PROJECT SUMMARY/ABSTRACT Role of glial circadian clock dysfunction in the pathogenesis of Alzheimer’s Disease Chronic disruptions of the circadian system, manifesting as sleep disturbances, day-night confusion, and “sundowning”, are well-described and debilitating symptoms of Alzheimer’s Disease. While circadian disruption has long been considered a consequence of the degenerative process in AD, accumulating human and mouse data suggest that circadian rhythm abnormalities may begin before overt cognitive symptoms, and could play an important contributory role in AD pathogenesis. Circadian rhythms are generated in cells by specific clock genes, which are expressed in neurons and glia throughout the brain and control 24-hour oscillations in transcription. We have discovered that abrogating the function of the circadian clock via deletion of the master clock gene Bmal1 in the brain causes severe gliosis, synaptic loss, neuroinflammation, and age- related neurodegeneration. The circadian clock is particularly robust in glial cells, regulating cellular activation and inflammatory responses in both astrocytes and microglia. Thus, we will address the bidirectional relationship between circadian clock disruption and amyloid-beta (Aβ)-related pathology in cellular and mouse models of AD, focusing on the function of clock genes in astrocytes and microglia. Using novel methods to interrogate cell type-specific transcription in vivo and in vitro, we will test the hypothesis that Aβ directly impairs the cellular circadian clocks of astrocytes and microglia in mouse AD models via an oxidative stress-dependent mechanism. We will then determine if cell type-specific Bmal1 deletion in astrocytes and microglia, respectively, will exacerbate neuroinflammation and synapse loss in the APP/PS1 mouse model of AD. We have identified specific circadian-controlled pathways in astrocytes and microglia that may mediate these effects, and will attempt to target these pathways therapeutically to mitigate neuroinflammation and synaptic degeneration in aged APP/PS1 mice.