Moreover, the cholesterol derivative hydroxycholesterol increases synuclein levels and reduces dopamine synthesis, probably by activating the liver X receptor. Statins strongly reduce the aggregation of synuclein in cultured neurons, whereas supplementation of the neurons with exogenous cholesterol increases synuclein aggregation and reduces neuron growth. Furthermore, statin treatment of a transgenic mouse model of PD reduced synuclein aggregation. Taken together, these studies suggest that reduction of plasma cholesterol in individuals with PD by statin treatment might attenuate the deposition of synuclein aggregates in the brain.Nevertheless, it is also possible that some of the beneficial effects of the statins in individuals with PD are due to the antiinflammatory properties of these drugs. For example, the concentration of hydroxycholesterol is increased in cerebrospinal fluid in both AD and HD, and correlates with the level of APOE, cholesterol and tau in this fluid. Interestingly, adenovirusmediated overexpression of cholesterol hydroxylase in young AD mice reduces amyloid deposits and limits cognitive decline. In addition, a positive correlation was observed between AD and plasma levels of another oxysterol, hydroxycholesterol.This oxysterol is produced outside the brain but crosses the bloodbrain barrier from the plasma when this barrier is compromised.The amount of plasma hydroxycholesterol correlates with the amount of cholesterol in the circulation.These observations might, therefore, provide a possible link between high levels of plasma cholesterol and AD.However, in the disease cerebrotendinous xanthomatosis, the enzyme that generates hydroxycholesterol from cholesterol is defective, so the amount of hydroxycholesterol in plasma is abnormally low yet neurodegeneration is prevalent.In individuals with SLOS, in addition to high levels of dehydrocholesterol in plasma and brain, the plasma also contains reduced amounts of hydroxycholesterol and increased amounts of hydroxycholesterol, compared with levels in unaffected individuals; the mechanism responsible for these differences is not clear.Finally, the levels of several nonenzymatically generated oxidation products of cholesterol are markedly increased in the plasma of individuals with NPC disease compared with nonaffected controls. Although alterations in the amount of oxygenated derivatives of cholesterol have not been shown to be directly responsible for the neurodegeneration in any of these diseases, the presence of abnormal amounts of these sterols in plasma might provide useful diagnostic biomarkers for the evaluation of disease progression. In most cases, a causal link between cholesterol metabolism and neurodegeneration has not been established.The exceptions are SLOS and NPC disease, which result from mutations in genes directly involved in the biosynthesis and intracellular trafficking of cholesterol, respectively.SLOS and NPC disease are caused by distinct alterations in cholesterol metabolism, and the two diseases exhibit different neurological impairments. In NPC disease, cholesterol accumulates in the lysosomal pathway of neurons and glial cells, whereas the cholesterol concentration of the plasma membrane and endoplasmic reticulum is reduced; importantly, the endoplasmic reticulum is the site at which cholesterol synthesis and acquisition are purchase Ginsenoside Rh2 exquisitely feedback regulated by cholesterol.Thus, in NPC disease, the primary reason for neuron death is generally considered to be the sequestration of cholesterol in late endosomes andor lysosomes.SLOS, in contrast, is caused by mutations in the final enzyme of the cholesterol biosynthetic pathway, resulting not only in abnormally low amounts of cholesterol but also in the accumulation of the cholesterol precursor dehydrocholesterol in plasma and cells of the brain.