24(S)-Hydroxycholesterol as a Modulator of Neuronal Signaling and Survival

Abstract

The major cholesterol metabolite in brain, 24S-hydroxycholesterol (24S-HC), serves as a vehicle for cholesterol removal. Its effects on neuronal function, however, have only recently begun to be investigated. Here we review that nascent work. Our own studies have demonstrated that 24S-HC has potent positive modulatory effects on NMDA receptor (NMDAR) function. This could have implications for brain plasticity but also for pathological NMDAR overuse. Other work has demonstrated effects of 24S-HC on neuronal survival and as a possible biomarker of neurodegenerative disease. Depending on circumstances, both upregulation/mimicry of 24S-HC signaling and downregulation/antagonism may have therapeutic potential. We are interested in the possibility that synthetic analogues of 24S-HC with positive effects at NMDARs may hold neurotherapeutic promise, given the role of NMDA receptor hypofunction in certain neuropsychiatric disorders.

Esterification of 24S-OHC induces formation of atypical lipid droplet-like structures, leading to neuronal cell death

“…In line with our observations, it has recently been reported that ER stress induces ligand-independent necroptosis in L929 mouse fibroblast cells (45). It should be noted, however, with regard to physiological relevance, that it is not clear that the changes observed in our present study would necessarily occur in accompaniment to the increase in CYP46A1 expression (14)(15)(16) or the increase in brain 24S-OHC level that has been observed in early-and middlestage AD (11)(12)(13). Whereas LD structures have been observed in brain tissue from AD patients and in AD mouse models (46)(47)(48), there remains a need to elucidate whether an increase in 24S-OHC esters and formation of atypical LD-like structures, as reported in our present study, occur in vivo as a consequence of the normal progression of AD.…”

LXR Regulation of Brain Cholesterol: From Development to Disease

“…24-OHC, the most abundant oxysterol in the brain, is generated by hydroxylation of cholesterol in neurons by the cytochrome P450 enzyme cholesterol 24-hydroxylase (CYP46A1) and the hydroxylated cholesterol species are normally then cleared from neurons, possibly in an ABCA1 dependent manner [7]. 24-OHC subsequently crosses the BBB largely by passive diffusion across membranes [8], and this clearance represents the major pathway of cholesterol efflux from the brain. 24-OHC also acts as either a pro-survival or pro-death factor in neurons.…”

Mapping of the Allosteric Site in Cholesterol Hydroxylase CYP46A1 for Efavirenz, a Drug That Stimulates Enzyme Activity

“…Unexpectedly, several inhibitory pharmaceuticals were also found to act, at specific concentrations, as enzyme activators enhancing CYP46A1-mediated 24HC production (7,13). Both increase and decrease of CYP46A1 activity have therapeutic potential (14); therefore, we began to ascertain the molecular basis of CYP46A1-drug interactions. Spectroscopic and crystallographic characterizations of substrate-free, substrate-bound, and seven CYP46A1-drug complexes established that inhibitory drugs bind to the enzyme active site because it is plastic and can accommodate compounds of different sizes and shapes because of a ligand-induced conformational fit (7, 9 -12).…”