The primary goal of this supplement project is to investigate whether manipulating the epigenetic modifier EZH2 expression and activity could alleviate cerebrovascular inflammation and the protect against Alzheimer disease (AD). Increasing evidence supports that cerebral vessel pathology is an important risk factor for AD. Cerebrovascular disease is an important cause of cognitive impairment and dementia in elderly patients. Moreover, neuroinflammation is a central mechanism in AD. New findings also reveal that late-onset AD in human is driven by epigenetic changes in the brain, suggesting that epigenetic marks could be the target of future Alzheimer's therapies. Thus, this Alzheimer’s-focused administrative supplement is a logical expansion and within the scope of our active parent R01 grant entitled “Epigenetic regulation of vascular endothelial genes and laminar flow atheroprotection”. EZH2 (Enhancer of Zeste Homolog 2) is a histone methyltransferase and a catalytic component of polycomb repressive complex 2 (PRC2), catalyzes tri-methylation of histone H3 at Lys 27 (H3K27me3) to regulate gene expression through epigenetic machinery. During conducting the studies proposed in our parent grant, my laboratory has discovered that the atheroprotective laminar blood flow decreased expression of EZH2 and the epigenetic marker H3K27me3 in vascular endothelial cells, and we have recently published an article showing that endothelial EZH2 inhibition attenuated vascular inflammation. During working on our parent RO1 project to investigate a critical role of EZH2 in regulation endothelial inflammation and atherosclerosis, we have also generated tamoxifen-inducible endothelium-specific EZH2 knockout mice and littermate control floxed wild-type mice. With these genetic mutant mouse models in hands, we are in an ideal position to assess whether modulating epigenetic marks would correct vascular inflammation in brain vascular beds and AD pathologies. In this proposal, we will investigate the new role of the epigenetic modifier EZH2 in regulation of brain inflammation and beta-amyloid deposit in 5XFAD transgenic mice (from Jackson laboratory) by crossing our conditional inducible endothelial-specific EZH2 floxed mice. 5XFAD moue model recapitulates major features of AD amyloid pathology and is a useful model of neurodegeneration and amyloid plaque formation. Furthermore, we will exploit the potent EZH2 inhibitor GSK126 to test whether pharmacological EZH2 inhibition ameliorates neurovascular inflammation and amyloid beta pathologies in 5XFAD mice. Collectively, the studies proposed herein provide a framework to begin defining a potential role of EZH2 in antagonizing cerebrovascular inflammation and the amyloid plaque formation in AD. The findings resulting from these studies should help us find a new strategy to prevent and treat Alzheimer's and other types of dementia, and eventually translate our research advances into improved care for people with AD.