91 - BDNF-p75NTR Signaling Axis Regulates Circadian Activation of Nrf2 in Astrocytes

Abstract

Circadian clock genes regulate energy metabolism partly through neurotrophins. The low affinity neurotrophin receptor p75NTR is a clock component directly regulated by the transcriptional factor Clock:Bmal1 complex. Brain-derived neurotrophic factor (BDNF) is expressed in brain and plays a key role in coordinating metabolic interactions between neurons and astrocytes. BDNF transduces signals through TrkB and p75NTR receptors, and the circadian control of p75NTR leads to daily resetting of glucose and glycogen metabolism in astrocytes to accommodate their functional interaction with neurons. Recent studies show that the circadian clock controls Nrf2-regulated antioxidant defense genes in mouse tissues. The protein level of Nrf2 in mouse lungs at early light phase is about 5-fold higher than that in the early dark phase. The Nrf2 gene has a E-box element and the Clock:Bmal1 complex stimulates transcription. However, the differences in the mRNA levels during the day are at most 1.7-fold, suggesting post-transcriptional regulation of Nrf2 protein may be much more important for the circadian control of Nrf2 activation. We propose a novel hypothesis that p75NTR-mediated signaling activates/stabilizes Nrf2 during light/rest phase in mouse brain astrocytes. Notably, stimulation of BDNF induces production of a lipid signal molecule ceramide through the p75NTR-neutral sphingomyelinase axis. Although high levels of ceramide are cytotoxic, physiological levels of ceramide activates PKCζ. An important target of PKCζ is casein kinase 2 (CK2), which plays a critical role in the regulation of circadian rhythm. As CK2 directly phosphorylates and stabilizes Nrf2, we propose that a p75NTR-ceramide-PKCζ-CK2 signaling pathway activates Nrf2, which in turn supports mitochondrial oxidative phosphorylation required for glycogenesis and lipogenesis in astrocytes.