BDNF differentially activates Nrf2 in astrocytes and neurons

Abstract

BDNF is the major neurotrophin in the brain playing a key role in the metabolic cooperation between astrocytes and neurons. BDNF transduce signals through high affinity TrkB receptors and the low affinity p75 receptor (p75NTR). Stimulation of p75NTR activates neutral sphingomyelinase to generate ceramide. As low levels of ceramide can activate atypical protein kinase C ζ (PKCζ), which phosphorylates and activates casein kinase 2 (CK2), we recently proposed that neurotrophins can activate p75NTR-ceramide-PKCζ-CK2 signaling pathway. Subsequently, CK2 directly phosphorylates and stabilizes/activates Nrf2. However, the receptor tyrosine kinase activity of full length TrkB (TrkB.FL) inhibits p75NTR-mediated ceramide generation. In contrast, the truncated form of TrkB (TrkB.T1), which lacks intracellular tyrosine kinase domain, supports p75NTR-mediated ceramide signaling. Astrocytes predominantly express TrkB.T1, but neurons express both TrkB.T1 and TrkB.FL. Notably, neurons increase the ratio of TrkB.T1 to TrkB.FL levels when they are stimulated. As p75NTR expression is controlled by the circadian rhythm, we discuss the significance of the time- and activity-dependent BDNF-TrkB.T1-p75NTR-Nrf2 signaling pathway for the metabolic interaction between astrocytes and neurons. [JSPS, BHF]