Date of Award

Spring 5-15-2019

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Neurosciences)

Degree Name

Doctor of Philosophy (PhD)

Degree Type



Sleep disruption and circadian dysfunction are common symptoms of aging and neurodegenerative diseases, including Alzheimer’s disease (AD). The molecular rhythms in transcription/translation that govern these behavioral processes are mediated by clock genes and can be abrogated by deletion of the master circadian transcription factor Bmal1 (Arntl). We have shown that disruption of clock gene function in the mouse brain causes astrogliosis, synaptic damage, oxidative stress, and exacerbated neurodegeneration. However, the molecular mechanisms linking the circadian clock to these phenotypes and their implications for AD pathology remain largely unknown. Astrocyte activation occurs in response to diverse insults, and plays a critical role in brain health and disease. We report that deletion of Bmal1 specifically in astrocytes causes a pronounced and unique astrogliosis phenotype both in vitro and in vivo, mediated in part by suppression of glutathione-s-transferase signaling. Functionally, loss of Bmal1 in astrocytes promotes neuronal death in vitro. This clock-controlled astrogliosis is characterized by a robust upregulation of a number of known astrocyte activation markers and a hyperinflammatory phenotype, including almost complete loss of the astrocytic inflammatory regulator and AD cerebrospinal fluid biomarker, Chi3l1 (YKL-40). The function of Chi3l1/YKL-40 in the setting of AD is unknown. Mutation of the BMAL1 repressors Per1 and Per2 increases expression of Chi3l1, reinforcing the idea that Chi3l1 is regulated by the circadian clock. The astrocytic clock also gates inflammatory induction of Chi3l1, while Chi3l1 deletion exaggerates LPS-induced astrocyte inflammation in vitro and neuroinflammation in vivo. These data suggest that BMAL1 may regulate neuroinflammation through Chi3l1. Surprisingly, Chi3l1 deletion mitigates astrocyte activation, promotes peri-plaque expression of the microglial lysosomal marker CD68, and leads to a significant suppression of Aβ deposition in a β-amyloidosis AD mouse model. Finally, in a large observational cohort of AD patients, we found that a variant in the human CHI3L1 gene, which decreases CSF YKL-40, was significantly associated with slower AD progression. In a preliminary study, we show that the microglial circadian clock may also contribute to regulation of the neuroinflammatory and neuroimmune responses. Together, our findings demonstrate that the core clock protein BMAL1 regulates astrocyte activation and function in vivo and reveal Chi3l1/YKL-40 as a clock-regulated modulator of AD pathogenesis both in mice and humans. Thus, we have elucidated a novel mechanism linking the circadian clock with neuroinflammation and AD.


English (en)

Chair and Committee

Erik S. Musiek

Committee Members

Erik D. Herzog, David M. Holtzman, Shin-ichiro Imai, Jason D. Ulrich,


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