Novel mechanism of alcohol self-administration and relapse

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Project Summary/Abstract Alzheimer's disease (AD) and its related dementias (AD/ADRD) are a set of irreversible and progressive neurodegenerative disorders that represent the most common cause of dementia in the United States. Tau- associated AD/ADRD neural pathology originates in the entorhinal cortex (EC) and spreads to the hippocampus (HPC) and other connected brain regions as disease severity progresses. Although links between alcohol use and Tau-associated pathology have been established, the mechanisms that underlie this unique interaction are not fully understood. In this Administrative Supplement, we propose to address this gap in knowledge by expanding the parent R01 to evaluate the genomic interaction between chronic alcohol drinking (12-weeks) and the development and progression of AD/ADRD neural pathology using an innovative AAV strategy for human Tau-P301L (huTau-P301L) “seeding” in the EC of C57BL/6J mice. We propose to utilize GeoMx Digital Spatial Profiling (DSP) with quantification by next-generation sequencing (NGS) to evaluate the interaction between alcohol drinking and huTau-P301L expression on the whole transcriptome (>18,000 genes) from neurons and glia in the EC, hippocampus, and other connected brain regions. We will also evaluate pathological huTau-P301 expression in the EC, propagation (spread) to the HPC and other nuclei, Tau misfolding, and Tau (AT8) hyperphosphorylation in a parallel immunohistochemistry study. These separate but integrated studies can be conducted during a 1-year period of the parent R01. This work is based on strong preliminary data generated under a prior project showing that alcohol drinking produced an early onset and profound increase in pathological human Tau-AT8 phosphorylation in the hippocampus that were time-locked with early onset and increased magnitude of hippocampal-dependent cognitive deficits in 3xTg-AD mice. Given this prominent involvement of Tau in our prior alcohol studies and its widely acknowledged function as a key mechanism of AD/ADRD, we predict that the proposed studies have a high probability of identifying a unique transcriptomic footprint of alcohol that contributes to AD/ADRD pathology. Identifying novel neural targets of alcohol that underlie AD/ADRD pathology has potential to lead to specific diagnostic and therapeutic strategies.