Chronic heavy or binge alcohol use is associated with dementia and increased risk for Alzheimer's disease (AD), though mechanisms connecting the disease pathologies have not been identified. AD pathology follows a temporal progression of proinflammatory signaling in brain with A? deposition, tau fibril formation, synapse loss, neurodegeneration, and cognitive decline. We find increased AD pathology proteins A?1-42 and phosphorylated (p)-tau-181 in human alcohol use disorder (AUD) brain and after chronic binge ethanol during early life in the 3x- Tg-AD mouse model. Toll-like Receptor (TLR) proinflammatory signaling is thought to precede gross pathology in AD, and is a prominent feature of AUD. We find AUD in young individuals is associated with AD protein accumulation, and chronic binge ethanol treatment in 3x-Tg-AD mice causes persistent upregulation of proinflammatory genes that correlated strongly with levels of neurotoxic A?1-42 and p-tau-181 protein. Thus, we hypothesize ethanol promotes AD neurotoxic protein pathology by enhancing proinflammatory signaling. Microglia have emerged as mediators of AD pathology, contributing to A? plaque formation, tau propagation, synapse loss and possibly neurodegeneration. Microglial change phenotype (e.g. resting, phagocytic, proinflammatory, pruning, or neurotoxic) and microglial activation is thought to precede and promote AD pathology. Human GWAS as well as human and AD mouse single nuclei RNA sequencing (snRNA-seq) have identified AD microglia as altered, having increased C1q (pro-synaptic pruning) and reduced resting state markers (e.g. Tmem119). In human AUD brain, we find reduced resting state microglia (reduced Tmem119) with proinflammatory microglia. Further, we find chronic binge ethanol in vivo persistently increases C1q and proinflammatory cytokines mirroring AD. Thus, we hypothesize proinflammatory microglial activation by chronic heavy/binge ethanol promotes AD A? and tau pathology, synapse loss and neurodegeneration. This hypothesis will be tested in human AD post-mortem brain (Aim 1), and the 3x-Tg-AD mouse model (Aim 2) that features progressive A? and tau pathology. Apoptotic neuronal cell death is a feature of AD pathology thought to contribute to irreversible cognitive decline. We find binge ethanol increases neurodegeneration in brain regions known to have neuronal loss in AD such as prefrontal cortex (PFC) and hippocampus. Our studies implicate proinflammatory Toll-like Receptor (TLR) activation and microglial to neuronal interactions that lead to apoptotic neuronal cell death. We find chronic binge ethanol increases HMGB1-TLR4 signaling to activate microglia. Proinflammatory microglia secrete the miRNA let-7b that we found activates TLR7 in neurons. Let-7b-TLR7 signaling in neurons induces apoptotic neuronal cell death via the TNF-receptor superfamily apoptosis-inducing ligand (TRAIL). TLR4, HMGB1, let-7 and TRAIL have each been implicated in AD pathology. However, a link in AD neurodegeneration has not been identified. We hypothesize chronic binge ethanol promotes AD neurodegeneration by enhancing TRAIL- mediated apoptotic neuronal cell death. This hypothesis will be tested in human AD post-mortem brain (Aim 1), and the 5xFAD AD mouse model (Aim 3) that features A?-induced apoptotic neuronal death.
Inflammation in the brain is involved in the pathology of Alzheimer's disease (AD) and alcohol use disorder (AUD). The goal of this project is to determine if heavy/binge alcohol use earlier in life can promote progression of Alzheimer's pathology. This project uses new and innovative therapeutic strategies to test this hypothesis and reverse alcohol-enhancement of AD pathology.
