As many essential elements of the immune system undergo circadian oscillations, a mechanism behind the relationship between circadian disruption (CD) and increased rates of Alzheimer’s disease and related dementias (ADRDs) could stem from dysregulation of circadian inflammatory responses. Microglia, the innate immune cells of the central nervous system, are involved in inflammation and immune responses and play a significant role in contributing to neuroinflammation associated with neurodegenerative diseases. In their resting state, microglia carry out continuous surveillance of the brain environment, sampling areas to maintain homeostasis. The ‘activated’ microglial state is itself an oversimplification and comprises multiple phenotypes, broadly differentiated into ‘pro-inflammatory’ and ‘anti-inflammatory’ states. The pro-inflammatory phenotype is associated with the release of mediators, which promote extermination of the stimulus, whereas the anti-inflammatory phenotype is associated with the release of mediators that promote wound healing, debris clearance and homeostasis. The disruption of macrophage/microglia function could be a mechanistic link between CD and ADRDs (Figure 1).
We hypothesize that circadian rhythms play a pivotal role in the nature and progression of macrophage/microglial responses towards amyloid beta (Aβ), and that by using patient-derived macrophages and neurons, we can address how CD impacts human macrophages at the individual level. To test this set of hypotheses, we are developing a high-throughput, 3D microscale neuronal organoid-on-a-chip (NOC) platform to serve as the screening module for evaluating the effect of CD on neuroinflammation. In particular, we are investigating the impact of continuous production of Aβ peptides on overexpression and activation of NADPH Oxidase isoform 2 (Nox2) in microglia and ultimately neuronal cell death, and that this activation is impacted by the circadian rhythm.
Jennifer Hurley – Rensselaer Polytechnic Institute
Mariana Figueiro – Icahn School of Medicine at Mount Sinai