Summary This is an “Alzheimer’s-Focused Administrative Supplement for NIH Grants that are Not Focused on Alzheimer’s Disease” in response to NOT-AG-21-018. The overarching hypothesis behind the present proposal is that a history of alcohol intoxication promotes Alzheimer’s Disease (AD) progression. We present preliminary results showing that repeated alcohol intoxication hastens the onset of cognitive impairment in the triple transgenic AD (3xTg-AD) mice and that male 3xTg-AD mice were more vulnerable to the cognitive impairment brought about by alcohol intoxication than female 3xTg-AD mice. Here we propose to generalize these findings to a well-established rat model of AD, the McGill-R-Thy1-APP transgenic rat model. The McGill-R-Thy1-APP rats express human APP751 with the Swedish and Indiana mutations, under the control of the murine Thy1.2 promoter. The McGill-R-Thy1-APP rats have been extensively characterized and show age-dependent accumulation of amyloid plaques, gliosis, cholinergic synapse loss, and cognitive impairment. Use of this rat model will allow us to validate and extend our results in mice while accurately paralleling the studies proposed in the parent grant with non-transgenic rats to investigate the molecular pathogenesis of Alcohol Use Disorder (AUD). Specifically, we aim to test if histories of repeated alcohol intoxication will result in early onset of cognitive impairment in the McGill-R- Thy1-APP rats as we have seen with 3xTg-AD mice and whether non-dependent alcohol intake also promotes cognitive impairment in McGill-R-Thy1-APP rats. The proposed studies will also determine if McGill-R-Thy1-APP rats differ from wild-type rats in motivation to drink alcohol and propensity to escalate alcohol intake in the paradigm of dependence-induced escalated drinking. Additionally, the proposed studies will determine if sex differences are present in the hypothesized vulnerability to the effects of alcohol intoxication in the McGill-R-Thy1-APP transgenic rat model. The sub-hypothesis is that neurodegeneration associated with AUD involves some overlapping gene regulatory networks as AD. This sub-hypothesis is supported by data from our group as well as the literature. To test this sub-hypothesis, we will parallel the parent grant by conducting gene expression analyses in a systems biology framework to dissect the gene regulatory networks involved in the interaction of moderate and excessive alcohol drinking with AD. Ultimately, the proposed experimental-computational approach will result in a better understanding of the molecular mechanisms that orchestrate the transition from moderate to excessive alcohol drinking in the setting of AD vulnerability and the role of alcohol in promoting AD progression. The parent grant does not propose any AD animal models nor any AD-focused experiments and the applicant does not have any AD-related funding. The results of the present Administrative Supplement will lay the foundations for a new R01 proposal.

Narrative To test the hypothesis that alcohol abuse promotes Alzheimer’s Disease (AD) progression and explore the mechanisms behind the interaction of alcohol and AD vulnerability, we will investigate the effect of a history of alcohol intoxication on AD disease progression and alcohol intake in McGill-R-Thy1-APP transgenic rats. Innovative systems biology strategies will be used in conjunction with RNA-Seq to dissect the gene regulatory networks involved in the interaction of AD and alcohol. Ultimately, the proposed experimental-computational approach will result in a better understanding of the molecular mechanisms that are behind the interaction of AUD and AD and will highlight candidate new therapeutic targets for AD progression.