NPC disease and SLOS are caused by mutations in genes involved in the biosynthesis or intracellular trafficking of cholesterol, respectively.However, the types of neurological impairments, and the areas of the brain that are most affected, differ between these diseases.Some, but not all, studies indicate that high levels of plasma cholesterol correlate with increased risk of developing AD.Moreover, inheritance of the E isoform of apolipoprotein E, a cholesterolcarrying protein, markedly increases the risk of developing AD.Whether or not treatment of AD with statins is beneficial remains controversial, and any benefit of statin treatment might be due to antiinflammatory properties of the drug.Cholesterol balance is also altered in HD and PD, although no causal link between dysregulated cholesterol homeostasis and neurodegeneration has been established.Some important considerations for treatment of neurodegenerative diseases are the impermeability of the bloodbrain barrier to many therapeutic agents and difficulties in reversing brain damage that has already occurred.This article focuses on how cholesterol balance in the brain is altered in several neurodegenerative diseases, and discusses some commonalities and differences among the diseases.Thus, the mechanisms underlying the association between altered cholesterol metabolism and neurodegeneration are being actively investigated, particularly in mouse models of these diseases.This article focuses on how normal cholesterol balance is maintained in the brain, and how this balance is altered in these disorders.In addition, some commonalities and differences in the dysregulation of cholesterol homeostasis in the brain in these neurodegenerative diseases are discussed.enzymatic steps. Cholesterol is required by mammals for the synthesis of steroid hormones and bile acids, for the organization of cell membranes, and for the formation and maintenance of lipid rafts, which are implicated in many aspects of brain function such as growth factor signaling, axon guidance and synaptic transmission.Thus, a deficiency or excess of cholesterol in the brain might be expected to have profound consequences.The biosynthesis of cholesterol is tightly regulated by the abundance of cholesterol, cholesterol is acquired both from endogenous synthesis and from exogenous lipoproteins delivered from the circulation.However, because plasma lipoproteins do not cross the intact bloodbrain barrier, nearly all cholesterol in the brain is synthesized in situ. This compartmentalization of cholesterol metabolism in the body explains why cholesterol homeostasis in the CNS is regulated independently of that in the peripheral circulation.Although the brain makes up only of body mass, approximately of total body cholesterol resides in the brain. Thus, the brain is highly enriched in cholesterol compared with other mammalian tissues: whereas the cholesterol concentration in most animal tissues is mgg tissue, the cholesterol concentration in the CNS is mgg tissue of cholesterol in the CNS is in the myelin that surrounds axons and facilitates the transmission of electrical signals.In the final step of the pathway, dehydrocholesterol is converted to cholesterol by the enzyme dehydrocholesterol reductase, the defective enzyme in SLOS.Nevertheless, cholesterol synthesis continues at a low rate in the mature brain, particularly in astrocytes; in the adult brain, the rate of cholesterol biosynthesis is higher in astrocytes than in neurons. In this manner, cholesterol is shuttled from astrocytes to neurons.