Circadian control of p75 neurotrophin receptor leads to alternate activation of Nrf2 and c-Rel to reset energy metabolism in astrocytes via brain-derived neurotrophic factor

Abstract

Circadian clock genes regulate energy metabolism partly through neurotrophins in the body. The low affinity neurotrophin receptor p75 is a clock component directly regulated by the transcriptional factor Clock:Bmal1 complex. Brain-derived neurotrophic factor (BDNF) is expressed in the brain and plays a key role in coordinating metabolic interactions between neurons and astrocytes. BDNF transduces signals through TrkB and p75 receptors. This review highlights a novel molecular mechanism by which BDNF via circadian control of p75 leads to daily resetting of glucose and glycogen metabolism in brain astrocytes to accommodate their functional interaction with neurons. Astrocytes store glycogen as an energy reservoir to provide active neurons with the glycolytic metabolite lactate. Astrocytes predominantly express the truncated receptor TrkB.T1 which lacks an intracellular receptor tyrosine kinase domain. TrkB.T1 retains the capacity to regulate cell morphology through regulation of Rho GTPases. In contrast, p75 mediates generation of the bioactive lipid ceramide upon stimulation with BDNF and inhibits PKA activation. As ceramide directly activates PKCζ, we discuss the importance of the TrkB.T1-p75-ceramide-PKCζ signaling axis in the stimulation of glycogen and lipid synthesis and activation of RhoA. Ceramide-PKCζ-casein kinase 2 signaling activates Nrf2 to support oxidative phosphorylation via upregulation of antioxidant enzymes. In the absence of p75, TrkB.T1 functionally interacts with adenosine AR and dopamine D1R receptors to enhance cAMP-PKA signaling and activate Rac1 and NF-κB c-Rel, favoring glycogen hydrolysis, gluconeogenesis and aerobic glycolysis. Thus, diurnal changes in p75 levels in astrocytes resets energy metabolism via BDNF to accommodate their metabolic interaction with neurons.

Circadian control of BDNF-mediated Nrf2 activation in astrocytes protects dopaminergic neurons from ferroptosis

“…As period 2 (Per2) levels are high in the early light/rest phase in local regions of rat brain [67,68] (Fig. 2 B), we predicted that the p75 NTR -Nrf2 signaling pathway also effectively functions in the similar time phase [31]. Currently, however, the circadian variation of p75 NTR protein in brain cells has yet to be investigated.…”

“…proposed that the BDNF-TrkB.T1-p75 NTR -ceramide signaling axis activates the PKCζ-CK2-Nrf2 pathway mainly in the light/rest phase in rodent astrocytes [31].…”

“…But in the dark/active phase, when neuronal activity increases, astrocytes undergo a metabolic shift towards increasing glycogen hydrolysis and glycolysis to produce lactate as a substrate for the TCA cycle in neurons. This phase change can occur simultaneously with the down-regulation of p75 NTR which results in the change of the functional partner of TrkB.T1 from p75 NTR to adenosine receptor A 2A (A 2A R) in astrocytes [31]. Thereafter A 2A R-mediated cAMP/PKA signaling dominates over ceramide-mediated CK2 and Nrf2 activities in the active phase.…”

“…Brain-derived neurotrophic factor (BDNF) is the major neurotrophin expressed in adult brain and has been implicated in regulating neuronal survival, differentiation, and synaptic plasticity. We recently proposed that BDNF plays a key role in circadian activation of Nrf2 in astrocytes and suggested that BDNF activates Nrf2 via receptor combination of the truncated form of TrkB.T1 and the low affinity receptor p75 NTR , which generate the lipid signal mediator ceramide upon stimulation [31]. As p75 NTR expression is directly controlled by the cell clock core transcription factor complex Clock-Bmal1, we thought activation of Nrf2 via BDNF depends on circadian rhythm [28].…”

“…NGF-and BDNF-mediated activation of Nrf2 and circadian rhythm. A,Stimulation of BDNF through full length receptor TrkB.FL with the tyrosine kinase domain suppresses p75 NTR -mediated ceramide generation and does not activate Nrf2.Truncated receptor TrkB.T1 without tyrosine kinase domain can activate Nrf2 via the BDNF-TrkB.T1-p75 NTR -ceramide-CK2 signaling pathway[31,76]. NGF has a higher affinity than BDNF for p75 NTR and can stimulate p75 NTR -ceramide-CK2-Nrf2 signaling pathway.…”