Abstract
AbstractBackgroundEpigenetic regulation plays substantial roles in human pathophysiology, which provides opportunities for intervention in human disorders through targeting epigenetic pathways. Emerging evidence from both preclinical and clinical studies suggested the potential in developing therapeutics of Alzheimer’s disease (AD) by targeting epigenetic regulatory proteins. Recently there has been keen interest in the family of bromodomain (BD)‐containing BET (bromodomain and extra terminal domain) proteins, which consists of 4 protein members. All BET proteins have two BD domains, which confer significant and complex regulatory mechanisms for AD.MethodHere, we developed domain‐specific small molecule probe targeting BD1 and evaluated expression of BET in AD transgenic animals compared to wild type animals using positron emission tomography‐based molecular imaging. We also investigated the effects of pharmacological inhibition of BET on AD cell models.ResultWe found that 5xFAD animals were characterized by increased signal in the brain in association with our BD1‐specific probe. Using BET inhibitors, AD‐related proteins were significantly changed.ConclusionOur study shows that BET protein may associate with AD by a gain of function mechanism and that inhibitors for specific domains may be utilized for AD in the presence of BET increase.
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