[en] Liver X receptors (LXRs) regulate immune cell function and cholesterol metabolism, both factors that are critically involved in Alzheimer's disease (AD). To investigate the therapeutic potential of long-term LXR activation in amyloid-β (Aβ) peptide deposition in an AD model, 13-month-old, amyloid plaque-bearing APP23 mice were treated with the LXR agonist TO901317. Postmortem analysis demonstrated that TO901317 efficiently crossed the blood-brain barrier. Insoluble and soluble Aβ levels in the treated APP23 mice were reduced by 80% and 40%, respectively, compared with untreated animals. Amyloid precursor protein (APP) processing, however, was hardly changed by the compound, suggesting that the observed effects were instead mediated by Aβ disposal. Despite the profound effect on Aβ levels, spatial learning in the Morris water maze was only slightly improved by the treatment. ABCA1 (ATP-binding cassette transporter 1) and apolipoprotein E (ApoE) protein levels were increased and found to be primarily localized in astrocytes. Experiments using primary microglia demonstrated that medium derived from primary astrocytes exposed to TO901317 stimulated phagocytosis of fibrillar Aβ. Conditioned medium from TO901317-treated ApoE(-/-) or LXRα(-/-) astrocytes did not increase phagocytosis of Aβ. In APP23 mice, long-term treatment with TO901317 strongly increased the association of microglia and Aβ plaques. Short-term treatment of APP/PS1 mice with TO901317 also increased this association, which was dependent on the presence of LXRα and was accompanied by increased ApoE lipidation. Together, these data suggest that astrocytic LXRα activation and subsequent release of ApoE by astrocytes is critical for the ability of microglia to remove fibrillar Aβ in response to treatment with TO901317.
Disciplines :
Neurology
Author, co-author :
Terwel, Dick; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Steffensen, Knut R; Department of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden
Verghese, Philip B; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
Kummer, Markus P; Department of Neurology, University of Bonn, 53127 Bonn, Germany
Gustafsson, Jan-Åke; Department of Biosciences and Nutrition, Karolinska Institutet, S-141 57 Huddinge, Sweden
Holtzman, David M; Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, United States
HENEKA, Michael ; Department of Neurology, University of Bonn, 53127 Bonn, Germany
External co-authors :
yes
Language :
English
Title :
Critical role of astroglial apolipoprotein E and liver X receptor-α expression for microglial Aβ phagocytosis.
Abildayeva K, Jansen PJ, Hirsch-Reinshagen V, Bloks VW, Bakker AH, Ramaekers FC, de Vente J, Groen AK, Wellington CL, Kuipers F, Mulder M (2006) 24(S)-Hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux. J Biol Chem 281:12799-12808.
Alberti S, Steffensen KR, Gustafsson JA (2000) Structural characterisation of the mouse nuclear oxysterol receptor genes LXRalpha and LXRbeta. Gene 243:93-103.
Alberti S, Schuster G, Parini P, Feltkamp D, Diczfalusy U, Rudling M, Angelin B, Björkhem I, Pettersson S, Gustafsson JA (2001) Hepatic cholesterol metabolism and resistance to dietary cholesterol in LXRbeta-deficient mice. J Clin Invest 107:565-573.
Andersson S, Gustafsson N, Warner M, Gustafsson JA (2005) Inactivation of liver Xreceptor beta leads to adult-onset motor neuron degeneration in male mice. Proc Natl Acad Sci U S A 102:3857-3862.
Baranowski M (2008) Biological role of liver X receptors. J Physiol Pharmacol 59:31-55.
Beaven SW, Tontonoz P (2006) Nuclear receptors in lipid metabolism: targeting the heart of dyslipidemia. Annu Rev Med 57:313-329.
Bischoff ED, Daige CL, Petrowski M, Dedman H, Pattison J, Juliano J, Li AC, Schulman IG (2010) Non-redundant roles for LXRalpha and LXRbeta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J Lipid Res 51:900-906.
Bolmont T, Haiss F, Eicke D, Radde R, Mathis CA, Klunk WE, Kohsaka S, Jucker M, Calhoun ME (2008) Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance. J Neurosci 28:4283-4292.
Buxbaum JN, Ye Z, Reixach N, Friske L, Levy C, Das P, Golde T, Masliah E, Roberts AR, Bartfai T (2008) Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of A beta toxicity. Proc Natl Acad Sci U S A 105:2681-2686.
DeMattos RB, Bales KR, Parsadanian M, O'Dell MA, Foss EM, Paul SM, Holtzman DM (2002) Plaque-associated disruption of CSF and plasma amyloid-beta (A beta) equilibrium in a mouse model of Alzheimer's disease. J Neurochem 81:229-236.
Fiévet C, Staels B (2009) Liver X receptor modulators: effects on lipid metabolism and potential use in the treatment of atherosclerosis. Biochem Pharmacol 77:1316-1327.
Floden AM, Combs CK (2006) beta-amyloid stimulates murine postnatal and adult microglia cultures in a unique manner. J Neurosci 26:4644-4648.
Fujita SC, Sakura K, Tsuchiya R, Hamanaka H (1999) Apolipoprotein E is found in astrocytes but not in microglia in the normal mouse brain. Neurosci Res 35:123-133.
Giulian D, Baker TJ (1986) Characterization of ameboid microglia isolated from developing mammalian brain. J Neurosci 6:2163-2178.
Giunta B, Zhou Y, Hou H, Rrapo E, Fernandez F, Tan J (2008) HIV-1 TAT inhibits microglial phagocytosis of Abeta peptide. Int J Clin Exp Pathol 1:260-275.
Grainger DJ, Reckless J, McKilligin E (2004) Apolipoprotein E modulates clearance of apoptotic bodies in vitro and in vivo, resulting in a systemic proinflammatory state in apolipoprotein E-deficient mice. J Immunol 173:6366-6375.
Jankowsky JL, Slunt HH, Gonzales V, Jenkins NA, Copeland NG, Borchelt DR (2004) APP processing and amyloid deposition in mice haploinsufficient for presenilin 1. Neurobiol Aging 25:885-892.
Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, Mann K, Lamb B, Willson TM, Collins JL, Richardson JC, Smith JD, Comery TA, Riddell D, Holtzman DM, Tontonoz P, Landreth GE (2008) ApoE promotes the proteolytic degradation of A beta. Neuron 58:681-693.
Kim HJ, Fan X, Gabbi C, Yakimchuk K, Parini P, Warner M, Gustafsson JA (2008) Liver X receptor beta (LXRbeta): a link between beta-sitosterol and amyotrophic lateral sclerosis-Parkinson's dementia. Proc Natl Acad Sci U S A 105:2094-2099.
Kim WS, Rahmanto AS, Kamili A, Rye KA, Guillemin GJ, Gelissen IC, Jessup W, Hill AF, Garner B (2007) Role of ABCG1 and ABCA1 in regulation of neuronal cholesterol efflux to apolipoprotein E discs and suppression of amyloid-beta peptide generation. J Biol Chem 282:2851-2861.
Koffie RM, Meyer-Luehmann M, Hashimoto T, Adams KW, Mielke ML, Garcia-Alloza M, Micheva KD, Smith SJ, Kim ML, Lee VM, Hyman BT, Spires-Jones TL (2009) Oligomeric amyloid beta associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques. Proc Natl Acad Sci U S A 106:4012-4017.
Koldamova R, Staufenbiel M, Lefterov I (2005a) Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280:43224-43235.
Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS (2005b) The liver X receptor ligand T0901317 decreases amyloid beta production in vitro and in a mouse model of Alzheimer's disease. J Biol Chem 280:4079-4088.
Kuo YM, Beach TG, Sue LI, Scott S, Layne KJ, Kokjohn TA, Kalback WM, Luehrs DC, Vishnivetskaya TA, Abramowski D, Sturchler-Pierrat C, Staufenbiel M, Weller RO, Roher AE (2001) The evolution of A beta peptide burden in the APP23 transgenic mice: implications for A beta deposition in Alzheimer disease. Mol Med 7:609-618.
Lefterov I, Bookout A, Wang Z, Staufenbiel M, Mangelsdorf D, Koldamova R (2007) Expression profiling in APP23 mouse brain: inhibition of A beta amyloidosis and inflammation in response to LXR agonist treatment. Mol Neurodegener 2:20.
Mulder M, Terwel D (1998) Possible link between lipid metabolism and cerebral amyloid angiopathy in Alzheimer's disease: a role for highdensity lipoproteins? Haemostasis 28:174-194.
Okura Y, Kohyama K, Park IK, Matsumoto Y (2008) Nonviral DNA vaccination augments microglial phagocytosis of beta-amyloid deposits as a major clearance pathway in an Alzheimer disease mouse model. J Neuropathol Exp Neurol 67:1063-1071.
Plump AS, Smith JD, Hayek T, Aalto-Setälä K, Walsh A, Verstuyft JG, Rubin EM, Breslow JL (1992) Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71:343-353.
Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, Warwick HK, Ring RH, Kirksey Y, Aschmies S, Xu J, Kubek K, Hirst WD, Gonzales C, Chen Y, Murphy E, Leonard S, Vasylyev D, Oganesian A, Martone RL, Pangalos MN, et al (2007) The LXR agonist TO901317 selectively lowers hippocampal Abeta42 and improves memory in the Tg2576 mouse model of Alzheimer's disease. Mol Cell Neurosci 34:621-628.
Roses AD (2006) On the discovery of the genetic association of apolipoprotein E genotypes and common late-onset Alzheimer disease. J Alzheimers Dis 9:361-366.
Scholtzova H, Kascsak RJ, Bates KA, Boutajangout A, Kerr DJ, Meeker HC, Mehta PD, Spinner DS, Wisniewski T (2009) Induction of Toll-like receptor 9 signaling as a method for ameliorating Alzheimer's diseaserelated pathology. J Neurosci 29:1846-1854.
Schrader-Fischer G, Paganetti PA (1996) Effect of alkalizing agents on the processing of the beta-amyloid precursor protein. Brain Res 716:91-100.
Steffensen KR, Neo SY, Stulnig TM, Vega VB, Rahman SS, Schuster GU, Gustafsson JA, Liu ET (2004) Genome-wide expression profiling; a panel of mouse tissues discloses novel biological functions of liver X receptors in adrenals. J Mol Endocrinol 33:609-622.
Sturchler-Pierrat C, Abramowski D, Duke M, Wiederhold KH, Mistl C, Rothacher S, Ledermann B, Bürki K, Frey P, Paganetti PA, Waridel C, Calhoun ME, Jucker M, Probst A, Staufenbiel M, Sommer B (1997) Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology. Proc Natl Acad Sci U S A 94:13287-13292.
Teplow DB (2006) Preparation of amyloid beta-protein for structural and functional studies. Methods Enzymol 413:20-33.
Tobin KA, Steineger HH, Alberti S, Spydevold O, Auwerx J, Gustafsson JA, Nebb HI (2000) Cross-talk between fatty acid and cholesterol metabolism mediated by liver X receptor-alpha. Mol Endocrinol 14:741-752.
Van Dam D, D'Hooge R, Staufenbiel M, Van Ginneken C, Van Meir F, De Deyn PP (2003) Age-dependent cognitive decline in the APP23 model precedes amyloid deposition. Eur J Neurosci 17:388-396.
Van Dam D, Coen K, De Deyn PP (2008) Cognitive evaluation of diseasemodifying efficacy of donepezil in the APP23 mouse model for Alzheimer's disease. Psychopharmacology 197:37-43.
Vanmierlo T, Rutten K, Dederen J, Bloks VW, van Vark-van der Zee LC, Kuipers F, Kiliaan A, Blokland A, Sijbrands EJ, Steinbusch H, Prickaerts J, Lutjohann D, Mulder M (2009) Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol Aging. Advance online publication. Retrieved Aug. 11, 2009. doi:10.1016/j.neurobiolaging.2009.07.005.
Vloeberghs E, Van Dam D, Franck F, Serroyen J, Geert M, Staufenbiel M, De Deyn PP (2008) Altered ingestive behavior, weight changes, and intact olfactory sense in an APPoverexpression model. Behav Neurosci 122:491-497.
Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, Paul SM, Holtzman DM (2005) Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 280:43236-43242.
Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, Knoten A, Jain S, Hirsch-Reinshagen V, Wellington CL, Bales KR, Paul SM, Holtzman DM (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118:671-682.
Wang L, Schuster GU, Hultenby K, Zhang Q, Andersson S, Gustafsson JA (2002) Liver X receptors in the central nervous system: from lipid homeostasis to neuronal degeneration. Proc Natl Acad Sci U S A 99:13878-13883.
Whitney KD, Watson MA, Goodwin B, Galardi CM, Maglich JM, Wilson JG, Willson TM, Collins JL, Kliewer SA (2001) Liver X receptor (LXR) regulation of the LMR alpha gene in human macrophages. J Biol Chem 276:43509-43515.
Whitney KD, Watson MA, Collins JL, Benson WG, Stone TM, Numerick MJ, Tippin TK, Wilson JG, Winegar DA, Kliewer SA (2002) Regulation of cholesterol homeostasis by the liver X receptors in the central nervous system. Mol Endocrinol 16:1378-1385.
Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y (2006) Profile and regulation of apolipoprotein E (ApoE) expression in the CNS in mice with targeting of green fluorescent protein gene to the ApoE locus. J Neurosci 26:4985-4994.
Zelcer N, Tontonoz P (2006) Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607-614.
