Pathogenesis, modulation, and therapy of Alzheimer’s disease: A perspective on roles of liver-X receptors

[1] Lim A., Tsuang D., Kukull W., Nochlin D., Leverenz J., McCormick W., et al., Clinico-neuropathological correlation of Alzheimer’s disease in a community-based case series, J. Am. Geriatr., 1999, 47, 564–569 10.1111/j.1532-5415.1999.tb02571.xSearch in Google Scholar

[2] Alzheimer’s Association, 2009 Alzheimer’s disease facts and figures, Alzheimers Dement., 2009, 5, 234–270 10.1016/j.jalz.2009.03.001Search in Google Scholar

[3] Barnes D.E., Yaffe K., The projected effect of risk factor reduction on Alzheimer’s disease prevalence, Lancet Neurol., 2011, 10, 819–828 http://dx.doi.org/10.1016/S1474-4422(11)70072-210.1016/S1474-4422(11)70072-2Search in Google Scholar

[4] Olgiati P., Politis A.M., Papadimitriou G.N., De Ronchi D., Serretti A., Genetics of late-onset Alzheimer’s disease: update from the alzgene database and analysis of shared pathways, Int. J. Alzheimers Dis., 2011, 2011, 832379 http://dx.doi.org/10.4061/2011/83237910.4061/2011/832379Search in Google Scholar PubMed PubMed Central

[5] Jones L., Holmans P.A., Hamshere M.L., Harold D., Moskvina V., Ivanov D., et al., Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer’s disease, PLoS One, 2010, 5, e13950 http://dx.doi.org/10.1371/journal.pone.001395010.1371/journal.pone.0013950Search in Google Scholar PubMed PubMed Central

[6] Palop J.J., Mucke L., Amyloid-beta-induced neuronal dysfunction in Alzheimer’s disease: from synapses toward neural networks, Nat. Neurosci., 2010, 13, 812–818 http://dx.doi.org/10.1038/nn.258310.1038/nn.2583Search in Google Scholar PubMed PubMed Central

[7] Šimić G., Stanić G., Mladinov M., Jovanov-Milošević N., Kostović I., Hof P.R., Does Alzheimer’s disease begin in the brainstem?, Neuropathol. Appl. Neurobiol., 2009, 35, 532–554 http://dx.doi.org/10.1111/j.1365-2990.2009.01038.x10.1111/j.1365-2990.2009.01038.xSearch in Google Scholar PubMed PubMed Central

[8] Di Paolo G., Kim T.W., Linking lipids to Alzheimer’s disease: cholesterol and beyond, Nat. Rev. Neurosci., 2011, 12, 284–296 http://dx.doi.org/10.1038/nrn301210.1038/nrn3012Search in Google Scholar PubMed PubMed Central

[9] Heneka M.T., O’Banion M.K., Terwel D., Kummer M.P., Neuroinflammatory processes in Alzheimer’s disease, J. Neural Transm., 2010, 117, 919–947 http://dx.doi.org/10.1007/s00702-010-0438-z10.1007/s00702-010-0438-zSearch in Google Scholar PubMed

[10] Citron M., Alzheimer’s disease: strategies for disease modification, Nat. Rev. Drug Discov., 2010, 9, 387–398 http://dx.doi.org/10.1038/nrd289610.1038/nrd2896Search in Google Scholar PubMed

[11] Zhang Z.D., Burch P.E., Cooney A.J., Lanz R.B., Pereira F.A., Wu J.Q., et al., Genomic analysis of the nuclear receptor family: New insights into structure, regulation, and evolution from the rat genome, Genome Res., 2004, 14, 580–90 http://dx.doi.org/10.1101/gr.216000410.1101/gr.2160004Search in Google Scholar PubMed PubMed Central

[12] Janowski B.A., Willy P.J., Devi T.R., Falck J.R., Mangelsdorf D.J., An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha, Nature, 1996, 383, 728–731 http://dx.doi.org/10.1038/383728a010.1038/383728a0Search in Google Scholar PubMed

[13] Apfel R., Benbrook D., Lernhardt E., Ortiz M.A., Salbert G., Pfahl M., A novel orphan receptor-specific for a subset of thyroid hormone-responsive elements and its interaction with the retinoid/thyroid hormone-receptor subfamily, Mol. Cell. Biol., 1994, 14, 7025–7035 10.1128/mcb.14.10.7025-7035.1994Search in Google Scholar PubMed PubMed Central

[14] Hu Y-W., Zheng L., Wang Q., Regulation of cholesterol homeostasis by liver X receptors, Clin. Chim. Acta, 2010, 411, 617–625 http://dx.doi.org/10.1016/j.cca.2009.12.02710.1016/j.cca.2009.12.027Search in Google Scholar PubMed

[15] Zhao C., Dahlman-Wright K., Liver X receptor in cholesterol metabolism, J. Endocrinol., 2010, 204, 233–240 http://dx.doi.org/10.1677/JOE-09-027110.1677/JOE-09-0271Search in Google Scholar PubMed

[16] Calayir E., Becker T., Kratzer A., Ebner B., Panzenbock U., Stefujl J., et al., LXR-agonists regulate apoM expression differentially in liver and intestine, Curr. Phar. Biotechnol., 2008, 9, 516–521 http://dx.doi.org/10.2174/13892010878678637610.2174/138920108786786376Search in Google Scholar PubMed

[17] Stefulj J., Panzenboeck U., Becker T., Hirschmugl B., Schweinzer C., Lang I., et al., Human Endothelial Cells of the Placental Barrier Efficiently Deliver Cholesterol to the Fetal Circulation via ABCA1 and ABCG1, Circ. Res., 2009, 104, 600–608 http://dx.doi.org/10.1161/CIRCRESAHA.108.18506610.1161/CIRCRESAHA.108.185066Search in Google Scholar PubMed

[18] Joseph S.B., Castrillo A., Laffitte B.A., Mangelsdorf D.J., Tontonoz P., Reciprocal regulation of inflammation and lipid metabolism by liver X receptors, Nat. Med., 2003, 9, 213–219 http://dx.doi.org/10.1038/nm82010.1038/nm820Search in Google Scholar PubMed

[19] Mitro N., Mak P.A., Vargas L., Godio C., Hampton E., Molteni V., et al., The nuclear receptor LXR is a glucose sensor, Nature, 2007, 445, 219–223 http://dx.doi.org/10.1038/nature0544910.1038/nature05449Search in Google Scholar PubMed

[20] Jakobsson T., Treuter E., Gustafsson J.A., Steffensen K.R., Liver X receptor biology and pharmacology: new pathways, challenges and opportunities, Trends Pharmacol. Sci., 2012, 33, 394–404 http://dx.doi.org/10.1016/j.tips.2012.03.01310.1016/j.tips.2012.03.013Search in Google Scholar PubMed

[21] Kim W.S., Bhatia S., Elliott D.A., Agholme L., Kågedal K., McCann H., et al., Increased ATP-binding cassette transporter A1 expression in Alzheimer’s disease hippocampal neurons, J. Alzheimers Dis., 2010, 21, 193–205 10.3233/JAD-2010-100324Search in Google Scholar PubMed

[22] Akram A., Schmeidler J., Katsel P., Hof P.R., Haroutunian V., Association of ApoE and LRP mRNA levels with dementia and AD neuropathology, Neurobiol. Aging, 2012, 33, 628.e1–14 http://dx.doi.org/10.1016/j.neurobiolaging.2011.04.01010.1016/j.neurobiolaging.2011.04.010Search in Google Scholar PubMed PubMed Central

[23] Akram A., Schmeidler J., Katsel P., Hof P.R., Haroutunian V., Increased expression of cholesterol transporter ABCA1 is highly correlated with severity of dementia in AD hippocampus, Brain Res., 2010, 1318, 167–177 http://dx.doi.org/10.1016/j.brainres.2010.01.00610.1016/j.brainres.2010.01.006Search in Google Scholar PubMed PubMed Central

[24] Vuletic S., Jin L.W., Marcovina S.M., Peskind E.R., Moller T., Albers J.J., Widespread distribution of PLTP in human CNS: evidence for PLTP synthesis by glia and neurons, and increased levels in Alzheimer’s disease, J. Lipid Res., 2003, 44, 1113–1123 http://dx.doi.org/10.1194/jlr.M300046-JLR20010.1194/jlr.M300046-JLR200Search in Google Scholar PubMed

[25] Wahrle S.E., Jiang H., Parsadanian M., Hartman R.E., Bales K.R., Paul S.M., et al., Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease, J. Biol. Chem., 2005, 280, 43236–43242 http://dx.doi.org/10.1074/jbc.M50878020010.1074/jbc.M508780200Search in Google Scholar PubMed

[26] Wahrle S.E., Jiang H., Parsadanian M., Kim J., Li A.M., Knoten A., et al., Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease, J. Clin. Invest., 2008, 118, 671–682 10.1172/JCI33622Search in Google Scholar PubMed PubMed Central

[27] Kim J., Jiang H., Park S., Eltorai A.E.M., Stewart F.R., Yoon H., et al., Haploinsufficiency of human APOE reduces amyloid deposition in a mouse model of amyloid-beta amyloidosis, J. Neurosci., 2011, 31, 18007–18012 http://dx.doi.org/10.1523/JNEUROSCI.3773-11.201110.1523/JNEUROSCI.3773-11.2011Search in Google Scholar PubMed PubMed Central

[28] Wang L., Schuster G.U., Hultenby K., Zhang Q.H., Andersson S., Gustafsson J.A., Liver X receptors in the central nervous system: From lipid homeostasis to neuronal degeneration, Proc. Natl. Acad. Sci. USA, 2002, 99, 3878–13883 http://dx.doi.org/10.1073/pnas.00202559910.1073/pnas.002025599Search in Google Scholar PubMed PubMed Central

[29] Andersson S., Gustafsson N., Warner M., Gustafsson J.A., Inactivation of liver X receptor beta leads to adult-onset motor neuron degeneration in male mice, Proc. Natl. Acad. Sci. USA, 2005, 102, 3857–3862 http://dx.doi.org/10.1073/pnas.050063410210.1073/pnas.0500634102Search in Google Scholar PubMed PubMed Central

[30] Fan X., Kim H-J., Bouton D., Warner M., Gustafsson J-A., Expression of liver X receptor beta is essential for formation of superficial cortical layers and migration of later-born neurons, Proc. Natl. Acad. Sci. USA, 2008, 105, 13445–13450 http://dx.doi.org/10.1073/pnas.080697410510.1073/pnas.0806974105Search in Google Scholar PubMed PubMed Central

[31] Zelcer N., Khanlou N., Clare R., Jiang Q., Reed-Geaghan E.G., Landreth G.E., et al., Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 10601–10606 http://dx.doi.org/10.1073/pnas.070109610410.1073/pnas.0701096104Search in Google Scholar PubMed PubMed Central

[32] Terwel D., Steffensen K.R., Verghese P.B., Kummer M.P., Gustafsson J.A., Holtzman D.M., et al., Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Abeta phagocytosis, J. Neurosci., 2011, 31, 7049–7059 http://dx.doi.org/10.1523/JNEUROSCI.6546-10.201110.1523/JNEUROSCI.6546-10.2011Search in Google Scholar PubMed PubMed Central

[33] Liu B., Li H., Repa J.J., Turley S.D., Dietschy J.M., Genetic variations and treatments that affect the lifespan of the NPC1 mouse, J. Lipid Res., 2008, 49, 663–669 http://dx.doi.org/10.1194/jlr.M700525-JLR20010.1194/jlr.M700525-JLR200Search in Google Scholar PubMed

[34] Adighibe O., Arepalli S., Duckworth J., Hardy J., Wavrant-De Vrieze F., Genetic variability at the LXR gene (NR1H2) may contribute to the risk of Alzheimer’s disease, Neurobiol. Aging, 2006, 27, 1431–1434 http://dx.doi.org/10.1016/j.neurobiolaging.2005.08.01010.1016/j.neurobiolaging.2005.08.010Search in Google Scholar PubMed

[35] Rodriguez-Rodriguez E., Llorca J., Mateo I., Infante J., Sanchez-Quintana C., Garcia-Gorostiaga I., et al., No association of genetic variants of liver X receptor-beta with Alzheimer’s disease risk, Am. J. Med. Genet. B.Neuropsychiatr. Genet., 2008, 147B, 650–653 http://dx.doi.org/10.1002/ajmg.b.3065210.1002/ajmg.b.30652Search in Google Scholar PubMed

[36] Giedraitis V., Kilander L., Degerman-Gunnarsson M., Sundelof J., Axelsson T., Syvanen A.C., et al., Genetic analysis of Alzheimer’s disease in the Uppsala Longitudinal Study of Adult Men, Dement. Geriatr. Cogn. Disord., 2009, 27, 59–68 http://dx.doi.org/10.1159/00019120310.1159/000191203Search in Google Scholar PubMed

[37] Rodriguez-Rodriguez E., Sanchez-Juan P., Mateo I., Infante J., Sanchez-Quintana C., Garcia-Gorostiaga I., et al., Interaction between CD14 and LXR beta genes modulates Alzheimer’s disease risk, J. Neurol. Sci., 2008, 264, 97–99 http://dx.doi.org/10.1016/j.jns.2007.08.00110.1016/j.jns.2007.08.001Search in Google Scholar PubMed

[38] Infante J., Rodriguez-Rodriguez E., Mateo I., Llorca J., Vazquez-Higuera J.L., Berciano J., et al., Gene-gene interaction between heme oxygenase-1 and liver X receptor-beta and Alzheimer’s disease risk, Neurobiol. Aging, 2010, 31, 710–714 http://dx.doi.org/10.1016/j.neurobiolaging.2008.05.02510.1016/j.neurobiolaging.2008.05.025Search in Google Scholar PubMed

[39] Viennois E., Mouzat K., Dufour J., Morel L., Lobaccaro J.M., Baron S., Selective liver X receptor modulators (SLiMs): What use in human health?, Mol. Cell. Endocrinol., 2012, 351, 129–141 http://dx.doi.org/10.1016/j.mce.2011.08.03610.1016/j.mce.2011.08.036Search in Google Scholar PubMed

[40] Leduc V., Jasmin-Belanger S., Poirier J., APOE and cholesterol homeostasis in Alzheimer’s disease, Trends Mol. Med., 2010, 16, 469–477 http://dx.doi.org/10.1016/j.molmed.2010.07.00810.1016/j.molmed.2010.07.008Search in Google Scholar PubMed

[41] Martins I.J., Berger T., Sharman M.J., Verdile G., Fuller S.J., Martins R.N., Cholesterol metabolism and transport in the pathogenesis of Alzheimer’s disease, J. Neurochem., 2009, 111, 1275–1308 http://dx.doi.org/10.1111/j.1471-4159.2009.06408.x10.1111/j.1471-4159.2009.06408.xSearch in Google Scholar PubMed

[42] Gamba P., Testa G., Sottero B., Gargiulo S., Poli G., Leonarduzzi G., The link between altered cholesterol metabolism and Alzheimer’s disease, Ann. NY Acad. Sci., 2012, 1259, 54–64 http://dx.doi.org/10.1111/j.1749-6632.2012.06513.x10.1111/j.1749-6632.2012.06513.xSearch in Google Scholar PubMed

[43] Whitney K.D., Watson M.A., Collins J.L., Benson W.G., Stone T.M., Numerick M.J., et al., Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system, Mol. Endocrinol., 2002, 16, 1378–1385 http://dx.doi.org/10.1210/me.16.6.137810.1210/me.16.6.1378Search in Google Scholar

[44] Fukumoto H., Deng A., Irizarry M.C., Fitzgerald M.L., Rebeck G.W., Induction of the cholesterol transporter ABCA1 in central nervous system cells by liver X receptor agonists increases secreted Abeta levels, J. Biol. Chem., 2002, 277, 48508–48513 http://dx.doi.org/10.1074/jbc.M20908520010.1074/jbc.M209085200Search in Google Scholar PubMed

[45] Koldamova R.P., Lefterov L.M., Ikonomovic M.D., Skoko J., Lefterov P.I., Isanskis B.A., et al., 22R-Hydroxycholesterol and 9-cis-retinoic acid induce ATP-binding cassette transporter A1 expression and cholesterol efflux in brain cells and decrease amyloid beta secretion, J. Biol. Chem., 2003, 278, 13244–13256 http://dx.doi.org/10.1074/jbc.M30004420010.1074/jbc.M300044200Search in Google Scholar PubMed

[46] Liang Y., Lin S.Z., Beyer T.P., Zhang Y.Y., Wu X., Bales K.R., et al., A liver X receptor and retinoid X receptor heterodimer mediates apolipoprotein E expression, secretion and cholesterol homeostasis in astrocytes, J. Neurochem., 2004, 88, 623–634 http://dx.doi.org/10.1111/j.1471-4159.2004.02183.x10.1111/j.1471-4159.2004.02183.xSearch in Google Scholar PubMed

[47] Abildayeva K., Jansen P.J., Hirsch-Reinshagen V., Bloks V.W., Bakker A.H.F., Ramaekers F.C.S., et al., 24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux, J. Biol. Chem., 2006, 281, 12799–12808 http://dx.doi.org/10.1074/jbc.M60101920010.1074/jbc.M601019200Search in Google Scholar PubMed

[48] Kim W.S., Chan S.L., Hill A.F., Guillemin G.J., Garner B., Impact of 27-hydroxycholesterol on amyloid-beta peptide production and ATP-binding cassette transporter expression in primary human neurons, J. Alzheimers Dis., 2009, 16, 121–131 10.3233/JAD-2009-0944Search in Google Scholar PubMed

[49] Prasanthi J.R.P., Huls A., Thomasson S., Thompson A., Schommer E., Ghribi O., Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells, Mol. Neurodegener., 2009, 4, 1 http://dx.doi.org/10.1186/1750-1326-4-110.1186/1750-1326-4-1Search in Google Scholar PubMed PubMed Central

[50] Nelissen K., Mulder M., Smets I., Timmermans S., Smeets K., Ameloot M., et al., Liver X receptors regulate cholesterol homeostasis in oligodendrocytes, J. Neurosci. Res., 2012, 90, 60–71 http://dx.doi.org/10.1002/jnr.2274310.1002/jnr.22743Search in Google Scholar PubMed

[51] Panzenboeck U., Kratzer I., Sovic A., Wintersperger A., Bernhart E., Harnmer A., et al., Regulatory effects of synthetic liver X receptor- and peroxisome-proliferator activated receptor agonists on sterol transport pathways in polarized cerebrovascular endothelial cells, Int. J. Biochem. Cell Biol., 2006, 38, 1314–1329 http://dx.doi.org/10.1016/j.biocel.2006.01.01310.1016/j.biocel.2006.01.013Search in Google Scholar PubMed

[52] Burns M.P., Vardanian L., Pajoohesh-Ganji A., Wang L.L., Cooper M., Harris D.C., et al., The effects of ABCA1 on cholesterol efflux and Abeta levels in vitro and in vivo, J. Neurochem., 2006, 98, 792–800 http://dx.doi.org/10.1111/j.1471-4159.2006.03925.x10.1111/j.1471-4159.2006.03925.xSearch in Google Scholar PubMed

[53] Eckert G.P., Vardanian L., Rebeck G.W., Burns M.P., Regulation of central nervous system cholesterol homeostasis by the liver X receptor agonist TO-901317, Neurosci. Lett., 2007, 423, 47–52 http://dx.doi.org/10.1016/j.neulet.2007.05.06310.1016/j.neulet.2007.05.063Search in Google Scholar PubMed

[54] Suon S., Zhao J., Villarreal S.A., Anumula N., Liu M.L., Carangia L.M., et al., Systemic treatment with liver X receptor agonists raises apolipoprotein E, cholesterol, and amyloid-beta peptides in the cerebral spinal fluid of rats, Mol. Neurodegener. 2010, 5, 44 http://dx.doi.org/10.1186/1750-1326-5-4410.1186/1750-1326-5-44Search in Google Scholar PubMed PubMed Central

[55] Koldamova R.P., Lefterov I.M., Staufenbiel M., Wolfe D., Huang S., Glorioso J.C., et al., The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease, J. Biol. Chem., 2005, 280, 4079–4088 http://dx.doi.org/10.1074/jbc.M41142020010.1074/jbc.M411420200Search in Google Scholar PubMed

[56] Lefterov I., Bookout A., Wang Z., Staufenbiel M., Mangelsdorf D., Koldamova R., Expression profiling in APP23 mouse brain: inhibition of A beta amyloidosis and inflammation in response to LXR agonist treatment, Mol. Neurodegener., 2007, 2, 20 http://dx.doi.org/10.1186/1750-1326-2-2010.1186/1750-1326-2-20Search in Google Scholar PubMed PubMed Central

[57] Riddell D.R., Zhou H., Comery T.A., Kouranova E., Lo C.F., Warwick H.K., et al., The LXR agonist TO901317 selectively lowers hippocampal A beta 42 and improves memory in the Tg2576 mouse model of Alzheimer’s disease, Mol. Cell. Neurosci., 2007, 34, 621–628 http://dx.doi.org/10.1016/j.mcn.2007.01.01110.1016/j.mcn.2007.01.011Search in Google Scholar PubMed

[58] Jiang Q., Lee C.Y.D., Mandrekar S., Wilkinson B., Cramer P., Zelcer N., et al., ApoE promotes the proteolytic degradation of A beta, Neuron, 2008, 58, 681–693 http://dx.doi.org/10.1016/j.neuron.2008.04.01010.1016/j.neuron.2008.04.010Search in Google Scholar PubMed PubMed Central

[59] Donkin J.J., Stukas S., Hirsch-Reinshagen V., Namjoshi D., Wilkinson A., May S., et al., ATP-binding cassette transporter A1 mediates the beneficial effects of the liver X receptor agonist GW3965 on object recognition memory and amyloid burden in amyloid precursor protein/presenilin 1 Mice, J. Biol. Chem., 2010, 285, 34144–34154 http://dx.doi.org/10.1074/jbc.M110.10810010.1074/jbc.M110.108100Search in Google Scholar PubMed PubMed Central

[60] Cui W.G., Sun Y., Wang Z.P., Xu C.C., Xu L., Wang F., et al., Activation of liver X receptor decreases BACE1 expression and activity by reducing membrane cholesterol levels, Neurochem. Res., 2011, 36, 1910–1921 http://dx.doi.org/10.1007/s11064-011-0513-310.1007/s11064-011-0513-3Search in Google Scholar PubMed

[61] Vanmierlo T., Rutten K., Dederen J., Bloks V.W., van Vark-van der Zee L.C., Kuipers F., et al., Liver X receptor activation restores memory in aged AD mice without reducing amyloid, Neurobiol. Aging, 2011, 32, 1262–1272 http://dx.doi.org/10.1016/j.neurobiolaging.2009.07.00510.1016/j.neurobiolaging.2009.07.005Search in Google Scholar PubMed

[62] Repa J.J., Li H., Frank-Cannon T.C., Valasek M.A., Turley S.D., Tansey M.G., et al., Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse, J. Neurosci., 2007, 27, 14470–14480 http://dx.doi.org/10.1523/JNEUROSCI.4823-07.200710.1523/JNEUROSCI.4823-07.2007Search in Google Scholar PubMed PubMed Central

[63] Karran E., Mercken M., De Strooper B., The amyloid cascade hypothesis for Alzheimer’s disease: an appraisal for the development of therapeutics, Nat. Rev. Drug Discov., 2011, 10, 698–712 http://dx.doi.org/10.1038/nrd350510.1038/nrd3505Search in Google Scholar PubMed

[64] Koldamova T., Lefterov I.M., Staufenbiel M., Wolfe D., Huang S.H., Glorioso J.C., et al., The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer’s disease, J. Biol. Chem., 2005, 280, 4079–4088 http://dx.doi.org/10.1074/jbc.M41142020010.1074/jbc.M411420200Search in Google Scholar PubMed

[65] Cui W., Sun Y., Wang Z., Xu C., Peng Y., Li R., Liver X receptor activation attenuates inflammatory response and protects cholinergic neurons in APP/PS1 transgenic mice, Neuroscience, 2012, 210, 200–210 http://dx.doi.org/10.1016/j.neuroscience.2012.02.04710.1016/j.neuroscience.2012.02.047Search in Google Scholar PubMed

[66] Sun Y., Yao J., Kim T.W., Tall A.R., Expression of liver X receptor target genes decreases cellular amyloid beta peptide secretion, J. Biol. Chem., 2003, 278, 27688–27694 http://dx.doi.org/10.1074/jbc.M30076020010.1074/jbc.M300760200Search in Google Scholar PubMed

[67] Czech C., Burns M.P., Vardanian L., Augustin A., Jacobsen H., Baumann K., et al., Cholesterol independent effect of LXR agonist TO-901317 on gamma-secretase, J. Neurochem., 2007, 101, 929–936 http://dx.doi.org/10.1111/j.1471-4159.2007.04467.x10.1111/j.1471-4159.2007.04467.xSearch in Google Scholar PubMed

[68] Burns M.P., Rebeck G.W., Intracellular cholesterol homeostasis and amyloid precursor protein processing, Biochim. Biophys. Acta, 2010, 1801, 853–859 http://dx.doi.org/10.1016/j.bbalip.2010.03.00410.1016/j.bbalip.2010.03.004Search in Google Scholar PubMed PubMed Central

[69] Schweinzer C., Kober A., Lang I., Etschmaier K., Scholler M., Kresse A., et al., Processing of endogenous AβPP in blood-brain barrier endothelial cells is modulated by liver-X receptor agonists and altered cellular cholesterol homeostasis, J. Alzheimers Dis., 2011, 27, 341–360 10.3233/JAD-2011-110854Search in Google Scholar PubMed

[70] Fitz N.F., Cronican A., Pham T., Fogg A., Fauq A.H., Chapman R., et al., Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice, J. Neurosci., 2010, 30, 6862–6872 http://dx.doi.org/10.1523/JNEUROSCI.1051-10.201010.1523/JNEUROSCI.1051-10.2010Search in Google Scholar PubMed PubMed Central

[71] Štefulj J., Perić M., Malnar M., Košiček M., Schweinzer C, Živković J., et al., Pharmacological activation of LXRs decreases amyloid-β levels in Niemann-Pick type C model cells, 2013, Curr. Pharm. Biotechnol., 5, (in press) Search in Google Scholar

[72] Akiyama H., Barger S., Barnum S., Bradt B., Bauer J., Cole G.M., et al., Inflammation and Alzheimer’s disease, Neurobiol. Aging, 2000, 21, 383–421 http://dx.doi.org/10.1016/S0197-4580(00)00124-X10.1016/S0197-4580(00)00124-XSearch in Google Scholar

[73] Lee Y.J., Han S.B., Nam S.Y., Oh K.W., Hong J.T., Inflammation and Alzheimer’s Disease, Arch. Pharm. Res., 2010, 33, 1539–1556 http://dx.doi.org/10.1007/s12272-010-1006-710.1007/s12272-010-1006-7Search in Google Scholar PubMed

[74] Tuppo E.E., Arias H.R., The role of inflammation in Alzheimer’s disease, Int. J. Biochem. Cell Biol., 2005, 37, 289–305 http://dx.doi.org/10.1016/j.biocel.2004.07.00910.1016/j.biocel.2004.07.009Search in Google Scholar PubMed

[75] Bensinger S.J., Tontonoz P., Integration of metabolism and inflammation by lipid-activated nuclear receptors, Nature, 2008, 454, 470–477 http://dx.doi.org/10.1038/nature0720210.1038/nature07202Search in Google Scholar PubMed

[76] Zelcer N., Tontonoz P., Liver X receptors as integrators of metabolic and inflammatory signaling, J. Clin. Invest., 2006, 116, 607–614 http://dx.doi.org/10.1172/JCI2788310.1172/JCI27883Search in Google Scholar PubMed PubMed Central

[77] Lee C.S., Joe E.H., Jou I., Oxysterols suppress inducible nitric oxide synthase expression in lipopolysaccharide-stimulated astrocytes through liver X receptor, Neuroreport, 2006, 17, 183–187 http://dx.doi.org/10.1097/01.wnr.0000198436.52259.4010.1097/01.wnr.0000198436.52259.40Search in Google Scholar PubMed

[78] Kim O.S., Lee C.S., Joe E.H., Jou I., Oxidized low density lipoprotein suppresses lipopolysaccharide-induced inflammatory responses in microglia: oxidative stress acts through control of inflammation, Biochem. Biophys. Res. Commun., 2006, 342, 9–18 http://dx.doi.org/10.1016/j.bbrc.2006.01.10710.1016/j.bbrc.2006.01.107Search in Google Scholar PubMed

[79] Zhang-Gandhi C.X., Drew P.D., Liver X receptor and retinoid X receptor agonists inhibit inflammatory responses of microglia and astrocytes, J. Neuroimmunol., 2007, 183, 50–59 http://dx.doi.org/10.1016/j.jneuroim.2006.11.00710.1016/j.jneuroim.2006.11.007Search in Google Scholar PubMed PubMed Central

[80] Lee J.H., Park S.M., Kim O.S., Lee C.S., Woo J.H., Park S.J., et al., Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gammastimulated brain astrocytes, Mol. Cell, 2009, 35, 806–817 http://dx.doi.org/10.1016/j.molcel.2009.07.02110.1016/j.molcel.2009.07.021Search in Google Scholar PubMed

[81] Morales J.R., Ballesteros I., Deniz J.M., Hurtado O., Vivancos J., Nombela F., et al., Activation of liver X receptors promotes neuroprotection and reduces brain inflammation in experimental stroke, Circulation, 2008, 118, 1450–1459 http://dx.doi.org/10.1161/CIRCULATIONAHA.108.78230010.1161/CIRCULATIONAHA.108.782300Search in Google Scholar PubMed

[82] Alzheimers A., 2012 Alzheimer’s disease facts and figures, Alzheimers Dement., 2012, 8, 131–168 http://dx.doi.org/10.1016/j.jalz.2012.02.00110.1016/j.jalz.2012.02.001Search in Google Scholar PubMed

[83] Spires T.L., Hyman B.T., Transgenic models of Alzheimer’s disease: learning from animals, NeuroRx, 2005, 2, 423–437 http://dx.doi.org/10.1602/neurorx.2.3.42310.1602/neurorx.2.3.423Search in Google Scholar PubMed PubMed Central

[84] Grefhorst A., Elzinga B.M., Voshol P.J., Plösch T., Kok T., Bloks V.W., et al., Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles, J. Biol. Chem., 2002, 277, 34182–34190 http://dx.doi.org/10.1074/jbc.M20488720010.1074/jbc.M204887200Search in Google Scholar PubMed

[85] Willy P.J., Mangelsdorf D.J., Unique requirements for retinoid dependent transcriptional activation by the orphan receptor LXR, Genes Dev., 1997, 11, 289–298 http://dx.doi.org/10.1101/gad.11.3.28910.1101/gad.11.3.289Search in Google Scholar PubMed

[86] Cramer P.E., Cirrito J.R., Wesson D.W., Lee C.Y.D., Karlo J.C., Zinn A.E., et al., ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models, Science, 2012, 335, 1503–1506 http://dx.doi.org/10.1126/science.121769710.1126/science.1217697Search in Google Scholar PubMed PubMed Central

[87] Fitz N.F., Cronican A.A., Lefterov I., Koldamova R., Comment on “ApoEdirected therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”, Science, 2013, 340, 924–c http://dx.doi.org/10.1126/science.123580910.1126/science.1235809Search in Google Scholar PubMed PubMed Central

[88] Price A.R., Xu G.L., Siemienski Z.B., Smithson L.A., Borchelt D.R., Golde T.E., et al., Comment on “ ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models “, Science, 2013, 340, 924–d http://dx.doi.org/10.1126/science.123408910.1126/science.1234089Search in Google Scholar PubMed

[89] Tesseur I., Lo A.C., Roberfroid A., Dietvorst S., Van Broeck B., Borgers M., et al., Comment on “ ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models “, Science, 2013, 340, 924–e http://dx.doi.org/10.1126/science.123393710.1126/science.1233937Search in Google Scholar PubMed

[90] Veeraraghavalu K., Zhang C., Miller S., Hefendehl J.K., Rajapaksha T.W., Ulrich J., et al., Comment on “ ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models “, Science, 2013, 340, 924–f http://dx.doi.org/10.1126/science.123550510.1126/science.1235505Search in Google Scholar PubMed

[91] Landreth G.E., Cramer P.E., Lakner M.M., Cirrito J.R., Wesson D.W., Brunden K.R., et al., Response to Comments on “ ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models “, Science, 2013, 340, 924–g http://dx.doi.org/10.1126/science.123411410.1126/science.1234114Search in Google Scholar PubMed PubMed Central

[92] Rigamonti E., Helin L., Lestavel S., Mutka A. L., Lepore M., Fontaine C., et al., Liver X receptor activation controls intracellular cholesterol trafficking and esterification in human macrophages, Circ. Res., 2005, 97, 682–689 http://dx.doi.org/10.1161/01.RES.0000184678.43488.9f10.1161/01.RES.0000184678.43488.9fSearch in Google Scholar PubMed

[93] Kotokorpi P., Ellis E., Parini P., Nilsson L.M., Strom S., Steffensen K.R., et al., Physiological differences between human and rat primary hepatocytes in response to liver X receptor activation by 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl) amino]propyloxy]phenylacetic acid hydrochloride (GW3965), Mol. Pharmacol., 2007, 72, 947–955 http://dx.doi.org/10.1124/mol.107.03735810.1124/mol.107.037358Search in Google Scholar PubMed