New aspects of 24(S)-hydroxycholesterol in modulating neuronal cell death

24(S)-Hydroxycholesterol (24S-OHC), which is enzymatically produced in the brain, has been known to play an important role in maintaining cholesterol homeostasis in the brain and has been proposed as a possible biomarker of neurodegenerative disease. Recent studies have revealed diverse functions of 24S-OHC and gained increased attention. For example, 24S-OHC at sublethal concentrations has been found to induce an adaptive response via activation of the liver X receptor signaling pathway, thereby protecting neuronal cells against subsequent oxidative stress. It has also been found that physiological concentrations of 24S-OHC suppress amyloid-β production via downregulation of amyloid precursor protein trafficking in neuronal cells. On the other hand, high concentrations of 24S-OHC have been found to induce a type of nonapoptotic programmed cell death in neuronal cells expressing little caspase-8. Because neuronal cell death induced by 24S-OHC has been found to proceed by a unique mechanism, which is different from but in some ways similar to necroptosis—necroptosis being a type of programmed necrosis induced by tumor necrosis factor α—neuronal cell death induced by 24S-OHC has been called “necroptosis-like” cell death. 24S-OHC-induced cell death is dependent on the formation of 24S-OHC esters but not on oxidative stress. This review article discusses newly reported aspects of 24S-OHC in neuronal cell death and sheds light on the possible importance of controlling 24S-OHC levels in the brain for preventing neurodegenerative disease. [Display omitted] •Cholesterol in converted to 24S-OHC by CYP46A1 in neurons within the brain.•24S-OHC plays a role in pathophysiology of neurodegenerative diseases.•24S-OHC induces apoptosis or necroptosis-like cell death depending on caspase-8.•24S-OHC-induced cell death is dependent on formation of 24S-OHC esters.•24S-OHC induces ROS-independent cell death in undifferentiated neuronal cells