The expression of neuronal sorting nexin 8 (SNX8) exacerbates abnormal cholesterol levels.

SNX8 is a PX-BAR domain sub-family of sorting nexins (SNXs), which is reported as a β-amyloid (Aβ) toxicity enhancer and associated with Alzheimer's disease. We have also described SNX8 as a novel activator of the sterol regulatory element binding protein (SREBP) transcription factor, a major regulator of cholesterol homeostasis. In that study, we have showed that SNX8 reduced an insulin-induced gene (INSIG)-dependent block of SREBP-mediated transcription. Here, for the first time, we investigated the expression and function of SNX8 within the CNS. We found that SNX8 was expressed within neurons, but not astrocytes or microglia, with neuronal localisation primarily in the soma. The protein levels of neuronal SNX8 were unchanged in the presence of moderately high cholesterol but were decreased by mevinolin (a cholesterol-lowering statin) and U18666a (which causes cholesterol to accumulate within the lysosome). To determine if SNX8 overexpression alters the levels of cholesterol, we engineered a GFP-SNX8 lentivirus. The overexpression of GFP-SNX8 had no effect on cholesterol in neurons under control conditions or in already strongly altered cholesterol conditions of mevinolin or U18666a. In contrast, in moderately high cholesterol, the overexpression of GFP-SNX8 caused redistribution of cholesterol within neurons creating a phenotype similar to U18666a treatment. Taken together, these data suggest that extreme changes in cholesterol reduce SNX8 expression and that overexpression of SNX8 exacerbates aberrant handling of neuronal cholesterol. This work further supports the role for SNX8 in regulating cholesterol levels, which could be important in understanding its role as an Aβ toxicity enhancer and its association with Alzheimer's disease.