Alcohol-Induced Metabolome-Epigenome Dysfunction and Alzheimer’s Disease Risk

PROJECT SUMMARY / ABSTRACT Epidemiological projections indicate a substantial rise in Alzheimer's disease (AD) cases, reaching an estimated 152 million by 2050. Among the multifaceted factors influencing AD progression, chronic alcohol consumption is implicated as a modifiable risk factor for AD. My long-term goal is to uncover mechanisms that contribute to the risk of developing early progression of AD upon alcohol consumption and develop therapeutic interventions to mitigate this risk. While recent studies indicate metabolic disorders and accelerated aging in individuals with Alcohol Use Disorder (AUD), energy metabolism emerged as a significantly altered pathway triggering early AD pathology. This project employs an interdisciplinary approach to understand the impact of alcohol on the brain, with a specific focus on elucidating the complex relationship between metabolic and epigenetic function. The overall objective of this study is to comprehend how these factors collectively contribute to the progression of AD following ethanol exposure. In Specific Aim 1, I will assess the influence of chronic ethanol exposure on metabolic function and tau pathology in the hippocampus using an AD model (rTg4510) expressing the mutant human tau MAPTP301L. Specific Aim 2 involves applying cutting-edge techniques, such as single nuclei multi-omics, to identify cell-type-specific epigenomic and transcriptomic signatures associated with alcohol-induced early progression of tau pathology. The focus of Specific Aim 3 is on creating a novel mouse model (rTg4510-ALDH2*2) expressing both human genetic mutations, ALDH2E504K and MAPTP301L to assess compromised metabolism and its impact on early AD progression. Additionally, we will investigate the potential rescue from ethanol-induced tauopathy and cognitive deficits using a pharmacological ALDH2 activator (Alda-1). The innovative findings from this study are expected to reveal the molecular signatures governing the detrimental effects of ethanol metabolism and their involvement in the progression or early development of AD. This, in turn, will lay the foundation for novel therapeutic approaches aimed at mitigating the risk of developing AD due to alcohol consumption. This project provides training in cutting-edge research skills, including single-nuclei multi-omics, and tailors toward understanding cell-type specific tau pathology. The University of Iowa is home to experts on neuropathology, Alzheimer’s disease, computational psychiatry, and molecular biology and offers an ideal collaborative environment for obtaining the necessary skills to transition into a successful independent research career. During the mentored (K99) phase, I will engage in activities designed to prepare for independence, including training in scientific presentations, laboratory management skills, grant writing, scientific peer-review, and interview preparation. This award will collectively equip me with cutting-edge skills and expertise in metabolic phenotyping, molecular biology, and tauopathy, ensuring a strong technical and conceptual foundation for starting my independent laboratory investigating mechanisms for the treatment of alcohol misuse and Alzheimer’s disease.