{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T12:01:18Z","timestamp":1790510478009,"version":"4.1.0"},"reference-count":100,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2020,4,11]],"date-time":"2020-04-11T00:00:00Z","timestamp":1586563200000},"content-version":"vor","delay-in-days":101,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"U.S. National Institute of Health","award":["AG067552"],"award-info":[{"award-number":["AG067552"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Cytochrome P450 46A1 encoded by CYP46A1 catalyzes cholesterol 24-hydroxylation and is a CNS-specific enzyme that controls cholesterol removal and turnover in the brain. Accumulating data suggest that increases in cytochrome P450 46A1 activity in mouse models of common neurodegenerative diseases affect various, apparently unlinked biological processes and pathways. Yet, the underlying reason for these multiple enzyme activity effects is currently unknown. Herein, we tested the hypothesis that cytochrome P450 46A1-mediated sterol flux alters physico-chemical properties of the plasma membranes and thereby membrane-dependent events. We used 9-month-old 5XFAD mice (an Alzheimer\u2019s disease model) treated for 6\u2009months with the anti-HIV drug efavirenz. These animals have previously been shown to have improved behavioural performance, increased cytochrome P450 46A1 activity in the brain, and increased sterol flux through the plasma membranes. We further examined 9-month-old Cyp46a1\u2212\/\u2212 mice, which have previously been observed to have cognitive deficits and decreased sterol flux through brain membranes. Synaptosomal fractions from the brain of efavirenz-treated 5XFAD mice had essentially unchanged cholesterol levels as compared to control 5XFAD mice. However with efavirenz treatment in these mice, there were changes in the membrane properties (increased cholesterol accessibility, ordering, osmotic resistance and thickness) as well as total glutamate content and ability to release glutamate in response to mild stimulation. Similarly, the cholesterol content in synaptosomal fractions from the brain of Cyp46a1\u2212\/\u2212 mice was essentially the same as in wild-type mice but knockout of Cyp46a1 was associated with changes in membrane properties and glutamate content and its exocytotic release. Changes in Cyp46a1\u2212\/\u2212 mice were in the opposite direction to those observed in efavirenz-treated versus control 5XFAD mice. Incubation of synaptosomal fractions with the inhibitors of glycogen synthase kinase 3, cyclin-dependent kinase 5, protein phosphatase 1\/2\u2009A, and protein phosphatase 2B revealed that increased sterol flux in efavirenz-treated versus control 5XFAD mice affected the ability of all four enzymes to modulate glutamate release. In contrast, in Cyp46a1\u2212\/\u2212 versus wild-type mice, decreased sterol flux altered the ability of only cyclin-dependent kinase 5 and protein phosphatase 2B to regulate the glutamate release. Collectively, our results support cytochrome P450 46A1-mediated sterol flux as an important contributor to the fundamental properties of the membranes, protein phosphorylation and synaptic transmission. Also, our data provide an explanation of how one enzyme, cytochrome P450 46A1, can affect multiple pathways and processes and serve as a common potential target for several neurodegenerative disorders.<\/jats:p>","DOI":"10.1093\/braincomms\/fcaa043","type":"journal-article","created":{"date-parts":[[2020,4,11]],"date-time":"2020-04-11T17:25:34Z","timestamp":1586625934000},"source":"Crossref","is-referenced-by-count":34,"title":["Brain sterol flux mediated by cytochrome P450 46A1 affects membrane properties and membrane-dependent processes"],"prefix":"10.1093","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1432-3455","authenticated-orcid":false,"given":"Alexey M","family":"Petrov","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Mast","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Young","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Denker","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9742-6232","authenticated-orcid":false,"given":"Irina A","family":"Pikuleva","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Case Western Reserve University, Cleveland, OH 44106, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,4,11]]},"reference":[{"key":"2020081109070893600_fcaa043-B1","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/2045-8118-10-29","article-title":"Localization of organic anion transporting polypeptide (Oatp) 1a4 and Oatp1c1 at the rat blood-retinal barrier","volume":"10","author":"Akanuma","year":"2013","journal-title":"Fluids Barriers CNS"},{"key":"2020081109070893600_fcaa043-B2","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1007\/978-1-4939-1752-5_10","volume-title":"Methods in membrane lipids","author":"Ashdown","year":"2015"},{"key":"2020081109070893600_fcaa043-B3","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/978-1-4020-5943-8_6","article-title":"Synaptosome proteomics","volume":"43","author":"Bai","year":"2007","journal-title":"Subcell Biochem"},{"key":"2020081109070893600_fcaa043-B4","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1039\/C5CP04239A","article-title":"The effect of hydrostatic pressure on model membrane domain composition and lateral compressibility","volume":"18","author":"Barriga","year":"2016","journal-title":"Phys Chem Chem Phys"},{"key":"2020081109070893600_fcaa043-B5","doi-asserted-by":"crossref","first-page":"30984","DOI":"10.1074\/jbc.272.49.30984","article-title":"Amphiphysin I is associated with coated endocytic intermediates and undergoes stimulation-dependent dephosphorylation in nerve terminals","volume":"272","author":"Bauerfeind","year":"1997","journal-title":"J Biol Chem"},{"key":"2020081109070893600_fcaa043-B6","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1016\/S0022-2275(20)32188-X","article-title":"Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation","volume":"39","author":"Bjorkhem","year":"1998","journal-title":"J Lipid Res"},{"key":"2020081109070893600_fcaa043-B7","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/brain\/awv384","article-title":"CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington\u2019s disease","volume":"139","author":"Boussicault","year":"2016","journal-title":"Brain"},{"key":"2020081109070893600_fcaa043-B8","doi-asserted-by":"crossref","first-page":"162","DOI":"10.1111\/j.1476-5381.1996.tb15380.x","article-title":"Inhibition by lifarizine of intracellular Ca2+ rises and glutamate exocytosis in depolarized rat cerebrocortical synaptosomes and cultured neurones","volume":"118","author":"Budd","year":"1996","journal-title":"Br J Pharmacol"},{"key":"2020081109070893600_fcaa043-B9","doi-asserted-by":"crossref","first-page":"5965","DOI":"10.1093\/hmg\/ddv268","article-title":"Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology","volume":"24","author":"Burlot","year":"2015","journal-title":"Hum Mol Genet"},{"key":"2020081109070893600_fcaa043-B10","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1111\/ejn.12911","article-title":"Inhibiting cholesterol degradation induces neuronal sclerosis and epileptic activity in mouse hippocampus","volume":"41","author":"Chali","year":"2015","journal-title":"Eur J Neurosci"},{"key":"2020081109070893600_fcaa043-B11","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1124\/mol.107.034942","article-title":"Glycogen synthase kinase 3 regulates N-methyl-D-aspartate receptor channel trafficking and function in cortical neurons","volume":"72","author":"Chen","year":"2007","journal-title":"Mol Pharmacol"},{"key":"2020081109070893600_fcaa043-B12","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1074\/mcp.D500009-MCP200","article-title":"Relative and absolute quantification of postsynaptic density proteome isolated from rat forebrain and cerebellum","volume":"5","author":"Cheng","year":"2006","journal-title":"Mol Cell Proteomics"},{"key":"2020081109070893600_fcaa043-B13","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1073\/pnas.0308652100","article-title":"Cyclin-dependent kinase 5 regulates dopaminergic and glutamatergic transmission in the striatum","volume":"101","author":"Chergui","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B14","doi-asserted-by":"crossref","first-page":"e74667","DOI":"10.1371\/journal.pone.0074667","article-title":"Area-specific alterations of synaptic plasticity in the 5XFAD mouse model of Alzheimer\u2019s disease: dissociation between somatosensory cortex and hippocampus","volume":"8","author":"Crouzin","year":"2013","journal-title":"PLoS One"},{"key":"2020081109070893600_fcaa043-B15","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.neuron.2009.04.024","article-title":"Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis","volume":"62","author":"Darios","year":"2009","journal-title":"Neuron"},{"key":"2020081109070893600_fcaa043-B16","doi-asserted-by":"crossref","first-page":"2383","DOI":"10.1093\/brain\/awv166","article-title":"CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer\u2019s disease","volume":"138","author":"Djelti","year":"2015","journal-title":"Brain"},{"key":"2020081109070893600_fcaa043-B17","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s12154-008-0010-6","article-title":"Sterols and membrane dynamics","volume":"1","author":"Dufourc","year":"2008","journal-title":"J Chem Biol"},{"key":"2020081109070893600_fcaa043-B18","doi-asserted-by":"crossref","first-page":"4565","DOI":"10.1113\/JP270590","article-title":"Membrane lipid rafts and neurobiology: age-related changes in membrane lipids and loss of neuronal function","volume":"594","author":"Egawa","year":"2016","journal-title":"J Physiol"},{"key":"2020081109070893600_fcaa043-B19","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1096\/fj.10-169383","article-title":"The AMPKgamma1 subunit plays an essential role in erythrocyte membrane elasticity, and its genetic inactivation induces splenomegaly and anemia","volume":"25","author":"Foretz","year":"2011","journal-title":"FASEB J"},{"key":"2020081109070893600_fcaa043-B20","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1046\/j.1471-4159.2002.01029.x","article-title":"Okadaic acid disrupts synaptic vesicle trafficking in a ribbon-type synapse","volume":"82","author":"Guatimosim","year":"2002","journal-title":"J Neurochem"},{"key":"2020081109070893600_fcaa043-B21","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1177\/36.10.2458408","article-title":"Ultrastructural discrimination of lipid droplets and vesicles in atherosclerosis: value of osmium-thiocarbohydrazide-osmium and tannic acid-paraphenylenediamine techniques","volume":"36","author":"Guyton","year":"1988","journal-title":"J Histochem Cytochem"},{"key":"2020081109070893600_fcaa043-B22","doi-asserted-by":"crossref","first-page":"e10924","DOI":"10.15252\/emmm.201910924","article-title":"Therapeutic implications of altered cholesterol homeostasis mediated by loss of CYP46A1 in human glioblastoma","volume":"12","author":"Han","year":"2020","journal-title":"EMBO Mol Med"},{"key":"2020081109070893600_fcaa043-B23","doi-asserted-by":"crossref","first-page":"149","DOI":"10.3233\/JAD-2009-0933","article-title":"Tau phosphorylation by cdk5 and Fyn in response to amyloid peptide Abeta (25-35): involvement of lipid rafts","volume":"16","author":"Hernandez","year":"2009","journal-title":"J Alzheimers Dis"},{"key":"2020081109070893600_fcaa043-B24","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1016\/S0896-6273(00)80851-X","article-title":"A phospho-switch controls the dynamic association of synapsins with synaptic vesicles","volume":"24","author":"Hosaka","year":"1999","journal-title":"Neuron"},{"key":"2020081109070893600_fcaa043-B25","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.nbd.2008.10.007","article-title":"GSK3 inhibitors show benefits in an Alzheimer\u2019s disease (AD) model of neurodegeneration but adverse effects in control animals","volume":"33","author":"Hu","year":"2009","journal-title":"Neurobiol Dis"},{"key":"2020081109070893600_fcaa043-B26","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/mt.2009.175","article-title":"Adeno-associated virus gene therapy with cholesterol 24-hydroxylase reduces the amyloid pathology before or after the onset of amyloid plaques in mouse models of Alzheimer\u2019s disease","volume":"18","author":"Hudry","year":"2010","journal-title":"Mol Ther"},{"key":"2020081109070893600_fcaa043-B27","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1146\/annurev.ne.17.030194.001251","article-title":"Synaptic vesicles and exocytosis","volume":"17","author":"Jahn","year":"1994","journal-title":"Annu Rev Neurosci"},{"key":"2020081109070893600_fcaa043-B28","first-page":"2277","article-title":"To be or not to be: PP2A as a dual player in CNS functions, its role in neurodegeneration, and its interaction with brain insulin signaling","volume":"76","author":"Javadpour","year":"2019","journal-title":"Cell Mol Life Sci"},{"key":"2020081109070893600_fcaa043-B29","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1038\/s41598-017-01247-9","article-title":"Nanoscale membrane domain formation driven by cholesterol","volume":"7","author":"Javanainen","year":"2017","journal-title":"Sci Rep"},{"key":"2020081109070893600_fcaa043-B30","doi-asserted-by":"crossref","first-page":"13793","DOI":"10.1038\/s41598-017-14002-x","article-title":"Mechanistic insights into the cholesterol-dependent binding of perfringolysin O-based probes and cell membranes","volume":"7","author":"Johnson","year":"2017","journal-title":"Sci Rep"},{"key":"2020081109070893600_fcaa043-B31","doi-asserted-by":"crossref","first-page":"3373","DOI":"10.1021\/bi3003132","article-title":"Modifications in perfringolysin O domain 4 alter the cholesterol concentration threshold required for binding","volume":"51","author":"Johnson","year":"2012","journal-title":"Biochemistry"},{"key":"2020081109070893600_fcaa043-B32","doi-asserted-by":"crossref","first-page":"2432","DOI":"10.1093\/brain\/awz174","article-title":"CYP46A1 gene therapy deciphers the role of brain cholesterol metabolism in Huntington\u2019s disease","volume":"142","author":"Kacher","year":"2019","journal-title":"Brain"},{"key":"2020081109070893600_fcaa043-B33","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.conb.2016.12.012","article-title":"The readily releasable pool of synaptic vesicles","volume":"43","author":"Kaeser","year":"2017","journal-title":"Curr Opin Neurobiol"},{"key":"2020081109070893600_fcaa043-B34","doi-asserted-by":"crossref","first-page":"5253","DOI":"10.4049\/jimmunol.178.8.5253","article-title":"Free cholesterol alters lipid raft structure and function regulating neutrophil Ca2+ entry and respiratory burst: correlations with calcium channel raft trafficking","volume":"178","author":"Kannan","year":"2007","journal-title":"J Immunol"},{"key":"2020081109070893600_fcaa043-B35","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1111\/j.1471-4159.1970.tb00535.x","article-title":"A light-scattering technique for the study of the permeability of rat brain synaptosomes in vitro","volume":"17","author":"Keen","year":"1970","journal-title":"J Neurochem"},{"key":"2020081109070893600_fcaa043-B36","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1016\/j.neuron.2010.08.003","article-title":"CDK5 serves as a major control point in neurotransmitter release","volume":"67","author":"Kim","year":"2010","journal-title":"Neuron"},{"key":"2020081109070893600_fcaa043-B37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.nbd.2008.10.006","article-title":"Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model","volume":"33","author":"Kimura","year":"2009","journal-title":"Neurobiol Dis"},{"key":"2020081109070893600_fcaa043-B38","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1016\/0006-3002(61)90599-6","article-title":"Some calculations on the turbidity of mitochondria and bacteria","volume":"51","author":"Koch","year":"1961","journal-title":"Biochim Biophys Acta"},{"key":"2020081109070893600_fcaa043-B39","doi-asserted-by":"crossref","first-page":"11394","DOI":"10.1073\/pnas.0805556105","article-title":"Biphasic requirement for geranylgeraniol in hippocampal long-term potentiation","volume":"105","author":"Kotti","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B40","doi-asserted-by":"crossref","first-page":"3869","DOI":"10.1073\/pnas.0600316103","article-title":"Brain cholesterol turnover required for geranylgeraniol production and learning in mice","volume":"103","author":"Kotti","year":"2006","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B41","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.neures.2004.12.018","article-title":"Regulation of synaptic vesicle recycling by calcineurin in different vesicle pools","volume":"51","author":"Kumashiro","year":"2005","journal-title":"Neurosci Res"},{"key":"2020081109070893600_fcaa043-B42","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.neuron.2016.02.033","article-title":"Membrane lipids in presynaptic function and disease","volume":"90","author":"Lauwers","year":"2016","journal-title":"Neuron"},{"key":"2020081109070893600_fcaa043-B43","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1073\/pnas.0307813100","article-title":"Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses","volume":"101","author":"Lee","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B44","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1126\/science.1174621","article-title":"Lipid rafts as a membrane-organizing principle","volume":"327","author":"Lingwood","year":"2010","journal-title":"Science"},{"key":"2020081109070893600_fcaa043-B45","doi-asserted-by":"crossref","first-page":"4328","DOI":"10.1007\/s12035-015-9369-x","article-title":"The role of Cdk5 in Alzheimer\u2019s disease","volume":"53","author":"Liu","year":"2016","journal-title":"Mol Neurobiol"},{"key":"2020081109070893600_fcaa043-B46","doi-asserted-by":"crossref","first-page":"7238","DOI":"10.1073\/pnas.96.13.7238","article-title":"cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain","volume":"96","author":"Lund","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B47","doi-asserted-by":"crossref","first-page":"22980","DOI":"10.1074\/jbc.M303415200","article-title":"Knockout of the cholesterol 24-hydroxylase gene in mice reveals a brain-specific mechanism of cholesterol turnover","volume":"278","author":"Lund","year":"2003","journal-title":"J Biol Chem"},{"key":"2020081109070893600_fcaa043-B48","doi-asserted-by":"crossref","first-page":"9799","DOI":"10.1073\/pnas.93.18.9799","article-title":"Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation","volume":"93","author":"Lutjohann","year":"1996","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B49","doi-asserted-by":"crossref","first-page":"e68534","DOI":"10.1371\/journal.pone.0068534","article-title":"Is it possible to improve memory function by upregulation of the cholesterol 24S-hydroxylase (CYP46A1) in the brain?","volume":"8","author":"Maioli","year":"2013","journal-title":"PLoS One"},{"key":"2020081109070893600_fcaa043-B50","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1016\/j.tins.2006.10.004","article-title":"Protein serine\/threonine phosphatases in neuronal plasticity and disorders of learning and memory","volume":"29","author":"Mansuy","year":"2006","journal-title":"Trends Neurosci"},{"key":"2020081109070893600_fcaa043-B51","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/S0960-9822(98)70297-0","article-title":"Calcium triggers calcineurin-dependent synaptic vesicle recycling in mammalian nerve terminals","volume":"8","author":"Marks","year":"1998","journal-title":"Curr Biol"},{"key":"2020081109070893600_fcaa043-B52","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1016\/j.neuron.2012.08.042","article-title":"A preferentially segregated recycling vesicle pool of limited size supports neurotransmission in native central synapses","volume":"76","author":"Marra","year":"2012","journal-title":"Neuron"},{"key":"2020081109070893600_fcaa043-B53","doi-asserted-by":"crossref","first-page":"3529","DOI":"10.1074\/jbc.M113.532846","article-title":"Pharmacologic stimulation of cytochrome P450 46A1 and cerebral cholesterol turnover in mice","volume":"289","author":"Mast","year":"2014","journal-title":"J Biol Chem"},{"key":"2020081109070893600_fcaa043-B54","doi-asserted-by":"crossref","first-page":"e0187168","DOI":"10.1371\/journal.pone.0187168","article-title":"Transcriptional and post-translational changes in the brain of mice deficient in cholesterol removal mediated by cytochrome P450 46A1 (CYP46A1)","volume":"12","author":"Mast","year":"2017","journal-title":"PLoS One"},{"key":"2020081109070893600_fcaa043-B55","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1167\/iovs.10-6021","article-title":"Cholestenoic acid is an important elimination product of cholesterol in the retina: comparison of retinal cholesterol metabolism with that in the brain","volume":"52","author":"Mast","year":"2011","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"2020081109070893600_fcaa043-B56","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.neuropharm.2017.06.026","article-title":"Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer\u2019s disease","volume":"123","author":"Mast","year":"2017","journal-title":"Neuropharmacology"},{"key":"2020081109070893600_fcaa043-B57","doi-asserted-by":"crossref","first-page":"2130","DOI":"10.1194\/jlr.M200293-JLR200","article-title":"On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function","volume":"43","author":"Meaney","year":"2002","journal-title":"J Lipid Res"},{"key":"2020081109070893600_fcaa043-B58","doi-asserted-by":"crossref","DOI":"10.1042\/AN20140006","article-title":"The Cdk5 inhibitor Roscovitine increases LTP induction in corticostriatal synapses","volume":"6","author":"Miranda-Barrientos","year":"2014","journal-title":"ASN Neuro"},{"key":"2020081109070893600_fcaa043-B59","doi-asserted-by":"crossref","first-page":"e48143","DOI":"10.15252\/embr.201948143","article-title":"NPC1 enables cholesterol mobilization during long-term potentiation that can be restored in Niemann-Pick disease type C by CYP46A1 activation","volume":"20","author":"Mitroi","year":"2019","journal-title":"EMBO Rep"},{"key":"2020081109070893600_fcaa043-B60","doi-asserted-by":"crossref","first-page":"3255","DOI":"10.1016\/j.bpj.2010.09.028","article-title":"Perfringolysin O association with ordered lipid domains: implications for transmembrane protein raft affinity","volume":"99","author":"Nelson","year":"2010","journal-title":"Biophys J"},{"key":"2020081109070893600_fcaa043-B61","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1038\/321772a0","article-title":"Synaptosomes possess an exocytotic pool of glutamate","volume":"321","author":"Nicholls","year":"1986","journal-title":"Nature"},{"key":"2020081109070893600_fcaa043-B62","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1111\/nan.12288","article-title":"The identification of raft-derived tau-associated vesicles that are incorporated into immature tangles and paired helical filaments","volume":"42","author":"Nishikawa","year":"2016","journal-title":"Neuropathol Appl Neurobiol"},{"key":"2020081109070893600_fcaa043-B63","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1007\/s00401-019-02019-7","article-title":"Restoring brain cholesterol turnover improves autophagy and has therapeutic potential in mouse models of spinocerebellar ataxia","volume":"138","author":"N\u00f3brega","year":"2019","journal-title":"Acta Neuropathol"},{"key":"2020081109070893600_fcaa043-B64","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer\u2019s disease mutations: potential factors in amyloid plaque formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J Neurosci"},{"key":"2020081109070893600_fcaa043-B65","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/978-90-481-8622-8_22","article-title":"Cholesterol-binding toxins and anti-cholesterol antibodies as structural probes for cholesterol localization","volume":"51","author":"Ohno-Iwashita","year":"2010","journal-title":"Subcell Biochem"},{"key":"2020081109070893600_fcaa043-B66","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.anaerobe.2003.09.003","article-title":"Perfringolysin O, a cholesterol-binding cytolysin, as a probe for lipid rafts","volume":"10","author":"Ohno-Iwashita","year":"2004","journal-title":"Anaerobe"},{"key":"2020081109070893600_fcaa043-B67","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1016\/j.bpj.2013.08.042","article-title":"The structural basis of cholesterol accessibility in membranes","volume":"105","author":"Olsen","year":"2013","journal-title":"Biophys J"},{"key":"2020081109070893600_fcaa043-B68","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1016\/j.pharep.2017.04.018","article-title":"Possible anti-depressant effect of efavirenz and pro-depressive-like effect of voriconazole in specified doses in various experimental models of depression in mice","volume":"69","author":"Patel","year":"2017","journal-title":"Pharmacol Rep"},{"key":"2020081109070893600_fcaa043-B69","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1007\/s13311-019-00737-0","article-title":"CYP46A1 activation by efavirenz leads to behavioral improvement without significant changes in amyloid plaque load in the brain of 5XFAD mice","volume":"16","author":"Petrov","year":"2019","journal-title":"Neurotherapeutics"},{"key":"2020081109070893600_fcaa043-B70","doi-asserted-by":"crossref","first-page":"8782","DOI":"10.1096\/fj.201900092R","article-title":"The key genes, phosphoproteins, processes, and pathways affected by efavirenz-activated CYP46A1 in the amyloid-decreasing paradigm of efavirenz treatment","volume":"33","author":"Petrov","year":"2019","journal-title":"FASEB J"},{"key":"2020081109070893600_fcaa043-B71","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s13311-019-00731-6","article-title":"Cholesterol 24-hydroxylation by CYP46A1: benefits of modulation for brain diseases","volume":"16","author":"Petrov","year":"2019","journal-title":"Neurotherapeutics"},{"key":"2020081109070893600_fcaa043-B72","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.plipres.2011.06.002","article-title":"Cholesterol metabolism in neurons and astrocytes","volume":"50","author":"Pfrieger","year":"2011","journal-title":"Prog Lipid Res"},{"key":"2020081109070893600_fcaa043-B73","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1194\/jlr.R200021-JLR200","article-title":"Lipid rafts: bringing order to chaos","volume":"44","author":"Pike","year":"2003","journal-title":"J Lipid Res"},{"key":"2020081109070893600_fcaa043-B74","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.tcb.2013.05.002","article-title":"Greasing the synaptic vesicle cycle by membrane lipids","volume":"23","author":"Puchkov","year":"2013","journal-title":"Trends Cell Biol"},{"key":"2020081109070893600_fcaa043-B75","doi-asserted-by":"crossref","first-page":"1676","DOI":"10.1002\/cne.21605","article-title":"Neuronal expression and subcellular localization of cholesterol 24-hydroxylase in the mouse brain","volume":"507","author":"Ramirez","year":"2008","journal-title":"J Comp Neurol"},{"key":"2020081109070893600_fcaa043-B76","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/S0896-6273(00)80146-4","article-title":"Definition of the readily releasable pool of vesicles at hippocampal synapses","volume":"16","author":"Rosenmund","year":"1996","journal-title":"Neuron"},{"key":"2020081109070893600_fcaa043-B77","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/j.bbalip.2016.01.003","article-title":"Sensing membrane thickness: lessons learned from cold stress","volume":"1861","author":"Saita","year":"2016","journal-title":"Biochim Biophys Acta"},{"key":"2020081109070893600_fcaa043-B78","doi-asserted-by":"crossref","first-page":"2531","DOI":"10.1002\/pmic.200401198","article-title":"Proteomic analysis of synaptosomes using isotope-coded affinity tags and mass spectrometry","volume":"5","author":"Schrimpf","year":"2005","journal-title":"Proteomics"},{"key":"2020081109070893600_fcaa043-B79","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.neuropharm.2012.06.053","article-title":"Lipid rafts, synaptic transmission and plasticity: impact in age-related neurodegenerative diseases","volume":"64","author":"Sebasti\u00e3o","year":"2013","journal-title":"Neuropharmacology"},{"key":"2020081109070893600_fcaa043-B80","doi-asserted-by":"crossref","first-page":"6195","DOI":"10.1046\/j.1432-1033.2002.03338.x","article-title":"The C-terminal domain of perfringolysin O is an essential cholesterol-binding unit targeting to cholesterol-rich microdomains","volume":"269","author":"Shimada","year":"2002","journal-title":"Eur J Biochem"},{"key":"2020081109070893600_fcaa043-B81","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1016\/j.arcmed.2012.10.015","article-title":"Deregulated Cdk5 activity is involved in inducing Alzheimer\u2019s disease","volume":"43","author":"Shukla","year":"2012","journal-title":"Arch Med Res"},{"key":"2020081109070893600_fcaa043-B82","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1021\/ja068008h","article-title":"Fluorescent biomembrane probe for ratiometric detection of apoptosis","volume":"129","author":"Shynkar","year":"2007","journal-title":"J Am Chem Soc"},{"key":"2020081109070893600_fcaa043-B83","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1172\/JCI0216390","article-title":"Cholesterol, lipid rafts, and disease","volume":"110","author":"Simons","year":"2002","journal-title":"J Clin Invest"},{"key":"2020081109070893600_fcaa043-B84","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1038\/emboj.2012.31","article-title":"Cholesterol loss during glutamate-mediated excitotoxicity","volume":"31","author":"Sodero","year":"2012","journal-title":"EMBO J"},{"key":"2020081109070893600_fcaa043-B85","doi-asserted-by":"crossref","first-page":"1643","DOI":"10.1016\/j.bbrc.2006.05.087","article-title":"Recruitment of active glycogen synthase kinase-3 into neuronal lipid rafts","volume":"345","author":"Sui","year":"2006","journal-title":"Biochem Biophys Res Commun"},{"key":"2020081109070893600_fcaa043-B86","doi-asserted-by":"crossref","first-page":"6417","DOI":"10.1523\/JNEUROSCI.0690-07.2007","article-title":"Brain-derived neurotrophic factor regulates cholesterol metabolism for synapse development","volume":"27","author":"Suzuki","year":"2007","journal-title":"J Neurosci"},{"key":"2020081109070893600_fcaa043-B87","doi-asserted-by":"crossref","first-page":"2590","DOI":"10.1523\/JNEUROSCI.22-07-02590.2002","article-title":"Cdk5\/p35 regulates neurotransmitter release through phosphorylation and downregulation of P\/Q-type voltage-dependent calcium channel activity","volume":"22","author":"Tomizawa","year":"2002","journal-title":"J Neurosci"},{"key":"2020081109070893600_fcaa043-B88","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1091\/mbc.e16-06-0420","article-title":"Remodeling of the postsynaptic plasma membrane during neural development","volume":"27","author":"Tulodziecka","year":"2016","journal-title":"Mol Biol Cell"},{"key":"2020081109070893600_fcaa043-B89","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1002\/jnr.22184","article-title":"Mutant huntingtin and glycogen synthase kinase 3-beta accumulate in neuronal lipid rafts of a presymptomatic knock-in mouse model of Huntington\u2019s disease","volume":"88","author":"Valencia","year":"2010","journal-title":"J Neurosci Res"},{"key":"2020081109070893600_fcaa043-B90","doi-asserted-by":"crossref","first-page":"459","DOI":"10.3233\/JHD-130080","article-title":"Striatal synaptosomes from Hdh140Q\/140Q knock-in mice have altered protein levels, novel sites of methionine oxidation, and excess glutamate release after stimulation","volume":"2","author":"Valencia","year":"2013","journal-title":"J Huntingtons Dis"},{"key":"2020081109070893600_fcaa043-B91","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1016\/j.stem.2018.12.013","article-title":"Cholesterol metabolism is a druggable axis that independently regulates tau and amyloid-beta in iPSC-derived Alzheimer\u2019s disease neurons","volume":"24","author":"van der Kant","year":"2019","journal-title":"Cell Stem Cell"},{"key":"2020081109070893600_fcaa043-B92","doi-asserted-by":"crossref","first-page":"364","DOI":"10.1111\/j.1471-4159.2007.04973.x","article-title":"Excitotoxic loss of post-synaptic sites is distinct temporally and mechanistically from neuronal death","volume":"104","author":"Waataja","year":"2008","journal-title":"J Neurochem"},{"key":"2020081109070893600_fcaa043-B93","doi-asserted-by":"crossref","first-page":"4926","DOI":"10.1073\/pnas.091090798","article-title":"Selective binding of perfringolysin O derivative to cholesterol-rich membrane microdomains (rafts)","volume":"98","author":"Waheed","year":"2001","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B94","doi-asserted-by":"crossref","first-page":"26369","DOI":"10.1074\/jbc.M110.121376","article-title":"Regulation of AMPA receptor trafficking and function by glycogen synthase kinase 3","volume":"285","author":"Wei","year":"2010","journal-title":"J Biol Chem"},{"key":"2020081109070893600_fcaa043-B95","doi-asserted-by":"crossref","first-page":"30295","DOI":"10.1074\/jbc.M111.273110","article-title":"Calcineurin selectively docks with the dynamin Ixb splice variant to regulate activity-dependent bulk endocytosis","volume":"286","author":"Xue","year":"2011","journal-title":"J Biol Chem"},{"key":"2020081109070893600_fcaa043-B96","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.chemphyslip.2016.05.003","article-title":"The role of cholesterol in membrane fusion","volume":"199","author":"Yang","year":"2016","journal-title":"Chem Phys Lipids"},{"key":"2020081109070893600_fcaa043-B97","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1016\/j.bpj.2009.06.025","article-title":"Roles of cholesterol in vesicle fusion and motion","volume":"97","author":"Zhang","year":"2009","journal-title":"Biophys J"},{"key":"2020081109070893600_fcaa043-B98","doi-asserted-by":"crossref","first-page":"3624","DOI":"10.1523\/JNEUROSCI.5223-09.2010","article-title":"GSK-3 beta inhibits presynaptic vesicle exocytosis by phosphorylating P\/Q-type calcium channel and interrupting SNARE complex formation","volume":"30","author":"Zhu","year":"2010","journal-title":"J Neurosci"},{"key":"2020081109070893600_fcaa043-B99","doi-asserted-by":"crossref","first-page":"18018","DOI":"10.1073\/pnas.0809714105","article-title":"Probing synaptic vesicle fusion by altering mechanical properties of the neuronal surface membrane","volume":"105","author":"Zhu","year":"2008","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020081109070893600_fcaa043-B100","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.bbamem.2007.03.026","article-title":"Use of cyclodextrins to manipulate plasma membrane cholesterol content: evidence, misconceptions and control strategies","volume":"1768","author":"Zidovetzki","year":"2007","journal-title":"Biochim Biophys Acta"}],"container-title":["Brain Communications"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/braincomms\/advance-article-pdf\/doi\/10.1093\/braincomms\/fcaa043\/33035817\/fcaa043.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/braincomms\/article-pdf\/2\/1\/fcaa043\/33640039\/fcaa043.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/braincomms\/article-pdf\/2\/1\/fcaa043\/33640039\/fcaa043.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T20:58:22Z","timestamp":1696021102000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/braincomms\/article\/doi\/10.1093\/braincomms\/fcaa043\/5819139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,1]]},"references-count":100,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2020,1,1]]}},"URL":"https:\/\/doi.org\/10.1093\/braincomms\/fcaa043","relation":{},"ISSN":["2632-1297"],"issn-type":[{"value":"2632-1297","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020]]},"published":{"date-parts":[[2020,1,1]]},"article-number":"fcaa043"}}