Speakers - NWC 2024

Abstract

Although the regulation of cholesterol homeostasis in the body has been extensively studied, there is little information on how this regulation takes place in the brain. Cholesterol does not cross the blood-brain barrier; therefore, cholesterol metabolism in the brain is independent of that in peripheral tissues. Lipoprotein receptors from the LDL receptor family (LRPs) have key roles in lipid particle accumulation in the bloodstream. For example, activating a specific LRP induces lipid uptake in several cells, tissues, and organisms both in vitro and in vivo. However, whether LRPs are involved in regulating cholesterol levels in the brain is still unknown.

To determine the role of lipoprotein receptors in the brain, we analyzed the expression of different LRPs and components and targets of their downstream signaling pathways in the brains of Wt and Lrp-/- mice and in a neuroblastoma cell line. Although several LRPs' expressions are increased in a time-dependent and dose-dependent manner in lipid-loaded neurons, specific LRPs do not participate in lipid uptake as neurons without lipoprotein receptors accumulate intracellular lipids similarly to control cells. Because the activation of the canonical WNT signaling pathway induces survival processes, we tested whether lipoprotein receptors were involved in apoptotic and/or autophagic processes and found that LRP has both anti-apoptotic and anti-autophagic functions, indicating a role for this receptor in neuronal survival. Furthermore, we show that LRP is indispensable for life as the brains of Lrp-/- mice show low but quantifiable LRP gene expression. Our results support a prosurvival role for LRP in the brain.