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 (A?)-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 A? 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.

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Patients with Alzheimer?s Disease have disturbances of circadian rhythms, the 24-hour cycles that control bodily processes such as sleep and hormone secretion. We will investigate how disruption of the circadian system in different cells of the brain influences inflammation and nerve cell injury in mouse models of Alzheimer?s Disease, and determine if therapies designed to bolster the circadian system might have protective effects.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Mackiewicz, Miroslaw
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Washington University
Schools of Medicine
Saint Louis
United States
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Lananna, Brian V; Nadarajah, Collin J; Izumo, Mariko et al. (2018) Cell-Autonomous Regulation of Astrocyte Activation by the Circadian Clock Protein BMAL1. Cell Rep 25:1-9.e5
Day, Gregory S; Musiek, Erik S; Morris, John C (2018) Rapidly Progressive Dementia in the Outpatient Clinic: More Than Prions. Alzheimer Dis Assoc Disord 32:291-297