Login Register Cart 0
Generic placeholder image

Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Role of Oxysterols in the Activation of the NLRP3 Inflammasome as a Potential Pharmacological Approach in Alzheimer's Disease

Author(s): Gabriela L. Martins, Cláudia N. Ferreira, András Palotás, Natália P. Rocha and Helton J. Reis*

Volume 21, Issue 2, 2023

Published on: 12 May, 2022

Page: [202 - 212] Pages: 11

DOI: 10.2174/1570159X20666220327215245

Price: $65

Abstract

Alzheimer's disease (AD), the most prevalent form of dementia, is a complex clinical condition with multifactorial origin posing a major burden to health care systems across the world. Even though the pathophysiological mechanisms underlying the disease are still unclear, both central and peripheral inflammation has been implicated in the process. Piling evidence shows that the nucleotide-binding domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated in AD. As dyslipidemia is a risk factor for dementia, and cholesterol can also activate the inflammasome, a possible link between lipid levels and the NLRP3 inflammasome has been proposed in Alzheimer's. It is also speculated that not only cholesterol but also its metabolites, the oxysterols, may be involved in AD pathology. In this context, mounting data suggest that NLRP3 inflammasome activity can be modulated by different peripheral nuclear receptors, including liver-X receptors, which present oxysterols as endogenous ligands. In light of this, the current review explores whether the activation of NLRP3 by nuclear receptors, mediated by oxysterols, may also be involved in AD and could serve as a potential pharmacological avenue in dementia.

Keywords: Alzheimer’s disease, cholesterol, oxysterols, NLRP3 inflammasome, LXR, dementia.

« Previous Next »
Graphical Abstract

[1]
Cipriani, G.; Danti, S.; Picchi, L.; Nuti, A.; Fiorino, M.D. Daily functioning and dementia. Dement. Neuropsychol., 2020, 14(2), 93-102.
[http://dx.doi.org/10.1590/1980-57642020dn14-020001] [PMID: 32595877]
[2]
Kumar, A.; Sidhu, J.; Goyal, A.; Tsao, J.W. Alzheimer disease. In: StatPearls; StatPearls Publishing: Treasure Island, FL, 2020.
[3]
Heppner, F.L.; Ransohoff, R.M.; Becher, B. Immune attack: the role of inflammation in Alzheimer disease. Nat. Rev. Neurosci., 2015, 16(6), 358-372.
[http://dx.doi.org/10.1038/nrn3880] [PMID: 25991443]
[4]
2021 Alzheimer’s disease facts and figures. Alzheimers Dement., 2021, 17(3), 327-406.
[http://dx.doi.org/10.1002/alz.12328] [PMID: 33756057]
[5]
Kinney, J.W.; Bemiller, S.M.; Murtishaw, A.S.; Leisgang, A.M.; Salazar, A.M.; Lamb, B.T. Inflammation as a central mechanism in Alzheimer’s disease. Alzheimers Dement. (N. Y.), 2018, 4(4), 575-590.
[http://dx.doi.org/10.1016/j.trci.2018.06.014] [PMID: 30406177]
[6]
Brosseron, F.; Krauthausen, M.; Kummer, M.; Heneka, M.T. Body fluid cytokine levels in mild cognitive impairment and Alzheimer’s disease: a comparative overview. Mol. Neurobiol., 2014, 50(2), 534-544.
[http://dx.doi.org/10.1007/s12035-014-8657-1] [PMID: 24567119]
[7]
Park, J-C.; Han, S-H.; Mook-Jung, I. Peripheral inflammatory biomarkers in Alzheimer’s disease: a brief review. BMB Rep., 2020, 53(1), 10-19.
[http://dx.doi.org/10.5483/BMBRep.2020.53.1.309] [PMID: 31865964]
[8]
Choi, D.; Choi, S.; Park, S.M. Effect of smoking cessation on the risk of dementia: a longitudinal study. Ann. Clin. Transl. Neurol., 2018, 5(10), 1192-1199.
[http://dx.doi.org/10.1002/acn3.633] [PMID: 30349854]
[9]
Kivimäki, M.; Luukkonen, R.; Batty, G.D.; Ferrie, J.E.; Pentti, J.; Nyberg, S.T.; Shipley, M.J.; Alfredsson, L.; Fransson, E.I.; Goldberg, M.; Knutsson, A.; Koskenvuo, M.; Kuosma, E.; Nordin, M.; Suominen, S.B.; Theorell, T.; Vuoksimaa, E.; Westerholm, P.; Westerlund, H.; Zins, M.; Kivipelto, M.; Vahtera, J.; Kaprio, J.; Singh-Manoux, A.; Jokela, M. Body mass index and risk of dementia: Analysis of individual-level data from 1.3 million individuals. Alzheimers Dement., 2018, 14(5), 601-609.
[http://dx.doi.org/10.1016/j.jalz.2017.09.016] [PMID: 29169013]
[10]
McFarlane, O. Kędziora-Kornatowska, K. Cholesterol and dementia: a long and complicated relationship. Curr. Aging Sci., 2020, 13(1), 42-51.
[http://dx.doi.org/10.2174/1874609812666190917155400] [PMID: 31530269]
[11]
Goedeke, L.; Fernández-Hernando, C. Regulation of cholesterol homeostasis. Cell. Mol. Life Sci., 2012, 69(6), 915-930.
[http://dx.doi.org/10.1007/s00018-011-0857-5] [PMID: 22009455]
[12]
Anchisi, L.; Dessì, S.; Pani, A.; Mandas, A. Cholesterol homeostasis: A key to prevent or slow down neurodegeneration. Front. Physiol., 2013, 3, 486.
[http://dx.doi.org/10.3389/fphys.2012.00486] [PMID: 23316166]
[13]
Ortiz, G.G.; Pacheco-Moisés, F.P.; Flores-Alvarado, L.J.; Macías-Islas, M.A.; Velázquez-Brizuela, I.E.; Ramírez-Anguiano, A.C. Alzheimer disease and metabolism: Role of cholesterol and membrane fluidity. Medicine: Mental and Behavioural Disorders and Diseases of the Nervous System; IntechOpen, 2013, pp. 145-173.
[http://dx.doi.org/10.5772/54091]
[14]
Ghribi, O. Potential mechanisms linking cholesterol to Alzheimer’s disease-like pathology in rabbit brain, hippocampal organotypic slices, and skeletal muscle. J. Alzheimers Dis., 2008, 15(4), 673-684.
[http://dx.doi.org/10.3233/JAD-2008-15412] [PMID: 19096164]
[15]
Safieh, M.; Korczyn, A.D.; Michaelson, D.M. ApoE4: an emerging therapeutic target for Alzheimer’s disease. BMC Med., 2019, 17(1), 64.
[http://dx.doi.org/10.1186/s12916-019-1299-4] [PMID: 30890171]
[16]
Farrall, A.J.; Wardlaw, J.M. Blood-brain barrier: ageing and microvascular disease--systematic review and meta-analysis. Neurobiol. Aging, 2009, 30(3), 337-352.
[http://dx.doi.org/10.1016/j.neurobiolaging.2007.07.015] [PMID: 17869382]
[17]
Ott, B.R.; Jones, R.N.; Daiello, L.A.; de la Monte, S.M.; Stopa, E.G.; Johanson, C.E.; Denby, C.; Grammas, P. Blood-cerebrospinal fluid barrier gradients in mild cognitive impairment and Alzheimer’s disease: relationship to inflammatory cytokines and chemokines. Front. Aging Neurosci., 2018, 10, 245.
[http://dx.doi.org/10.3389/fnagi.2018.00245] [PMID: 30186149]
[18]
Martins, G.L.; Duarte, R.C.F.; Mukhamedyarov, M.A.; Palotás, A.; Ferreira, C.N.; Reis, H.J. Inflammatory and infectious processes serve as links between atrial fibrillation and Alzheimer’s disease. Int. J. Mol. Sci., 2020, 21(9), 3226.
[http://dx.doi.org/10.3390/ijms21093226] [PMID: 32370194]
[19]
Pourcet, B.; Duez, H. Circadian control of inflammasome pathways: implications for circadian medicine. Front. Immunol., 2020, 11, 1630.
[http://dx.doi.org/10.3389/fimmu.2020.01630] [PMID: 32849554]
[20]
Swanson, K.V.; Deng, M.; Ting, J.P-Y. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat. Rev. Immunol., 2019, 19(8), 477-489.
[http://dx.doi.org/10.1038/s41577-019-0165-0] [PMID: 31036962]
[21]
Hanslik, K.L.; Ulland, T.K. The role of microglia and the Nlrp3 Inflammasome in Alzheimer’s disease. Front. Neurol., 2020, 11, 570711.
[http://dx.doi.org/10.3389/fneur.2020.570711] [PMID: 33071950]
[22]
Duez, H.; Pourcet, B. Nuclear receptors in the control of the NLRP3 inflammasome pathway. Front. Endocrinol. (Lausanne), 2021, 12, 630536.
[http://dx.doi.org/10.3389/fendo.2021.630536] [PMID: 33716981]
[23]
Parsamanesh, N.; Moossavi, M.; Bahrami, A.; Fereidouni, M.; Barreto, G.; Sahebkar, A. NLRP3 inflammasome as a treatment target in atherosclerosis: A focus on statin therapy. Int. Immunopharmacol., 2019, 73, 146-155.
[http://dx.doi.org/10.1016/j.intimp.2019.05.006] [PMID: 31100709]
[24]
Shao, B-Z.; Xu, Z-Q.; Han, B-Z.; Su, D-F.; Liu, C. NLRP3 inflammasome and its inhibitors: a review. Front. Pharmacol., 2015, 6, 262.
[http://dx.doi.org/10.3389/fphar.2015.00262] [PMID: 26594174]
[25]
Sheedy, F.J.; Grebe, A.; Rayner, K.J.; Kalantari, P.; Ramkhelawon, B.; Carpenter, S.B.; Becker, C.E.; Ediriweera, H.N.; Mullick, A.E.; Golenbock, D.T.; Stuart, L.M.; Latz, E.; Fitzgerald, K.A.; Moore, K.J. CD36 coordinates NLRP3 inflammasome activation by facilitating intracellular nucleation of soluble ligands into particulate ligands in sterile inflammation. Nat. Immunol., 2013, 14(8), 812-820.
[http://dx.doi.org/10.1038/ni.2639] [PMID: 23812099]
[26]
Warnatsch, A.; Ioannou, M.; Wang, Q.; Papayannopoulos, V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science, 2015, 349(6245), 316-320.
[http://dx.doi.org/10.1126/science.aaa8064] [PMID: 26185250]
[27]
Duewell, P.; Kono, H.; Rayner, K.J.; Sirois, C.M.; Vladimer, G.; Bauernfeind, F.G.; Abela, G.S.; Franchi, L.; Nuñez, G.; Schnurr, M.; Espevik, T.; Lien, E.; Fitzgerald, K.A.; Rock, K.L.; Moore, K.J.; Wright, S.D.; Hornung, V.; Latz, E. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature, 2010, 464(7293), 1357-1361.
[http://dx.doi.org/10.1038/nature08938] [PMID: 20428172]
[28]
Karasawa, T.; Takahashi, M. The crystal-induced activation of NLRP3 inflammasomes in atherosclerosis. Inflamm. Regen., 2017, 37(1), 18.
[http://dx.doi.org/10.1186/s41232-017-0050-9] [PMID: 29259717]
[29]
Hendrikx, T.; Jeurissen, M.L.; van Gorp, P.J.; Gijbels, M.J.; Walenbergh, S.M.; Houben, T.; van Gorp, R.; Pöttgens, C.C.; Stienstra, R.; Netea, M.G.; Hofker, M.H.; Donners, M.M.; Shiri-Sverdlov, R. Bone marrow-specific caspase-1/11 deficiency inhibits atherosclerosis development in Ldlr(-/-) mice. FEBS J., 2015, 282(12), 2327-2338.
[http://dx.doi.org/10.1111/febs.13279] [PMID: 25817537]
[30]
Usui, F.; Shirasuna, K.; Kimura, H.; Tatsumi, K.; Kawashima, A.; Karasawa, T.; Hida, S.; Sagara, J.; Taniguchi, S.; Takahashi, M. Critical role of caspase-1 in vascular inflammation and development of atherosclerosis in Western diet-fed apolipoprotein E-deficient mice. Biochem. Biophys. Res. Commun., 2012, 425(2), 162-168.
[http://dx.doi.org/10.1016/j.bbrc.2012.07.058] [PMID: 22819845]
[31]
Rajamäki, K.; Lappalainen, J.; Oörni, K.; Välimäki, E.; Matikainen, S.; Kovanen, P.T.; Eklund, K.K. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One, 2010, 5(7), e11765.
[http://dx.doi.org/10.1371/journal.pone.0011765] [PMID: 20668705]
[32]
Heneka, M.T.; Kummer, M.P.; Stutz, A.; Delekate, A.; Schwartz, S.; Vieira-Saecker, A.; Griep, A.; Axt, D.; Remus, A.; Tzeng, T.C.; Gelpi, E.; Halle, A.; Korte, M.; Latz, E.; Golenbock, D.T. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature, 2013, 493(7434), 674-678.
[http://dx.doi.org/10.1038/nature11729] [PMID: 23254930]
[33]
Ising, C.; Venegas, C.; Zhang, S.; Scheiblich, H.; Schmidt, S.V.; Vieira-Saecker, A.; Schwartz, S.; Albasset, S.; McManus, R.M.; Tejera, D.; Griep, A.; Santarelli, F.; Brosseron, F.; Opitz, S.; Stunden, J.; Merten, M.; Kayed, R.; Golenbock, D.T.; Blum, D.; Latz, E.; Buée, L.; Heneka, M.T. NLRP3 inflammasome activation drives tau pathology. Nature, 2019, 575(7784), 669-673.
[http://dx.doi.org/10.1038/s41586-019-1769-z] [PMID: 31748742]
[34]
Zhang, Y.; Dong, Z.; Song, W. NLRP3 inflammasome as a novel therapeutic target for Alzheimer’s disease. Signal Transduct. Target. Ther., 2020, 5(1), 37.
[http://dx.doi.org/10.1038/s41392-020-0145-7] [PMID: 32296063]
[35]
Halle, A.; Hornung, V.; Petzold, G.C.; Stewart, C.R.; Monks, B.G.; Reinheckel, T.; Fitzgerald, K.A.; Latz, E.; Moore, K.J.; Golenbock, D.T. The NALP3 inflammasome is involved in the innate immune response to amyloid-β. Nat. Immunol., 2008, 9(8), 857-865.
[http://dx.doi.org/10.1038/ni.1636] [PMID: 18604209]
[36]
Stancu, I-C.; Cremers, N.; Vanrusselt, H.; Couturier, J.; Vanoosthuyse, A.; Kessels, S.; Lodder, C.; Brône, B.; Huaux, F.; Octave, J.N.; Terwel, D.; Dewachter, I. Aggregated Tau activates NLRP3-ASC inflammasome exacerbating exogenously seeded and non-exogenously seeded Tau pathology in vivo. Acta Neuropathol., 2019, 137(4), 599-617.
[http://dx.doi.org/10.1007/s00401-018-01957-y] [PMID: 30721409]
[37]
Tejera, D.; Mercan, D.; Sanchez-Caro, J.M.; Hanan, M.; Greenberg, D.; Soreq, H.; Latz, E.; Golenbock, D.; Heneka, M.T. Systemic inflammation impairs microglial Aβ clearance through NLRP3 inflammasome. EMBO J., 2019, 38(17), e101064.
[http://dx.doi.org/10.15252/embj.2018101064] [PMID: 31359456]
[38]
Italiani, P.; Puxeddu, I.; Napoletano, S.; Scala, E.; Melillo, D.; Manocchio, S.; Angiolillo, A.; Migliorini, P.; Boraschi, D.; Vitale, E.; Di Costanzo, A. Circulating levels of IL-1 family cytokines and receptors in Alzheimer’s disease: new markers of disease progression? J. Neuroinflammation, 2018, 15(1), 342.
[http://dx.doi.org/10.1186/s12974-018-1376-1] [PMID: 30541566]
[39]
Gamba, P.; Testa, G.; Gargiulo, S.; Staurenghi, E.; Poli, G.; Leonarduzzi, G. Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease. Front. Aging Neurosci., 2015, 7, 119.
[http://dx.doi.org/10.3389/fnagi.2015.00119] [PMID: 26150787]
[40]
Testa, G.; Staurenghi, E.; Zerbinati, C.; Gargiulo, S.; Iuliano, L.; Giaccone, G.; Fantò, F.; Poli, G.; Leonarduzzi, G.; Gamba, P. Changes in brain oxysterols at different stages of Alzheimer’s disease: Their involvement in neuroinflammation. Redox Biol., 2016, 10, 24-33.
[http://dx.doi.org/10.1016/j.redox.2016.09.001] [PMID: 27687218]
[41]
Choi, C.; Finlay, D.K. Diverse immunoregulatory roles of oxysterols—the oxidized cholesterol metabolites. Metabolites, 2020, 10(10), 384.
[http://dx.doi.org/10.3390/metabo10100384] [PMID: 32998240]
[42]
Saint-Pol, J.; Gosselet, F. Oxysterols and the NeuroVascular Unit (NVU): A far true love with bright and dark sides. J. Steroid Biochem. Mol. Biol., 2019, 191, 105368.
[http://dx.doi.org/10.1016/j.jsbmb.2019.04.017] [PMID: 31026511]
[43]
Weigel, T.K.; Kulas, J.A.; Ferris, H.A. Oxidized cholesterol species as signaling molecules in the brain: diabetes and Alzheimer’s disease. Neuronal Signal., 2019, 3(4), NS20190068.
[http://dx.doi.org/10.1042/NS20190068] [PMID: 32269839]
[44]
Varma, V.R. Büşra Lüleci, H.; Oommen, A.M.; Varma, S.; Blackshear, C.T.; Griswold, M.E.; An, Y.; Roberts, J.A.; O’Brien, R.; Pletnikova, O.; Troncoso, J.C.; Bennett, D.A.; Çakır, T.; Legido-Quigley, C.; Thambisetty, M. Abnormal brain cholesterol homeostasis in Alzheimer’s disease-a targeted metabolomic and transcriptomic study. NPJ Aging Mech. Dis., 2021, 7(1), 11.
[http://dx.doi.org/10.1038/s41514-021-00064-9] [PMID: 34075056]
[45]
Gamba, P.; Giannelli, S.; Staurenghi, E.; Testa, G.; Sottero, B.; Biasi, F.; Poli, G.; Leonarduzzi, G. The controversial role of 24-S-hydroxycholesterol in Alzheimer’s disease. Antioxidants, 2021, 10(5), 740.
[http://dx.doi.org/10.3390/antiox10050740] [PMID: 34067119]
[46]
Gamba, P.; Staurenghi, E.; Testa, G.; Giannelli, S.; Sottero, B.; Leonarduzzi, G. A crosstalk between brain cholesterol oxidation and glucose metabolism in Alzheimer’s disease. Front. Neurosci., 2019, 13, 556.
[http://dx.doi.org/10.3389/fnins.2019.00556] [PMID: 31213973]
[47]
Marwarha, G.; Ghribi, O. Does the oxysterol 27-hydroxycholesterol underlie Alzheimer’s disease-Parkinson’s disease overlap? Exp. Gerontol., 2015, 68, 13-18.
[http://dx.doi.org/10.1016/j.exger.2014.09.013] [PMID: 25261765]
[48]
Gamba, P.; Guglielmotto, M.; Testa, G.; Monteleone, D.; Zerbinati, C.; Gargiulo, S.; Biasi, F.; Iuliano, L.; Giaccone, G.; Mauro, A.; Poli, G.; Tamagno, E.; Leonarduzzi, G. Up-regulation of β-amyloidogenesis in neuron-like human cells by both 24- and 27-hydroxycholesterol: protective effect of N-acetyl-cysteine. Aging Cell, 2014, 13(3), 561-572.
[http://dx.doi.org/10.1111/acel.12206] [PMID: 24612036]
[49]
Zhang, X.; Xi, Y.; Yu, H.; An, Y.; Wang, Y.; Tao, L.; Wang, Y.; Liu, W.; Wang, T.; Xiao, R. 27-hydroxycholesterol promotes Aβ accumulation via altering Aβ metabolism in mild cognitive impairment patients and APP/PS1 mice. Brain Pathol., 2019, 29(4), 558-573.
[http://dx.doi.org/10.1111/bpa.12698] [PMID: 30582229]
[50]
Loera-Valencia, R.; Vazquez-Juarez, E.; Muñoz, A.; Gerenu, G.; Gómez-Galán, M.; Lindskog, M.; DeFelipe, J.; Cedazo-Minguez, A.; Merino-Serrais, P. High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus. Sci. Rep., 2021, 11(1), 3736.
[http://dx.doi.org/10.1038/s41598-021-83008-3] [PMID: 33580102]
[51]
Famer, D.; Meaney, S.; Mousavi, M.; Nordberg, A.; Björkhem, I.; Crisby, M. Regulation of α- and β-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the α-secretase pathway. Biochem. Biophys. Res. Commun., 2007, 359(1), 46-50.
[http://dx.doi.org/10.1016/j.bbrc.2007.05.033] [PMID: 17532301]
[52]
Benussi, L.; Ghidoni, R.; Dal Piaz, F.; Binetti, G.; Di Iorio, G.; Abrescia, P. The level of 24-hydroxycholesteryl esters is an early marker of Alzheimer’s disease. J. Alzheimers Dis., 2017, 56(2), 825-833.
[http://dx.doi.org/10.3233/JAD-160930] [PMID: 27983556]
[53]
Lathe, R.; Sapronova, A.; Kotelevtsev, Y. Atherosclerosis and Alzheimer--diseases with a common cause? Inflammation, oxysterols, vasculature. BMC Geriatr., 2014, 14(1), 36.
[http://dx.doi.org/10.1186/1471-2318-14-36] [PMID: 24656052]
[54]
Papassotiropoulos, A.; Lambert, J-C.; Wavrant-De Vrièze, F.; Wollmer, M.A.; von der Kammer, H.; Streffer, J.R.; Maddalena, A.; Huynh, K.D.; Wolleb, S.; Lutjohann, D.; Schneider, B.; Thal, D.R.; Grimaldi, L.M.; Tsolaki, M.; Kapaki, E.; Ravid, R.; Konietzko, U.; Hegi, T.; Pasch, T.; Jung, H.; Braak, H.; Amouyel, P.; Rogaev, E.I.; Hardy, J.; Hock, C.; Nitsch, R.M. Cholesterol 25-hydroxylase on chromosome 10q is a susceptibility gene for sporadic Alzheimer’s disease. Neurodegener. Dis., 2005, 2(5), 233-241.
[http://dx.doi.org/10.1159/000090362] [PMID: 16909003]
[55]
Rose, K.; Allan, A.; Gauldie, S.; Stapleton, G.; Dobbie, L.; Dott, K.; Martin, C.; Wang, L.; Hedlund, E.; Seckl, J.R.; Gustafsson, J.A.; Lathe, R. Neurosteroid hydroxylase CYP7B: vivid reporter activity in dentate gyrus of gene-targeted mice and abolition of a widespread pathway of steroid and oxysterol hydroxylation. J. Biol. Chem., 2001, 276(26), 23937-23944.
[http://dx.doi.org/10.1074/jbc.M011564200] [PMID: 11290741]
[56]
Yau, J.L.; Rasmuson, S.; Andrew, R.; Graham, M.; Noble, J.; Olsson, T.; Fuchs, E.; Lathe, R.; Seckl, J.R. Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer’s disease. Neuroscience, 2003, 121(2), 307-314.
[http://dx.doi.org/10.1016/S0306-4522(03)00438-X] [PMID: 14521990]
[57]
Jang, J.; Park, S.; Jin Hur, H.; Cho, H-J.; Hwang, I.; Pyo Kang, Y. Im, I.; Lee, H.; Lee, E.; Yang, W.; Kang, H.C.; Won Kwon, S.; Yu, J.W.; Kim, D.W. 25-hydroxycholesterol contributes to cerebral inflammation of X-linked adrenoleukodystrophy through activation of the NLRP3 inflammasome. Nat. Commun., 2016, 7(1), 13129.
[http://dx.doi.org/10.1038/ncomms13129] [PMID: 27779191]
[58]
Wong, M.Y.; Lewis, M.; Doherty, J.J.; Shi, Y.; Cashikar, A.G.; Amelianchik, A. 25-Hydroxycholesterol amplifies microglial IL-1β production in an apoE isoform-dependent manner. J. Neuroinflammation, 2020, 17(1), 1-17.
[http://dx.doi.org/10.1186/s12974-020-01869-3] [PMID: 31900165]
[59]
Chen, S.; Zhou, C.; Yu, H.; Tao, L.; An, Y.; Zhang, X.; Wang, Y.; Wang, Y.; Xiao, R. 27-Hydroxycholesterol contributes to lysosomal membrane permeabilization-mediated pyroptosis in co-cultured SH-SY5Y cells and C6 cells. Front. Mol. Neurosci., 2019, 12, 14.
[http://dx.doi.org/10.3389/fnmol.2019.00014] [PMID: 30881285]
[60]
Alatshan, A. Benkő S. Nuclear Receptors as Multiple Regulators of NLRP3 Inflammasome Function. Front. Immunol., 2021, 12, 630569.
[http://dx.doi.org/10.3389/fimmu.2021.630569] [PMID: 33717162]
[61]
Wang, X.; Collins, H.L.; Ranalletta, M.; Fuki, I.V.; Billheimer, J.T.; Rothblat, G.H.; Tall, A.R.; Rader, D.J. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J. Clin. Invest., 2007, 117(8), 2216-2224.
[http://dx.doi.org/10.1172/JCI32057] [PMID: 17657311]
[62]
Bilotta, M.T.; Petillo, S.; Santoni, A.; Cippitelli, M. Liver X receptors: regulators of cholesterol metabolism, inflammation, autoimmunity, and cancer. Front. Immunol., 2020, 11, 584303.
[http://dx.doi.org/10.3389/fimmu.2020.584303] [PMID: 33224146]
[63]
Ghisletti, S.; Huang, W.; Ogawa, S.; Pascual, G.; Lin, M-E.; Willson, T.M.; Rosenfeld, M.G.; Glass, C.K. Parallel SUMOylation-dependent pathways mediate gene- and signal-specific transrepression by LXRs and PPARgamma. Mol. Cell, 2007, 25(1), 57-70.
[http://dx.doi.org/10.1016/j.molcel.2006.11.022] [PMID: 17218271]
[64]
Li, Z.; Martin, M.; Zhang, J.; Huang, H-Y.; Bai, L.; Zhang, J. KLF4 regulation of Ch25h and LXR mitigates atherosclerosis susceptibility. Circulation, 2017, 136(14), 1315.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.027462] [PMID: 28794002]
[65]
Yu, S-X.; Chen, W.; Hu, X-Z.; Feng, S-Y.; Li, K-Y.; Qi, S.; Lei, Q.Q.; Hu, G.Q.; Li, N.; Zhou, F.H.; Ma, C.Y.; Du, C.T.; Yang, Y.J. Liver X receptors agonists suppress NLRP3 inflammasome activation. Cytokine, 2017, 91, 30-37.
[http://dx.doi.org/10.1016/j.cyto.2016.12.003] [PMID: 27987394]
[66]
Sohrabi, Y.; Sonntag, G.V.H.; Braun, L.C.; Lagache, S.M.M.; Liebmann, M.; Klotz, L.; Godfrey, R.; Kahles, F.; Waltenberger, J.; Findeisen, H.M. LXR activation induces a proinflammatory trained innate immunity-phenotype in human monocytes. Front. Immunol., 2020, 11, 353.
[http://dx.doi.org/10.3389/fimmu.2020.00353] [PMID: 32210962]
[67]
Derangère, V.; Chevriaux, A.; Courtaut, F.; Bruchard, M.; Berger, H.; Chalmin, F.; Causse, S.Z.; Limagne, E.; Végran, F.; Ladoire, S.; Simon, B.; Boireau, W.; Hichami, A.; Apetoh, L.; Mignot, G.; Ghiringhelli, F.; Rébé, C. Liver X receptor β activation induces pyroptosis of human and murine colon cancer cells. Cell Death Differ., 2014, 21(12), 1914-1924.
[http://dx.doi.org/10.1038/cdd.2014.117] [PMID: 25124554]
[68]
Fitz, N.F.; Nam, K.N.; Koldamova, R.; Lefterov, I. Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer’s disease. Br. J. Pharmacol., 2019, 176(18), 3599-3610.
[http://dx.doi.org/10.1111/bph.14668] [PMID: 30924124]
[69]
Koldamova, R.P.; Lefterov, I.M.; Staufenbiel, M.; Wolfe, D.; Huang, S.; Glorioso, J.C.; Walter, M.; Roth, M.G.; Lazo, J.S. The liver X receptor ligand T0901317 decreases amyloid β production in vitro and in a mouse model of Alzheimer’s disease. J. Biol. Chem., 2005, 280(6), 4079-4088.
[http://dx.doi.org/10.1074/jbc.M411420200] [PMID: 15557325]
[70]
Burns, M.P.; Vardanian, L.; Pajoohesh-Ganji, A.; Wang, L.; Cooper, M.; Harris, D.C.; Duff, K.; Rebeck, G.W. The effects of ABCA1 on cholesterol efflux and Abeta levels in vitro and in vivo. J. Neurochem., 2006, 98(3), 792-800.
[http://dx.doi.org/10.1111/j.1471-4159.2006.03925.x] [PMID: 16771834]
[71]
Riddell, D.R.; Zhou, H.; Comery, T.A.; Kouranova, E.; Lo, C.F.; Warwick, H.K.; Ring, R.H.; Kirksey, Y.; Aschmies, S.; Xu, J.; Kubek, K.; Hirst, W.D.; Gonzales, C.; Chen, Y.; Murphy, E.; Leonard, S.; Vasylyev, D.; Oganesian, A.; Martone, R.L.; Pangalos, M.N.; Reinhart, P.H.; Jacobsen, J.S. The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease. Mol. Cell. Neurosci., 2007, 34(4), 621-628.
[http://dx.doi.org/10.1016/j.mcn.2007.01.011] [PMID: 17336088]
[72]
Komati, R.; Spadoni, D.; Zheng, S.; Sridhar, J.; Riley, K.E.; Wang, G. Ligands of therapeutic utility for the liver X receptors. Molecules, 2017, 22(1), 88.
[http://dx.doi.org/10.3390/molecules22010088] [PMID: 28067791]
[73]
Brown, A.J.; Sharpe, L.J.; Rogers, M.J. Oxysterols: From physiological tuners to pharmacological opportunities. Br. J. Pharmacol., 2021, 178(16), 3089-3103.
[http://dx.doi.org/10.1111/bph.15073] [PMID: 32335907]
[74]
Ma, L.; Nelson, E.R. Oxysterols and nuclear receptors. Mol. Cell. Endocrinol., 2019, 484, 42-51.
[http://dx.doi.org/10.1016/j.mce.2019.01.016] [PMID: 30660701]
[75]
Jetten, A.M.; Kang, H.S.; Takeda, Y. Retinoic acid-related orphan receptors α and γ key regulators of lipid/glucose metabolism, inflammation, and insulin sensitivity. Front. Endocrinol. (Lausanne), 2013, 4, 1.
[http://dx.doi.org/10.3389/fendo.2013.00001] [PMID: 23355833]
[76]
Mutemberezi, V.; Guillemot-Legris, O.; Muccioli, G.G. Oxysterols: From cholesterol metabolites to key mediators. Prog. Lipid Res., 2016, 64, 152-169.
[http://dx.doi.org/10.1016/j.plipres.2016.09.002] [PMID: 27687912]
[77]
Santori, F.R.; Huang, P.; van de Pavert, S.A.; Douglass, E.F., Jr; Leaver, D.J.; Haubrich, B.A.; Keber, R.; Lorbek, G.; Konijn, T.; Rosales, B.N.; Rozman, D.; Horvat, S.; Rahier, A.; Mebius, R.E.; Rastinejad, F.; Nes, W.D.; Littman, D.R. Identification of natural RORγ ligands that regulate the development of lymphoid cells. Cell Metab., 2015, 21(2), 286-298.
[http://dx.doi.org/10.1016/j.cmet.2015.01.004] [PMID: 25651181]
[78]
Billon, C.; Murray, M.H.; Avdagic, A.; Burris, T.P. RORγ regulates the NLRP3 inflammasome. J. Biol. Chem., 2019, 294(1), 10-19.
[http://dx.doi.org/10.1074/jbc.AC118.002127] [PMID: 30455347]
[79]
García, J.A.; Volt, H.; Venegas, C.; Doerrier, C.; Escames, G.; López, L.C.; Acuña-Castroviejo, D. Disruption of the NF-κB/NLRP3 connection by melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice. FASEB J., 2015, 29(9), 3863-3875.
[http://dx.doi.org/10.1096/fj.15-273656] [PMID: 26045547]
[80]
Baker, E.; Sims, R.; Leonenko, G.; Frizzati, A.; Harwood, J.C.; Grozeva, D.; Morgan, K.; Passmore, P.; Holmes, C.; Powell, J.; Brayne, C.; Gill, M.; Mead, S.; Bossù, P.; Spalletta, G.; Goate, A.M.; Cruchaga, C.; Maier, W.; Heun, R.; Jessen, F.; Peters, O.; Dichgans, M. FröLich, L.; Ramirez, A.; Jones, L.; Hardy, J.; Ivanov, D.; Hill, M.; Holmans, P.; Allen, N.D.; Morgan, B.P.; Seshadri, S.; Schellenberg, G.D.; Amouyel, P.; Williams, J.; Escott-Price, V. Gene-based analysis in HRC imputed genome wide association data identifies three novel genes for Alzheimer’s disease. PLoS One, 2019, 14(7), e0218111.
[http://dx.doi.org/10.1371/journal.pone.0218111] [PMID: 31283791]
[81]
Morello, F.; Saglio, E.; Noghero, A.; Schiavone, D.; Williams, T.A.; Verhovez, A.; Bussolino, F.; Veglio, F.; Mulatero, P. LXR-activating oxysterols induce the expression of inflammatory markers in endothelial cells through LXR-independent mechanisms. Atherosclerosis, 2009, 207(1), 38-44.
[http://dx.doi.org/10.1016/j.atherosclerosis.2009.04.001] [PMID: 19426978]
[82]
Pikuleva, I.A.; Cartier, N. Cholesterol hydroxylating cytochrome P450 46A1: from mechanisms of action to clinical applications. Front. Aging Neurosci., 2021, 13, 696778.
[http://dx.doi.org/10.3389/fnagi.2021.696778] [PMID: 34305573]
[83]
Alves, S.; Michaelsen-Preusse, K.; Audrain, M.; Badin, R.A.; Lamazière, A.; Rey, E. AAV-CYP46A1 brain delivery mitigates Alzheimer’s disease: From mouse models to non-human primates. Alzheimer’s & Dementia: J. Alzheimer’s Assoc., 2018, 14(7), P1658-P1659.
[http://dx.doi.org/10.1016/j.jalz.2018.06.3028]
[84]
Burlot, M-A.; Braudeau, J.; Michaelsen-Preusse, K.; Potier, B.; Ayciriex, S.; Varin, J.; Gautier, B.; Djelti, F.; Audrain, M.; Dauphinot, L.; Fernandez-Gomez, F.J.; Caillierez, R.; Laprévote, O.; Bièche, I.; Auzeil, N.; Potier, M.C.; Dutar, P.; Korte, M.; Buée, L.; Blum, D.; Cartier, N. Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology. Hum. Mol. Genet., 2015, 24(21), 5965-5976.
[http://dx.doi.org/10.1093/hmg/ddv268] [PMID: 26358780]
[85]
Mast, N.; Saadane, A.; Valencia-Olvera, A.; Constans, J.; Maxfield, E.; Arakawa, H.; Li, Y.; Landreth, G.; Pikuleva, I.A. Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer’s disease. Neuropharmacology, 2017, 123, 465-476.
[http://dx.doi.org/10.1016/j.neuropharm.2017.06.026] [PMID: 28655608]
[86]
Petrov, A.M.; Lam, M.; Mast, N.; Moon, J.; Li, Y.; Maxfield, E.; Pikuleva, I.A. CYP46A1 activation by efavirenz leads to behavioral improvement without significant changes in amyloid plaque load in the brain of 5XFAD mice. Neurotherapeutics, 2019, 16(3), 710-724.
[http://dx.doi.org/10.1007/s13311-019-00737-0] [PMID: 31062296]
[87]
van der Kant, R.; Goldstein, L.S.B.; Ossenkoppele, R. Amyloid-β-independent regulators of tau pathology in Alzheimer disease. Nat. Rev. Neurosci., 2020, 21(1), 21-35.
[http://dx.doi.org/10.1038/s41583-019-0240-3] [PMID: 31780819]
[88]
Mast, N.; Verwilst, P.; Wilkey, C.J.; Guengerich, F.P.; Pikuleva, I.A. In vitro activation of cytochrome P450 46A1 (CYP46A1) by efavirenz-related compounds. J. Med. Chem., 2020, 63(12), 6477-6488.
[http://dx.doi.org/10.1021/acs.jmedchem.9b01383] [PMID: 31617715]
[89]
Mast, N.; Lin, J.B.; Pikuleva, I.A. Marketed drugs can inhibit cytochrome P450 27A1, a potential new target for breast cancer adjuvant therapy. Mol. Pharmacol., 2015, 88(3), 428-436.
[http://dx.doi.org/10.1124/mol.115.099598] [PMID: 26082378]
[90]
Loera-Valencia, R.; Cedazo-Minguez, A.; Kenigsberg, P.A.; Page, G.; Duarte, A.I.; Giusti, P.; Zusso, M.; Robert, P.; Frisoni, G.B.; Cattaneo, A.; Zille, M.; Boltze, J.; Cartier, N.; Buee, L.; Johansson, G.; Winblad, B. Current and emerging avenues for Alzheimer’s disease drug targets. J. Intern. Med., 2019, 286(4), 398-437.
[http://dx.doi.org/10.1111/joim.12959] [PMID: 31286586]
[91]
Lam, M.; Mast, N.; Pikuleva, I.A. Drugs and scaffold that inhibit cytochrome P450 27A1 in vitro and in vivo. Mol. Pharmacol., 2018, 93(2), 101-108.
[http://dx.doi.org/10.1124/mol.117.110742] [PMID: 29192124]
[92]
Hanyu, H.; Hirao, K.; Shimizu, S.; Sato, T.; Kiuchi, A.; Iwamoto, T. Nilvadipine prevents cognitive decline of patients with mild cognitive impairment. Int. J. Geriatr. Psychiatry, 2007, 22(12), 1264-1266.
[http://dx.doi.org/10.1002/gps.1851] [PMID: 18033677]
[93]
Paris, D.; Bachmeier, C.; Patel, N.; Quadros, A.; Volmar, C-H.; Laporte, V.; Ganey, J.; Beaulieu-Abdelahad, D.; Ait-Ghezala, G.; Crawford, F.; Mullan, M.J. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier. Mol. Med., 2011, 17(3-4), 149-162.
[http://dx.doi.org/10.2119/molmed.2010.00180] [PMID: 21170472]
[94]
Lawlor, B.; Segurado, R.; Kennelly, S.; Olde Rikkert, M.G.M.; Howard, R.; Pasquier, F.; Börjesson-Hanson, A.; Tsolaki, M.; Lucca, U.; Molloy, D.W.; Coen, R.; Riepe, M.W.; Kálmán, J.; Kenny, R.A.; Cregg, F.; O’Dwyer, S.; Walsh, C.; Adams, J.; Banzi, R.; Breuilh, L.; Daly, L.; Hendrix, S.; Aisen, P.; Gaynor, S.; Sheikhi, A.; Taekema, D.G.; Verhey, F.R.; Nemni, R.; Nobili, F.; Franceschi, M.; Frisoni, G.; Zanetti, O.; Konsta, A.; Anastasios, O.; Nenopoulou, S.; Tsolaki-Tagaraki, F.; Pakaski, M.; Dereeper, O.; de la Sayette, V.; Sénéchal, O.; Lavenu, I.; Devendeville, A.; Calais, G.; Crawford, F.; Mullan, M. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med., 2018, 15(9), e1002660.
[http://dx.doi.org/10.1371/journal.pmed.1002660] [PMID: 30248105]
[95]
Abdullah, L.; Crawford, F.; Tsolaki, M.; Börjesson-Hanson, A.; Olde Rikkert, M.; Pasquier, F.; Wallin, A.; Kennelly, S.; Ait-Ghezala, G.; Paris, D.; Hendrix, S.; Blennow, K.; Lawlor, B.; Mullan, M. The influence of baseline Alzheimer’s disease severity on cognitive decline and CSF biomarkers in the NILVAD trial. Front. Neurol., 2020, 11, 149.
[http://dx.doi.org/10.3389/fneur.2020.00149] [PMID: 32210906]
[96]
Lonnemann, N.; Hosseini, S.; Marchetti, C.; Skouras, D.B.; Stefanoni, D.; D’Alessandro, A.; Dinarello, C.A.; Korte, M. The NLRP3 inflammasome inhibitor OLT1177 rescues cognitive impairment in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA, 2020, 117(50), 32145-32154.
[http://dx.doi.org/10.1073/pnas.2009680117] [PMID: 33257576]
[97]
Dempsey, C.; Rubio Araiz, A.; Bryson, K.J.; Finucane, O.; Larkin, C.; Mills, E.L.; Robertson, A.A.B.; Cooper, M.A.; O’Neill, L.A.J.; Lynch, M.A. Inhibiting the NLRP3 inflammasome with MCC950 promotes non-phlogistic clearance of amyloid-β and cognitive function in APP/PS1 mice. Brain Behav. Immun., 2017, 61, 306-316.
[http://dx.doi.org/10.1016/j.bbi.2016.12.014] [PMID: 28003153]
[98]
Zahid, A.; Li, B.; Kombe, A.J.K.; Jin, T.; Tao, J. Pharmacological inhibitors of the NLRP3 inflammasome. Front. Immunol., 2019, 10, 2538.
[http://dx.doi.org/10.3389/fimmu.2019.02538] [PMID: 31749805]
[99]
Stachel, S.J.; Zerbinatti, C.; Rudd, M.T.; Cosden, M.; Suon, S.; Nanda, K.K.; Wessner, K.; DiMuzio, J.; Maxwell, J.; Wu, Z.; Uslaner, J.M.; Michener, M.S.; Szczerba, P.; Brnardic, E.; Rada, V.; Kim, Y.; Meissner, R.; Wuelfing, P.; Yuan, Y.; Ballard, J.; Holahan, M.; Klein, D.J.; Lu, J.; Fradera, X.; Parthasarathy, G.; Uebele, V.N.; Chen, Z.; Li, Y.; Li, J.; Cooke, A.J.; Bennett, D.J.; Bilodeau, M.T.; Renger, J. Identification and in vivo evaluation of liver X receptor β-selective agonists for the potential treatment of Alzheimer’s disease. J. Med. Chem., 2016, 59(7), 3489-3498.
[http://dx.doi.org/10.1021/acs.jmedchem.6b00176] [PMID: 27011007]
[100]
Matsuoka, H.; Katayama, M.; Ohishi, A.; Miya, K.; Tokunaga, R.; Kobayashi, S.; Nishimoto, Y.; Hirooka, K.; Shima, A.; Michihara, A. Orphan nuclear receptor RORα regulates enzymatic metabolism of cerebral 24S-hydroxycholesterol through CYP39A1 intronic response element activation. Int. J. Mol. Sci., 2020, 21(9), 3309.
[http://dx.doi.org/10.3390/ijms21093309] [PMID: 32392803]
[101]
Wang, Y.; Billon, C.; Walker, J.K.; Burris, T.P. Therapeutic effect of a synthetic RORα/γ agonist in an animal model of autism. ACS Chem. Neurosci., 2016, 7(2), 143-148.
[http://dx.doi.org/10.1021/acschemneuro.5b00159] [PMID: 26625251]
[102]
Skerrett, R.; Pellegrino, M.P.; Casali, B.T.; Taraboanta, L.; Landreth, G.E. Combined liver X receptor/peroxisome proliferator-activated receptor γ agonist treatment reduces amyloid β levels and improves behavior in amyloid precursor protein/presenilin 1 mice. J. Biol. Chem., 2015, 290(35), 21591-21602.
[http://dx.doi.org/10.1074/jbc.M115.652008] [PMID: 26163517]
[103]
Heneka, M.T.; Fink, A.; Doblhammer, G. Effect of pioglitazone medication on the incidence of dementia. Ann. Neurol., 2015, 78(2), 284-294.
[http://dx.doi.org/10.1002/ana.24439] [PMID: 25974006]
[104]
Gold, M.; Alderton, C.; Zvartau-Hind, M.; Egginton, S.; Saunders, A.M.; Irizarry, M.; Craft, S.; Landreth, G.; Linnamägi, U.; Sawchak, S. Rosiglitazone monotherapy in mild-to-moderate Alzheimer’s disease: results from a randomized, double-blind, placebo-controlled phase III study. Dement. Geriatr. Cogn. Disord., 2010, 30(2), 131-146.
[http://dx.doi.org/10.1159/000318845] [PMID: 20733306]
[105]
Moutinho, M.; Landreth, G.E. Therapeutic potential of nuclear receptor agonists in Alzheimer’s disease. J. Lipid Res., 2017, 58(10), 1937-1949.
[http://dx.doi.org/10.1194/jlr.R075556] [PMID: 28264880]
[106]
Kalinin, S.; Richardson, J.C.; Feinstein, D.L. A PPARdelta agonist reduces amyloid burden and brain inflammation in a transgenic mouse model of Alzheimer’s disease. Curr. Alzheimer Res., 2009, 6(5), 431-437.
[http://dx.doi.org/10.2174/156720509789207949] [PMID: 19874267]
[107]
Chamberlain, S.; Gabriel, H.; Strittmatter, W.; Didsbury, J. An exploratory phase IIa study of the PPAR Delta/gamma agonist T3D-959 assessing metabolic and cognitive function in subjects with mild to moderate Alzheimer’s disease. J. Alzheimers Dis., 2020, 73(3), 1085-1103.
[http://dx.doi.org/10.3233/JAD-190864] [PMID: 31884472]
[108]
Sáez-Orellana, F.; Octave, J-N.; Pierrot, N. Alzheimer’s disease, a lipid story: involvement of peroxisome proliferator-activated receptor α. Cells, 2020, 9(5), 1215.
[http://dx.doi.org/10.3390/cells9051215] [PMID: 32422896]
[109]
Chandra, S.; Roy, A.; Jana, M.; Pahan, K. Cinnamic acid activates PPARα to stimulate Lysosomal biogenesis and lower Amyloid plaque pathology in an Alzheimer’s disease mouse model. Neurobiol. Dis., 2019, 124, 379-395.
[http://dx.doi.org/10.1016/j.nbd.2018.12.007] [PMID: 30578827]
[110]
Pierrot, N.; Ris, L.; Stancu, I-C.; Doshina, A.; Ribeiro, F.; Tyteca, D.; Baugé, E.; Lalloyer, F.; Malong, L.; Schakman, O.; Leroy, K.; Kienlen-Campard, P.; Gailly, P.; Brion, J.P.; Dewachter, I.; Staels, B.; Octave, J.N. Sex-regulated gene dosage effect of PPARα on synaptic plasticity. Life Sci. Alliance, 2019, 2(2), e201800262.
[http://dx.doi.org/10.26508/lsa.201800262] [PMID: 30894406]

Rights & Permissions Print Cite
Article Metrics
45
3
World Autism Awareness Day
© 2024 Bentham Science Publishers | Privacy Policy