Project Summary

Sleep problems and circadian disturbances are early features of many neurodegenerative diseases,
including Alzheimer’s disease (AD) and Huntington’s disease (HD). Both diseases are also associated with
central and peripheral immune system dysfunction. Here, we hypothesize that circadian and immune
abnormalities are closely interconnected in neurodegenerative diseases. In order to test this hypothesis, we
shall first examine wild type mice and characterize diurnal/circadian rhythms in microglia and borderassociated
macrophages of the central nervous system (CNS). In comparison, we shall examine
diurnal/circadian rhythms in liver macrophages, skin Langerhans cells and circulating monocytes. The impact
of entrainment (light, nutrition) and conflicting Zeitgeber will be explored in microglia versus liver
macrophages. We shall then conditionally delete the circadian clock gene Bmal1 in microglia to test the
consequences for neural function. Next, we shall probe whether diurnal/circadian rhythms are dysregulated
in myeloid cells from transgenic mouse models of HD and AD and how this relates to the disease process.
We shall compare microglia from different brain regions that are differentially affected by neuronal
dysfunction. In addition, we shall assess diurnal/circadian rhythms in peripheral myeloid cells. In order to
determine the functional significance of circadian alterations in microglia for neurodegeneration, we shall
examine HD and AD transgenic mice with conditional deletion of Bmal1 in microglia. Finally, we shall
translate our findings to humans by using induced pluripotent stem cells (iPSCs) to generate microglia-like
cells. CRISPR/Cas9-mediated knockout of BMAL1 in iPSCs will allow us to explore the impact of clock
disruption in human iPSC-derived microglia. The results will enhance our understanding of the pathogenic
role of circadian disruption in myeloid cells for neurodegenerative diseases.