Consequently, cholesterol is delivered to the neurons.Moreover, a role for APOE in nerve repair has been indicated, because APOE synthesis in glial cells increases by up to fold after a nerve injury. APOE therefore seems to be a key player in regulating cholesterol homeostasis and distribution among cells of the brain.Cholesterol has a remarkably long halflife in the brain. There is a low rate of cholesterol synthesis in the adult brain, and cholesterol cannot be degraded in the CNS, but a steadystate level of cholesterol is maintained in the CNS because a small fraction. The conversion of cholesterol to hydroxycholesterol that is expressed in a subset of neurons, represents a major mechanism by which excess cholesterol is eliminated from the brain.In contrast to cholesterol, hydroxycholesterol can cross the bloodbrain barrier, enter the peripheral circulation and be eliminated from the body in bile. Cholesterol and NPC disease A direct association between impaired cholesterol metabolism in the brain and neurodegeneration has been clearly demonstrated in NPC disease.This disease is a relatively rare autosomal recessive inherited disorder that causes progressive neurodegeneration and premature death, and is often accompanied by hepatosplenomegaly and lung disease. NPC disease is caused by mutations in either the NPC or NPC gene.Because the NPC and NPC proteins are ubiquitously expressed in animal tissues, it is not clear why the brain is the most severely affected tissue in NPC disease.NPC and NPC each bind to cholesterol and act in tandem in late endosomes andor lysosomes to mediate the egress of unesterified cholesterol derived from endocytosed lipoproteins. Accordingly, the amount of cholesterol in the plasma membrane and endoplasmic reticulum. It is possible, therefore, that some of the neurological deficits in NPC disease might be attributable to a deficiency, rather than an excess, of cholesterol in axons.Consistent with this idea, NPC and NPC are present in recycling endosomes in presynaptic nerve terminals, and synaptic vesicle morphology and composition are altered by NPC deficiency. As is the case in many other neurodegenerative disorders, neuroinflammation is pronounced in the brains of both individuals with NPC disease and mouse models of the disease.Subsequently, NPC directly transfers the cholesterol to NPC, located in the limiting membrane of the lysosome, so that the hydrophobic cholesterol molecule does not have to travel through the aqueous milieu of the lysosomal lumen.No effective treatment is currently available for NPC disease.Therefore, substrate reduction therapy using miglustat, an inhibitor of glycosphingolipid synthesis, is currently being tested in individuals with NPC disease, but with Targetmol’s Spermine limited success. In an exciting development, however, recent experiments have suggested a novel therapeutic approach for the treatment of NPC disease.Although cyclodextrin does not cross the bloodbrain barrier efficiently, small amounts of cyclodextrin can enter the brain from the peripheral circulation.Consistent with this mechanism, my laboratory has shown that. A similar conclusion regarding the mechanism of action of cyclodextrin was also reached from studies in intact mice. SLOS is the most common of this class of disorders. SLOS is an autosomal recessive, neurodegenerative and developmental disease caused by mutations in the gene encoding dehydrocholesterol reductase, the enzyme that catalyzes the final step in the cholesterol biosynthetic pathway.