Cholesterol and oxygenated cholesterol concentrations are markedly elevated in peripheral tissue but not in brain from mice with the Niemann-Pick type C phenotype

Niemann-Pick disease type C (NP-C) is a rare genetic disorder characterized by progressive neurodegeneration, frequent developmental delay and early d eath. Tissues of affected individuals accumulate large quantities of free c holesterol in lysosomes. Because cytotoxic oxygenated derivatives of choles terol are known to form readily when cholesterol concentrations are elevate d, we searched for these compounds in liver, kidney, spleen and brain from mice with the NP-C phenotype. In order of abundance, we identified 7 alpha- and 7 beta-hydroxycholesterol, 5 alpha,6 alpha-epoxycholestan-3 beta-o1, 4 beta-hydroxycholesterol, cholest-4-en-3 beta,7 alpha-diol and cholest-4-en -3 beta,6 beta-diol in most tissue samples. Cholesterol concentrations in a ffected mice were increased 3-fold in kidney and 7- to 8-fold in spleen and liver compared to controls (all p < 0.001) but were unchanged in brain. Al though oxysterol levels were markedly elevated in non-brain tissue, the oxy sterol and cholesterol concentrations increased proportionally so that oxys terols expressed as percentage of total sterols were the same for all anima ls (0.34 +/- 0.19% averaged over all organs in affected animals vs 0.40 +/- 0.42% in control mice). In contrast to peripheral tissue, we could not det ect any increase in either absolute or relative oxysterol levels in the bra ins of affected and control mice (49 +/- 61 vs 53 +/- 43 mu g/g wet weight and 0.45 +/- 0.52 vs 0.47 +/- 0.37%, respectively). Thus, brain sterols are normal in NP-C mice and it is unlikely that an accumulation of cytotoxic o xygenated derivatives of cholesterol could account for the progressive neur opathology seen in the disease.