is clear that a combination of genetic, environmental, and age-related factors contribute to disease development and progression. However, how these diverse factors coalesce to lead to a pathogenic state remains poorly understood. Moreover, the molecular changes that occur in distinct cell types in the brain in AD and how brain aging affects these changes are not fully known. Of relevance to these critical unanswered questions, recent studies have revealed the importance of RNA regulatory pathways during both brain aging and AD. In particular, chemical modifications to mRNA have emerged as important regulators of gene expression in the brain with links to AD in both human and animal studies. The most abundant internal mRNA modification is adenosine methylation (m6A), which is found in thousands of mRNAs in the brain and which plays critical roles in regulating mRNA processing and expression in cells. Dysregulation of m6A leads to defects in neurodevelopment, learning and memory, and synaptic plasticity, and abnormal expression of m6A writer, reader, and eraser proteins has been linked to AD in both humans and mice. Our recent studies have also shown that some AD-associated mRNAs undergo dynamic methylation in distinct cell types in the brain with age. However, the effects of this dynamic methylation on gene expression during aging are unknown. Moreover, how mRNA methylation is differentially regulated within distinct brain cell types during AD has not been explored. Here, we will address both of these gaps in knowledge by determining how age-dependent differential methylation in the brain influences the expression of AD-associated genes and identifying the m6A reader proteins that mediate m6A function with age (Aim 1). Then, we will determine for the first time how m6A is altered in the AD mouse brain at single-cell resolution (Aim 2). Finally, we will investigate the effects of m6A on gene expression in distinct cell types in the AD mouse brain during disease progression (Aim 3). Altogether, these studies will provide important new insights into the role of m6A in regulating cell type-specific gene expression during brain aging and in AD, and they will provide critical new datasets for the research community.
