Stress-induced upregulation of VLDL receptor alters Wnt-signaling in neurons

Lipoprotein receptor family members hold multiple roles in the brain, and alterations in lipoprotein receptor expression and function are implicated in neuronal stress, developmental disorders and neurodegenerative diseases, such as Alzheimer's disease. Berberine (BBR), a nutraceutical shown to have both neuroprotective and neurotoxic properties, is suggested to regulate lipoprotein receptor expression. We show that subtoxic concentration of BBR regulates neuronal lipoprotein receptor expression in a receptor- and time-dependent fashion in cerebellar granule neurons (CGN). Similarly to BBR, subtoxic concentrations of neuronal stressors cobalt chloride, thapsigargin and rotenone increased very-low-density lipoprotein receptor (VLDLR) mRNA and protein expression in CGN suggesting a conserved pathway for stress-induced upregulation of VLDLR in neurons. We also show that VLDLR upregulation is accompanied by transiently increased stabilization of hypoxia-induced factor 1 alpha (HIF-1α) and decreased β-catenin levels affecting the Wnt pathway through GSK3β phosphorylation, a crucial player in neurodegenerative processes. Our results indicate that neuronal stress differentially regulates lipoprotein receptor expression in neurons, with VLDLR upregulation as a common element as a modulator of neuronal Wnt signaling.