Lipid dynamics in neurons

Abstract

Compared with other organs, the brain is highly enriched in cholesterol. Essentially all cholesterol in the brain is synthesized within the brain; the blood–brain barrier prevents the import of plasma lipoproteins into the brain. Consequently, the brain operates an independent lipoprotein transport system in which glial cells produce ApoE (apolipoprotein E)-containing lipoproteins that are thought to deliver cholesterol to neurons for axonal growth and repair. We have shown that ApoE-containing lipoproteins generated by glial cells stimulate axon extension. ApoE associated with lipoprotein particles, and a receptor of the low-density lipoprotein receptor family, are required for stimulation of axon growth. NPC (Niemann–Pick type C) disease is a severe neurological disorder caused by mutations in the NPC1 or NPC2 gene. A hallmark of this disease is impaired transport of cholesterol out of late endosomes/lysosomes and the accumulation of cholesterol in these organelles. Although cholesterol accumulates in cell bodies of neurons from NPC1-deficient mice, the cholesterol content of axons is reduced. The presence of NPC1 in endosomal structures in nerve terminals, and the finding of aberrant synaptic vesicles, suggest that defects in synaptic vesicle recycling contribute to neurological abnormalities characteristic of NPC disease. We have also shown that ApoE-containing lipoproteins produced by glial cells from NCP1-deficient mice are of normal composition and stimulate axon extension.