On the fluxes of side-chain oxidized oxysterols across blood-brain and blood-CSF barriers and origin of these steroids in CSF

In contrast to cholesterol itself the side-chain oxidized metabolites 24S-hydroxycholesterol (24OH) and 27-hydroxycholesterol (27OH) are able to pass the blood-brain barrier and the blood-CSF barrier. Most 27OH in circulation is formed extracerebrally and according to catheterization experiments about 5 mg of it is taken up by the brain per 24 h. 24OH is almost exclusively produced in the brain and about 6 mg fluxes from the brain into the circulation per 24 h. In addition to these major fluxes a very minor fraction of these two oxysterols flux from the circulation into CSF. Isotope experiments have shown that almost all 27OH in CSF originates from the circulation and evidence has been presented that this is the case also with a substantial part of 24OH. The levels of both 24011 and 27OH in CSF are thus affected by the integrity of the blood-CSF barrier with higher levels when the barrier is defect. Both levels of 24OH and 27OH in CSF are increased in connection with neurodegeneration and in general the increase in 24OH levels is higher than the increase in 27OH levels. A number of observations in different type of patients including measurements of other biochemical markers support that the increase in levels of 24OH due to neurodegeneration is due to a release of this oxysterol or its precursor cholesterol from dying neuronal cells. In contrast the increase in levels of 27OH is likely to be a consequence of reduced metabolism due to loss of the neuronal enzyme CYP7B1. We discuss the driving forces behind the fluxes of oxysterols in the brain, the limitations in the flux across the barriers and the diagnostic potential for side-chain oxidized oxysterols in CSF.