Journal
NEUROSCIENTIST
Volume 22, Issue 2, Pages 132-144Publisher
SAGE PUBLICATIONS INC
DOI: 10.1177/1073858414568122
Keywords
glutamate; cholesterol; 24(S)-hydroxycholesterol; NMDA; apoptosis; Alzheimer's disease
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Funding
- Sage Therapeutics
- Bantly Foundation
- NIH grant [MH078823, MH101874, MH104506, MH077791, AA017413]
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The major cholesterol metabolite in brain, 24(S)-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 N-methyl-d-aspartate (NMDA) receptor (NMDAR) function. This could have implications not only 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 down-regulation/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.
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