The role of CYP46A1 and its metabolic product, 24S-hydroxycholesterol, in Neuro 2A cell death

(1) Basis Independent Silicon Valley, San Jose, California, (2) Department of Neurology, University of California San Francisco, San Francisco, California

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Cholesterol is a major component of neuronal cell membrane and myelin sheath. Therefore, maintaining cholesterol homeostasis is crucial for brain functioning and development. Brain cholesterol is synthesized de novo. To achieve homeostasis, excess cholesterol is removed by its conversion into 24S-hydroxycholesterol (24S-HC), which crosses the blood-brain barrier to enter the blood stream for clearance. This conversion is facilitated by the brain-specific protein, CYP46A1 (cholesterol 24-hydroxylase). Previous studies reported that hypoxia-ischemia caused disruption of cholesterol homeostasis. Increases of CYP46A1 and 24S-HC in neonatal mouse brain correlated with hypoxicischemic brain damage. Blood level of 24S-HC was also elevated and is a potential diagnostic biomarker for brain damage severity. However, how CYP46A1 and 24S-HC are functionally involved in neuronal cell death is unknown. Finding the direct effect of CYP46A1 and 24S-HC on brain cell damage will help assess the possibility of using 24S-HC for brain damage diagnosis. We hypothesized that hypoxiaischemia upregulated CYP46A1 expression, leading to an increase in 24S-HC, thus triggering cell death. In this study, we either transfected Neuro 2A cells with CYP46A1 cDNA or treated the cells with 24SHC. Cell viability was measured to evaluate their effect on cell damage. Cells expressing CYP46A1 had significantly less viability compared to the negative control. Up to 55% reduction in cell viability was also observed in 24S-HC-treated cells. This work supports that CYP46A1 and 24S-HC could directly trigger cell death. The direct involvement of 24S-HC in cell death provides further evidence that 24S-HC can be a promising biomarker for diagnosing brain damage severity.

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cholesterol brain damage brain development neurons cell death