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.