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.
AbildayevaKJansenPJHirsch-ReinshagenVBloksVWBakkerAHRamaekersFC, and others. 2006. 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J Biol Chem281(18):12799–808.
BartzokisG. 2011. Alzheimer’s disease as homeostatic responses to age-related myelin breakdown. Neurobiol Aging32(8):1341–71.
4.
BennettPJSimmondsMA. 1996. The influence of membrane cholesterol on the GABAA receptor. Br J Pharmacol117(1):87–92.
5.
BielskaAAOlsenBNGaleSEMydock-McGraneLKrishnanKBakerNA, and others. 2014. Side-chain oxysterols modulate cholesterol accessibility through membrane remodeling. Biochemistry53(18):3042–51.
6.
BielskaAASchlesingerPCoveyDFOryDS. 2012. Oxysterols as non-genomic regulators of cholesterol homeostasis. Trends Endocrinol Metab23(3):99–106.
7.
BjörkhemILövgren-SandblomALeoniVMeaneySBrodinLSalvesonL, and others. 2013. Oxysterols and Parkinson’s disease: evidence that levels of 24S-hydroxycholesterol in cerebrospinal fluid correlates with the duration of the disease. Neurosci Lett555:102–5.
8.
BjörkhemIMeaneyS. 2004. Brain cholesterol: long secret life behind a barrier. Arterioscler Thromb Vasc Biol24(5):806–15.
9.
BogdanovicNBretillonLLundEGDiczfalusyULannfeltLWinbladB, and others. 2001. On the turnover of brain cholesterol in patients with Alzheimer’s disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells. Neurosci Lett314(1-2):45–8.
10.
BrownJ3rdTheislerCSilbermanSMagnusonDGottardi-LittellNLeeJM, and others. 2004. Differential expression of cholesterol hydroxylases in Alzheimer’s disease. J Biol Chem279(33):34674–81.
11.
BrownMSGoldsteinJL. 1974. Suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and inhibition of growth of human fibroblasts by 7-ketocholesterol. J Biol Chem249(22):7306–14.
12.
CalkinACTontonozP. 2012. Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR. Nat Rev Mol Cell Biol13(4):213–24.
13.
ChisariMEisenmanLNCoveyDFMennerickSZorumskiCF. 2010. The sticky issue of neurosteroids and GABAA receptors. Trends Neurosci33(7):299–306.
14.
CioffiCL. 2013. Modulation of NMDA receptor function as a treatment for schizophrenia. Bioorg Med Chem Lett23(18):5034–44.
15.
CollingridgeGLBlissTV. 1995. Memories of NMDA receptors and LTP. Trends Neurosci18(2):54–56.
16.
CollingridgeGLVolianskisABannisterNFranceGHannaLMercierM, and others. 2013. The NMDA receptor as a target for cognitive enhancement. Neuropharmacology64:13-26.
17.
CysterJGDangEVReboldiAYiT. 2014. 25-Hydroxy cholesterols in innate and adaptive immunity. Nat Rev Immunol14(11):731–43.
18.
DietschyJMTurleySD. 2004. Thematic review series: brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal. J Lipid Res45(8):1375–97.
19.
EmnettCMEisenmanLNMohanJTaylorAADohertyJJPaulSM, and others. 2014. Interaction between positive allosteric modulators and trapping blockers of the NMDA receptor channel. Br J PharmacolNov6. doi:10.1111/bph.13007. [Epub ahead of print]
20.
EmnettCMEisenmanLNTaylorAMIzumiYZorumskiCFMennerickS. 2013. Indistinguishable synaptic pharmacodynamics of the N-methyl-d-aspartate receptor channel blockers memantine and ketamine. Mol Pharmacol84(6):935–47.
21.
FamerDMeaneySMousaviMNordbergABjorkhemICrisbyM. 2007. Regulation of α- and β-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway. Biochem Biophys Res Commun359(1):46–50.
22.
FantiniJCarlusDYahiN. 2011. The fusogenic tilted peptide (67-78) of α-synuclein is a cholesterol binding domain. Biochim Biophys Acta1808(10):2343-51.
23.
FerreraPMercado-GomezOSilva-AguilarMValverdeMAriasC. 2008. Cholesterol potentiates beta-amyloid-induced toxicity in human neuroblastoma cells: involvement of oxidative stress. Neurochem Res33(8):1509–17.
24.
GambaPLeonarduzziGTamagnoEGuglielmottoMTestaGSotteroB, and others. 2011. Interaction between 24-hydroxycholesterol, oxidative stress, and amyloid-beta in amplifying neuronal damage in Alzheimer’s disease: three partners in crime. Aging Cell10(3):403–17.
25.
GambaPTestaGSotteroBGargiuloSPoliGLeonarduzziG. 2012. The link between altered cholesterol metabolism and Alzheimer’s disease. Ann N Y Acad Sci1259:54–64.
26.
GarciaANMunizMTSouza e SilvaHRda SilvaHAAthayde-JuniorL. 2009. Cyp46 polymorphisms in Alzheimer’s disease: a review. J Mol Neurosci39(3):342–5.
27.
HalfordRWRussellDW. 2009. Reduction of cholesterol synthesis in the mouse brain does not affect amyloid formation in Alzheimer’s disease, but does extend lifespan. Proc Natl Acad Sci U S A106(9):3502–6.
28.
HardinghamGEBadingH. 2010. Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci11(10):682–96.
29.
HedegaardMHansenKBAndersenKTBrauner-OsborneHTraynelisSF. 2012. Molecular pharmacology of human NMDA receptors. Neurochem Int61(4):601–9.
30.
HoginsJCrawfordDCJiangXMennerickS. 2011. Presynaptic silencing is an endogenous neuroprotectant during excitotoxic insults. Neurobiol Dis43(2):516–25.
31.
HongCTontonozP. 2014. Liver X receptors in lipid metabolism: opportunities for drug discovery. Nat Rev Drug Discov13(6):433–44.
32.
HuHZhouYLengTLiuAWangYYouX, and others. 2014. The major cholesterol metabolite cholestane-3beta,5alpha,6beta-triol functions as an endogenous neuroprotectant. J Neurosci34(34):11426–38.
IzumiYZorumskiCF. 2014. Metaplastic effects of subanesthetic ketamine on CA1 hippocampal function. Neuropharmacology86:273–81.
35.
KandutschAAChenHW. 1974. Inhibition of sterol synthesis in cultured mouse cells by cholesterol derivatives oxygenated in the side chain. J Biol Chem249(19):6057–61.
36.
KottiTHeadDDMcKennaCERussellDW. 2008. Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation. Proc Natl Acad Sci U S A105(32):11394–9.
37.
KottiTJRamirezDMPfeifferBEHuberKMRussellDW. 2006. Brain cholesterol turnover required for geranylgeraniol production and learning in mice. Proc Natl Acad Sci U S A103(10):3869–74.
38.
LangTBrunsDWenzelDRiedelDHolroydPThieleC, and others. 2001. SNAREs are concentrated in cholesterol-dependent clusters that define docking and fusion sites for exocytosis. EMBO J. 20(9):2202–2213.
39.
LeeCYSeetRCHuangSHLongLHHalliwellB. 2009. Different patterns of oxidized lipid products in plasma and urine of dengue fever, stroke, and Parkinson’s disease patients: cautions in the use of biomarkers of oxidative stress. Antioxid Redox Signal11(3):407–20.
40.
LeoniVCacciaC. 2013. Potential diagnostic applications of side chain oxysterols analysis in plasma and cerebrospinal fluid. Biochem Pharmacol86(1):26–36.
41.
LeoniVCacciaC. 2014. Study of cholesterol metabolism in Huntington’s disease. Biochem Biophys Res Commun446(3):697–701.
42.
LeoniVLongJDMillsJADi DonatoSPaulsenJS, PREDICT-HD study group. 2013a. Plasma 24S-hydroxycholesterol correlation with markers of Huntington disease progression. Neurobiol Dis55:37–43.
43.
LeoniVMariottiCNanettiLSalvatoreESquitieriFBentivoglioAR, and others. 2011. Whole body cholesterol metabolism is impaired in Huntington’s disease. Neurosci Lett494(3):245–9.
44.
LeoniVSolomonALovgren-SandblomAMinthonLBlennowKHanssonO, and others. 2013b. Diagnostic power of 24S-hydroxycholesterol in cerebrospinal fluid: candidate marker of brain health. J Alzheimers Dis36(4):739–47.
45.
LinsenbardtAJTaylorAEmnettCMDohertyJJKrishnanKCoveyDF, and others. 2014. Different oxysterols have opposing actions at N-methyl-d-aspartate receptors. Neuropharmacology85C:232–42.
46.
LundEGXieCKottiTTurleySDDietschyJMRussellDW. 2003. Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover. J Biol Chem278(25):22980–8.
47.
LutjohannDBreuerOAhlborgGNennesmoISidenADiczfalusyU, and others. 1996. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A93(18):9799–804.
48.
LutjohannDPapassotiropoulosABjorkhemILocatelliSBagliMOehringRD, and others. 2000. Plasma 24S-hydroxycholesterol (cerebrosterol) is increased in Alzheimer and vascular demented patients. J Lipid Res41(2):195–8.
49.
MastNCharvetCPikulevaIAStoutCD. 2010. Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain. J Biol Chem285(41):31783–95.
50.
MeaneyS. 2014. Epigenetic regulation of cholesterol homeostasis. Front Genet5:311.
51.
MeljonATheofilopoulosSShackletonCHWatsonGLJavittNBKnolkerHJ, and others. 2012. Analysis of bioactive oxysterols in newborn mouse brain by LC/MS. J Lipid Res53(11):2469–83.
52.
MeljonAWangYGriffithsWJ. 2014. Oxysterols in the brain of the cholesterol 24-hydroxylase knockout mouse. Biochem Biophys Res Commun446(3):768–74.
53.
MoghaddamBJavittD. 2012. From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment. Neuropsychopharmacology37(1):4–15.
54.
MohnARGainetdinovRRCaronMGKollerBH. 1999. Mice with reduced NMDA receptor expression display behaviors related to schizophrenia. Cell98(4):427–36.
55.
OhtsukiSItoSMatsudaAHoriSAbeTTerasakiT. 2007. Brain-to-blood elimination of 24S-hydroxycholesterol from rat brain is mediated by organic anion transporting polypeptide 2 (oatp2) at the blood-brain barrier. J Neurochem103(4):1430–8.
56.
OkabeAUranoYItohSSudaNKotaniRNishimuraY, and others. 2013. Adaptive responses induced by 24S-hydroxycholesterol through liver X receptor pathway reduce 7-ketocholesterol-caused neuronal cell death. Redox Biol2:28–35.
57.
OlsenBNSchlesingerPHOryDSBakerNA. 2012. Side-chain oxysterols: from cells to membranes to molecules. Biochim Biophys Acta1818(2):330–6.
58.
OryDS. 2000. Niemann-Pick type C: a disorder of cellular cholesterol trafficking. Biochim Biophys Acta1529(1-3):331–9.
59.
PapassotiropoulosALutjohannDBagliMLocatelliSJessenFBuschfortR, and others. 2002. 24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia. J Psychiatr Res36(1):27–32.
60.
PapassotiropoulosAStrefferJRTsolakiMSchmidSThalDNicosiaF, and others. 2003. Increased brain beta-amyloid load, phosphorylated tau, and risk of Alzheimer disease associated with an intronic CYP46 polymorphism. Arch Neurol60(1):29–35.
61.
PaulSMDohertyJJRobichaudAJBelfortGMChowBYHammondRS, and others. 2013. The major brain cholesterol metabolite 24(S)-hydroxycholesterol is a potent allosteric modulator of N-methyl-d-aspartate receptors. J Neurosci33(44):17290–300.
62.
PfriegerFWUngererN. 2011. Cholesterol metabolism in neurons and astrocytes. Prog Lipid Res50(4):357–71.
63.
PoliGBiasiFLeonarduzziG. 2013. Oxysterols in the pathogenesis of major chronic diseases. Redox Biol1(1):125–30.
64.
PorterFDScherrerDELanierMHLangmadeSJMoluguVGaleSE, and others. 2010. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Transl Med2(56):56ra81.
65.
RamirezDMAnderssonSRussellDW. 2008. Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain. J Comp Neurol507(5):1676–93.
66.
RankinSEAddonaGHKloczewiakMABuggeBMillerKW. 1997. The cholesterol dependence of activation and fast desensitization of the nicotinic acetylcholine receptor. Biophys J73(5):2446–55.
RussellDWHalfordRWRamirezDMShahRKottiT. 2009. Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain. Annu Rev Biochem78:1017–40.
71.
ShafaatiMMastNBeckONayefRHeoGYBjorkhem-BergmanL, and others. 2010. The antifungal drug voriconazole is an efficient inhibitor of brain cholesterol 24S-hydroxylase in vitro and in vivo. J Lipid Res51(2):318–23.
72.
SpannNJGlassCK. 2013. Sterols and oxysterols in immune cell function. Nat Immunol14(9):893–900.
73.
SturleySLPattersonMCPentchevP. 2009. Unraveling the sterol-trafficking defect in Niemann-Pick C disease. Proc Natl Acad Sci U S A106(7):2093–4.
74.
TraynelisSFWollmuthLPMcBainCJMennitiFSVanceKMOgdenKK, and others. 2010. Glutamate receptor ion channels: structure, regulation, and function. Pharmacol Rev62(3):405–96.
75.
UranoYOchiaiSNoguchiN. 2013. Suppression of amyloid-beta production by 24S-hydroxycholesterol via inhibition of intracellular amyloid precursor protein trafficking. FASEB J27(10):4305–15.
76.
ValdezCMSmithMAPerryGPhelixCFSantamariaF. 2010. Cholesterol homeostasis markers are localized to mouse hippocampal pyramidal and granule layers. Hippocampus20(8):902–5.
77.
ValenzaMLeoniVTarditiAMariottiCBjorkhemIDi DonatoS, and others. 2007. Progressive dysfunction of the cholesterol biosynthesis pathway in the R6/2 mouse model of Huntington’s disease. Neurobiol Dis28(1):133–42.
78.
ValenzaMRigamontiDGoffredoDZuccatoCFenuSJamotL, and others. 2005. Dysfunction of the cholesterol biosynthetic pathway in Huntington’s disease. J Neurosci25(43):9932–9.
79.
WangLSchusterGUHultenbyKZhangQAnderssonSGustafssonJA. 2002. Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci U S A99(21):13878–83.
80.
WasserCRErtuncMLiuXKavalaliET. 2007. Cholesterol-dependent balance between evoked and spontaneous synaptic vesicle recycling. J Physiol579(Pt 2):413–29.
81.
YamanakaKSaitoYYamamoriTUranoYNoguchiN. 2011. 24(S)-hydroxycholesterol induces neuronal cell death through necroptosis, a form of programmed necrosis. J Biol Chem286(28):24666–73.
82.
YamanakaKUranoYTakabeWSaitoYNoguchiN. 2014. Induction of apoptosis and necroptosis by 24(S)-hydroxycholesterol is dependent on activity of acyl-CoA:cholesterol acyltransferase 1. Cell Death Dis5:e990.
83.
ZampieriSMellonSHButtersTDNevyjelMCoveyDFBembiB, and others. 2009. Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone. J Cell Mol Med13(9B):3786–96.
84.
ZhangJRColemanTLangmadeSJScherrerDELaneLLanierMH, and others. 2008. Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking. J Clin Invest118(6):2281–90.
