Conclusions
The dominating neuro-oxysterol and neuro-sterol in brain are
24S-hydroxycholesterol and cholesterol. During embryonic development and
in the new-born 24S,25-EC is more abundant than 24S-HC in brain. Besides
the dominating neuro-oxysterols there are numerous other oxysterols
present in brain but at lower concentrations. This is also true for the
neuro-sterols where comparatively low-levels of cholesterol precursors
are evident. It is however, the most abundant species that appear to be
most widely biochemically active. For example, both 24S-HC and 24S,25-EC
are ligands to LXR, 24S-HC is an inverse agonist to RORα and RORγ, while
24S,25-EC is an inverse agonist to RORγ only. Both 24S-HC and 24S,25-EC
are reported as agonists to SMO and to activate Hh signalling, while
24S-HC is a positive allosteric modulator of the NMDARs while 24S,25-EC
has not been tested. In addition, both 24S-HC and 24S,25-EC will bind to
INSIG and modulate SREBP-2 regulated cholesterol biosynthesis. Why this
redundancy one may ask. The answer may be provided by theCyp46a1-/- mouse which does not synthesise
24S-HC via its usual pathway and 24S-HC is only present in trace amounts
in brain, however, other than some learning difficulties theCyp46a1-/- mouse has a mild phenotype. Even in
the absence of CYP46A1 in this mouse 24S,25-EC is still the most
abundant oxysterol in brain, although at a reduced level compared to the
wild-type, and may take on the roles normally performed by the more
abundant 24S-HC. Significantly, the Cyp46A1-/-mouse shows impaired learning and in hippocampal LTP in vitro ,
and while 24S-HC acts as a PAM of the NMDARs and induce LTP, 24S,25-EC
has not been reported to do so. So perhaps, the roles of 24S-HC are so
important, biology has devised a back-up system using 24S,25-EC.
Besides these two dominating neuro-oxysterols lower abundance relatives
may perform specific roles in defined cell populations, at different
times and in response to different stimuli.