Elucidating the epigenetic role of alcohol dependence in Alzheimer s disease

University Of Miami School Of Medicine, Coral Gables FL

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Abstract

Elucidating the Epigenetic Role of Alcohol Dependence in Alzheimer?s Disease PROJECT SUMMARY Alzheimer?s disease (AD) is the 6th leading cause of death in the United States of America. Recently, in a large study involving 31,624,156 adults1, alcohol use disorder was identified as the strongest modifiable risk factor for onset of AD and related dementias with a hazard ratio greater than 3.3 for both men and women. In the course of progressing with the aims of our current grant titled ?Epigenetic Signaling Pathways Contributing to Alcohol Dependence? we observed that two of our epigenetic (chromatin modifying) targets for alcohol dependence ? PR domain containing 2 (PRDM2)2 and lysine-specific demethylase 6B (KDM6B) ? are potentially involved in Alzheimer?s disease (AD) pathogenesis. Both enzymes have been shown to be differentially expressed in AD brain. We have recently demonstrated that PRDM2 has a causal effect on alcohol dependence in a rodent model2. Here, of particular interest is KDM6B, which has been strongly linked to inflammation. Indeed, we hypothesize that alcoholism and AD share common inflammation- related mechanisms under epigenetic control. Interestingly, KDM6B activates transforming growth factor (TGF)-? signaling through the SMAD3 pathway. TGF-? has been shown to induce A? deposition in cerebral blood vessels and meninges of TGF-? overexpressing transgenic mice and accelerate AD-like pathogenesis in an AD animal model3. Conversely, interrupting TGF-? signaling has been shown to mitigate AD-like pathology in an AD mouse model4. Having demonstrated elevated KDM6B expression in the brain of alcohol dependent subjects, we hypothesize that heavy alcohol use may trigger AD-like phenotype such as A? accumulation and downstream associated cascades by increasing KDM6B-induced inflammation and TGF- ? signaling. We also hypothesize that interrupting KDM6B activity will result in decreased TGF-? signaling and mitigation of AD-phenotype. Through the experiments proposed in this application we plan to determine the effects of KDM6B and PRDM2 on the expression of AD-related genes and pathogenesis in AD cell and animal models. We also plan to attempt rescuing alcohol-induced acceleration of AD phenotype with a novel small molecule KDM6B inhibitor. All the funds from the current R01 are allocated to completing the aims proposed in the original grant and cannot be used to pursue our AD leads. Funds from this supplement will allow us to clarify the possible link between alcohol dependence, epigenetics and Alzheimer?s disease while maintaining the original scope of the original grant.