ORCID
http://orcid.org/0000-0001-8476-6246
Date of Award
Winter 12-15-2022
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
The circadian clock and inflammation have a well-described bidirectional relationship in the peripheral immune system: the circadian clock regulates inflammatory responses, but inflammation also impacts oscillatory gene transcription controlled by the clock. The purpose of this thesis work is to understand if manipulation of the circadian clock can impact Alzheimer’s disease pathology, and if pathology itself can alter the circadian clock and its outputs. Here, I show that astrocyte-specific disruption of the circadian clock via deletion of the clock gene Bmal1 surprisingly decreased intra-neuronal protein pathologies. Further investigation found that deletion of the circadian clock resulted in a transcriptomic profile in astrocytes that allowed for easier degradation of misfolded proteins. Interestingly, by looking at single nuclei sequencing from patients with Alzheimer’s disease, we found similar transcriptional profiles in astrocytes of people with Alzheimer’s disease. By knocking out the circadian clock in astrocytes, we inadvertently showed that targeting protein degradation pathways in astrocytes could reduce protein pathologies. To show that pathology could impact the circadian clock, we used ribosomal profiling to isolate RNA from astrocytes or microglia in vivo every two hours over a 24 hour period from wild-type mice, or mice with amyloid plaque pathology, and found that amyloid plaque pathology had a very large impact on genes that were being rhythmically expressed, a phenomenon called circadian reprogramming. We also observed circadian reprogramming in astrocyte and microglia during normal aging. Interestingly, we found that about half of the 48 Alzheimer’s disease risk factor genes were rhythmically expressed in at least one of our datasets, suggesting that circadian clock may in fact play a prominent role in the progression of disease pathology. Together, these findings do in fact show that circadian rhythms and Alzheimer’s disease pathology have a bidirectional relationship and that targeting the circadian system for future therapeutics could be beneficial for alleviating disease.
Language
English (en)
Chair and Committee
Erik S Musiek
Committee Members
Joshua B Rubin
Recommended Citation
Sheehan, Patrick, "The Bidirectional Relationship between the Circadian Clock and Alzheimer’s disease" (2022). Arts & Sciences Electronic Theses and Dissertations. 2754.
https://openscholarship.wustl.edu/art_sci_etds/2754