Characterization of the roles of neuronal cholesterol biosynthesis and ORP4 in hippocampal neurons and glia

Abstract

Cholesterol is an essential component of cell membranes and plays important roles in cell signalling. The brain contains a quarter of the body’s total cholesterol pool, all of which is synthesized in situ by neurons and glia, which are the structurally and functionally distinct cells of the brain. Neurons synthesize large quantities of cholesterol during development, but rely more so on glial synthesis in the adult brain. Yet neuronal cholesterol synthesis is maintained into maturity, suggesting a specific role for this process. Oxysterol-binding protein-related protein 4 (ORP4) is highly expressed in the hippocampus, and binds and transfers cholesterol and phosphatidylinositol-4-phosphate in vitro. I investigated the roles of neuronal cholesterol biosynthesis and ORP4 in hippocampal cells. My findings implicate neuronal cholesterol synthesis in regulating spine density and provide evidence for a role of ORP4 in glial proliferation, mitochondrial morphology, and the regulation of neuronal proteins involved in mitochondrial homeostasis.