Dysregulation of sphingolipid and sterol metabolism by ApoE4 in HIV dementia

Background: Polymorphisms in apolipoprotein E have been associated with worse prognoses in numerous neurodegenerative conditions, including HIV dementia (HIVD). Despite these correlative observations, there has been little evidence suggesting a mechanism whereby the expression of ApoE4 renders neurons susceptible to insult. Methods: Electrospray ionization tandem mass spectrometry was used to quantify levels of sphingolipids and sterols in brains of HIVD patients. Data were stratified according to APOE genotype. Results: The authors found evidence of dysregulated lipid and sterol metabolism in HIVD patients with an APOE4 genotype. They also found elevations of sphingomyelin, ceramide, and cholesterol in the medial frontal cortex, parietal cortex, and cerebellum of HIVD patients with an APOE3/4 or APOE4/4 genotype compared with HIVD patients with an APOE3/3 genotype. There was no difference in the number of astrocytes or activated microglia in any brain region of the two patient populations, suggesting that modification of lipid metabolism in HIVD patients with an APOE4 genotype was not the result of increased CNS inflammation. Conclusions: HIV dementia patients with an APOE4 genotype may be sensitized to neural insults because of dysregulations in lipid metabolism.