Objectives: Niemann Pick Disease Type C (NP-C) is a rare neurodegenerative condition affecting
infants, children and adults. The majority of patients have NPC1 mutations, resulting
and cholesterol esterification and trafficking defects. 95% of brain cholesterol is
synthesized in situ and this is converted to oxysterols by direct oxidation or by
action of oxysterol biosynthetic enzymes. 24-hydroxycholesterol is the main oxysterol
that is transported out of the brain and blood levels may reflect neurodegeneration.
The present study aimed to elucidate the serial levels of cholesterol and cholesterol
oxidation products in the brains of NP-C mice and sera of NP-C patients.
Methods: The brains of 7-week old and 12-week old NP-C mice were obtained and sub-dissected
by region. Seven postnatal weeks is the time of onset of symptoms in the NPC mice.
12 week old NPC mice have marked tremor and ataxia and death usually occurs at 12–14
weeks. Serial blood samples from 3 NP-C patients ranging 8–21 in age and age matched
controls were obtained. Cholesterol and oxysterol levels were evaluated with gas chromatography/mass
spectrometry (GC/MS).
Results: There was no net increase in cholesterol levels in the different regions of NP-C
mouse brains and in the sera of NP-C patients. An increase in 7 beta-hydroxycholesterol
was observed in the diencephalon of the mice. 7 beta-hydroxycholesterol may be the
oxysterol that has a pathogenic role in the neurodegeneration seen in specific regions
of the brain. An increase in 24- hydroxycholesterol was observed in serial samples
of sera of NP-C patients.
Conclusion: The above results showed that that there was increased cholesterol synthesis and
oxysterol formation in brain regions undergoing neurodegeneration in NPC. 24 hydroxycholesterol
levels were higher in patients than in controls, suggesting that this may be a useful
marker for the progression of disease in patients.
