PROJECT SUMMARY/ABSTRACT Role of REV-ERB Proteins in Neuroinflammation and Alzheimer’s Disease Circadian rhythm disruption is observed in Alzheimer’s Disease, and emerging data suggests that circadian dysfunction may contribute to the neurodegenerative process. However, mechanisms connecting circadian dysfunction to Alzheimer’s Disease-related neurodegeneration remain unclear. On a molecular level, core circadian clock genes mediate circadian rhythms, and also serve as critical transcriptional and metabolic regulators in a variety of organs, including the brain. We have shown that genetic disruption of the circadian clock by deletion of the master clock gene Bmal1 causes severe gliosis, oxidative damage, and synaptic degeneration in mouse brain, suggesting a link between core clock function and neurodegeneration. We have subsequently found that the deletion of REV-ERBα, a component of the core clock which is directly regulated by BMAL1, also causes spontaneous microglial activation and neuroinflammation. Our data shows that REV- ERBα expression is suppressed in the cortex of amyloid plaque-bearing APP/PS1 mice, a model of Alzheimer’s Disease, and in activated microglia. REV-ERBα and its homolog REV-ERBβ are nuclear receptors which, aside from their function in the circadian clock, have been implicated in regulation of inflammation and metabolism. We hypothesize that REV-ERBs serve to link the circadian clock to neuroinflammation and neurodegeneration. We will examine the cell-autonomous function of REV-ERBs in regulating microglial activation and neuroinflammation, and identify transcriptional pathways regulated by REV-ERBs in microglia. We will determine if REV-ERBs control microglial synaptic phagocytosis in the brain via transcriptional regulation of complement genes. Because they are nuclear receptors, REV-ERBs can be manipulated pharmacologically. Thus, we will examine the effects of cell type specific genetic deletion of REV-ERBs, or activation or inhibition of REV-ERB function with small molecule agonists, on neuroinflammation and neurodegeneration in a mouse model of Alzheimer’s Disease. These studies will shed new light on molecular mechanisms linking the circadian clock and Alzheimer’s Disease-related neurodegeneration, and illuminate the novel strategy of directly targeting the circadian clock for neuroprotection.