ABSTRACT Aging is a significant risk factor for cognitive decline and dementia. With an increase in the average human lifespan, there is a need to protect the aging brain from cognitive decline and lower the risk of neurodegeneration. Among the important age-related changes in the brain that renders neurons susceptible to degeneration and disease, are the loss of epigenetic control leading to dysfunctional gene expression. These epigenetic changes have the potential to be targeted for reversal to prevent or ameliorate age-associated declines. Histone acetylation is crucial to the regulation of the epigenetic landscape associated with gene activation required for memory and is dependent on the activity of Acetyl CoA synthetase 2 (ACSS2). We have discovered that ACSS2, which generates acetyl-CoA, is chromatin bound in hippocampal neurons and provides acetyl-CoA for the histone acetyltransferase CBP for learning and memory. Furthermore, ACSS2 knockout (KO) mice have compromised learning and memory. These findings underscore the remarkable role of ACSS2 for brain function. Hence, I hypothesize that enhancing ACSS2-dependent chromatin processes in neurons will confer resilience to cognitive decline and epigenomic dysfunction due to aging and Alzheimer's disease (AD). Here I will investigate whether enhancement of ACSS2-dependent chromatin processes can protect neurons against age- and disease-associated epigenomic dysregulation and cognitive decline in the mouse. I aim to (1) Determine whether ACSS2 upregulation enhances neuronal function and increases resilience to age-associated cognitive decline, and (2) Determine whether ACSS2 upregulation confers resilience to AD. I will upregulate ACSS2 in human induced pluripotent stem cells (iPSC)-derived cortical neurons and study the effect of ACSS2 upregulation on chromatin accessibility, gene expression, and histone acetylation during neuronal activity. I will also examine the effect of ACSS2 upregulation to ameliorate AD-tau-related pathology in primary mouse neurons transfected with human AD-tau. Lastly, I will examine if it is possible to improve cognitive function in aged mouse brain with tissue specific upregulation of ACSS2 and assess the effects on AD-tau-associated dementia in an AD mouse model. Overall, these studies will advance our understanding of the molecular mechanisms and function of ACSS2-dependent histone acetylation in neurons and ACSS2-dependent features that could preserve cognitive function. As epigenetic-metabolic mechanisms can be targeted with small molecules, this work provides the foundation for new approaches to protect the brain against the onslaughts of aging.

PROJECT NARRATIVE The prevalence and incidence of age-associated diseases, including Alzheimer's disease (AD) is expected to continue to increase dramatically. Aging is driven by major changes to the epigenetic landscape that alters the expression of neuronal genes and reduced resilience of the brain. ACSS2 as an epigenetic modifier and regulator of neuronal gene expression, has the potential to promote cognitive ability and increase resilience in the aged brain against disease-associated brain decline.