ROLE OF GLIAL CIRCADIAN CLOCK DYSFUNCTION IN THE PATHOGENESIS OF ALZHEIMER'S DISEASE

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 (AD). 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. These cellular clocks are synchronized to the external environment by the central clock in the suprachiasmatic nucleus in the brain. Cellular circadian clocks are particularly robust in glial cells, regulating cellular activation and inflammatory responses in both astrocytes and microglia. We have found that the circadian clock protein BMAL1 regulates astrocyte activation, neuroinflammation, and amyloid plaque deposition in mice. We have also found that amyloid plaques cause large-scale alterations in circadian transcriptional rhythms in astrocytes. Thus, we will address the bidirectional relationship between circadian clock disruption and AD-related pathology in mouse models of AD, focusing on how the central and cellular clocks regulate astrocyte responses to protein aggregation. Using novel methods to interrogate cell type- specific transcription in vivo, we will compare the effects of central vs. cellular clock disruption on circadian function in astrocytes, both in healthy brain and in a model of AD. We then evaluate the effects of central and cellular clock disruption on pathology caused by Aβ and tau, and determine specific clock-regulated pathways in astrocytes that control protein degradation and inflammation. By understanding the bidirectional relationship between circadian rhythms and astrocyte function, we hope to identify novel therapeutic targets to prevent protein aggregation and inflammation in Alzheimer’s Disease.