The LXR/RXR Approaches in Alzheimer�s Disease: Is the Blood-Brain Barrier the Forgotten Partner?

Julien Saint-Pol^1,2,3, Pietra Candela^1,2,3, Laurence Fenart^1,2,3and Fabien Gosselet^1,2,3*

¹Univ Lille Nord de France F-59000, Lille, France

²UArtois, LBHE, EA2465 F-62300, Lens, France

³Université d’Artois, Laboratoire de la barrière hémato-encéphalique (LBHE), EA 2465-IMPRT-IFR114 F-59000, Lille, France

Corresponding Author:

Fabien Gosselet
Université d’Artois, Laboratoire de la barrière hémato-encéphalique (LBHE)
EA 2465-IMPRT 114, Faculté Jean Perrin
Rue Jean Souvraz, SP 18, F-62300 Lens, France
Tel: +33 (0)3 21 79 17 80
Fax: +33 (0)3 21 79 17 36
E-mail: fabien.gosselet@univ-artois.fr

Received date: December 02, 2013; Accepted date: December 07, 2013; Published date: December 20, 2013

Citation: Saint-Pol J, Candela P, Fenart L, Gosselet F (2013) The LXR/ RXR Approaches in Alzheimer’s Disease: Is the Blood-Brain Barrier the Forgotten Partner? J Alzheimers Dis Parkinsonism 3:e131. doi: 10.4172/2161-0460.1000e131

Copyright: © 2013 Saint-Pol J, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Visit for more related articles at Journal of Alzheimers Disease & Parkinsonism

Alzheimer’s disease (AD) is a neurodegenerative pathology mainly associated with amyloid-β (Aβ) peptide aggregation and deposition in brain parenchyma and perivascular spaces [1]. This hallmark results from altered natural processes of clearance of these peptides from brain [2]. Finding a treatment for AD has become the main challenge of the 21^st century for the scientific community due to the progressive increase of people affected and the rising costs of care [3]. Since the last decade, a new promising therapeutical strategy based on the stimulation of liver X receptors (LXRs) by agonists has arisen to slow down the evolution of AD. LXRs are ligand-activated transcription factors which are involved in cellular cholesterol metabolism by regulating the expression of target genes [4]. These nuclear receptors have been linked with the onset and progression of AD since APP/PS1 mice deficient for LXRs showed a greater number of Aβ plaques in brain parenchyma and an accelerated cognitive decline [5]. The close relationship between LXRs and AD is associated with the transporter ATP Binding Cassette sub-family A member 1 (ABCA1) [6] which regulate the cerebral cholesterol release to apolipoprotein E (ApoE) [7]. Indeed, ABCA1 depletion in AD-related mice models led to an increased deposition of Aβ peptides in brain [8-11] where as it is over expression reduced the cerebral Aβ burden [12]. Moreover, the stimulation of LXRs with synthetic agonists such as T0901317 or GW3965 in AD-related mice models demonstrated a significant decrease of cerebral Aβ burden [13-18] associated with the increased expression of ABCA1 and ApoE which contribute to the degradation of Aβ peptides by microglial cells. Indeed, the ABCA1-mediated lipidation of ApoE promotes the formation of Aβ -ApoE complexes which are degraded by the microglial cells through a phagocytic process [7]. In addition to this effect on cerebral Aβ burden, 24S-hydroxycholesterol (24S-OHC) and 27-hydroxycholesterol (27- OHC), two oxysterols known to be natural endogenous agonists of LXRs, have been described to decrease the activity of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), the key secretase involved in Aβ peptide production [19-21]. Thus, stimulating the LXR pathway appears to be an attractive therapeutic approach in AD.

As a type II nuclear receptor, LXR forms an obligate heterodimer with a retinoid X receptor (RXR) to be functional. Moreover, LXR is a permissive RXR partner, i.e. the stimulation of RXR induces the activation of LXR pathway with or without LXR agonists, and therefore promotes the expression of LXR target genes [22,23]. Since the LXR pathway is an attractive therapeutic target in AD, it was postulated that stimulating RXRs could also have an effect on Aβ peptide deposition and clearance through the activation of LXR target genes [24]. In February 2012, Landreth’s team published that bexarotene, a RXR agonist initially used in cutaneous T-cell lymphoma treatment, not only decreased the cerebral Aβ burden by stimulating Aβ plaques phagocytosis by microglial cells following an ABCA1/ApoE-mediated process, but also improved the cognitive function of AD-related mice models after unique or chronic treatments [25]. However, some comments and studies published one year later reported divergent results in different AD-related mice models [26-30] and beagle dogs [29] even if the same dose of bexarotene were used. Indeed, excepting a slight decrease of brain soluble or insoluble Aβ peptide levels [26,30], these studies showed that bexarotene modified neither the size nor the number of Aβ plaques [26,28-30]. Moreover, the initial benefit effect of bexarotene on cognitive functions was either not reproduced [26,27], or questionable [29] in view of the induced adverse effects such as cutaneous irritation, weight loss, dyslipidemia, hypersensitivity, hypothyroidism or leukopenia [29,31]. These divergent observations are currently explained by the different preparations for bexarotene which could alter its affinity for the RXRs, the different periods of treatment and the different animal models used [32]. However, none of these studies have taken into account the blood-brain barrier (BBB) despite its key roles in AD [33,34] and its alteration observed in some AD-related mice models [35,36] which could explain the previous discrepancies.

The BBB, located within the brain capillaries and formed by the brain capillary endothelial cells (BCECs) surrounded by brain pericytes and astrocytes which are necessary to induce and maintain the BBB phenotype [37,38], is involved in Aβ peptide exchanges, synthesis and degradation mechanisms [33]. Indeed, BCECs express the amyloid precursor protein (APP) [39,40] and the secretases involved in its amyloidogenic cleavage such as BACE1 [40]. BCECs are therefore able to secrete soluble fragments of APP and Aß peptides mainly in their abluminal side (i.e. cerebral side) which could exacerbate the perivascular amyloid deposition [33,40,41]. BCECs express also the enzymes responsible for Aβ peptide degradation such as insulin degrading enzyme (IDE) or neprilysin (NEP) [33,42]. Moreover, the BBB regulates the cerebral pool of Aβ peptides by bidirectional exchanges between blood and brain through influx (from blood to brain) and efflux (from brain to blood) transport processes [34]. Aβ peptide influx across the BBB is driven by the receptor for advanced glycation end-products (RAGE) and restricted by the transporters ABCB1 and ABCG2. These receptor/transporters are expressed at the luminal side (i.e. blood side) of BCECs [43-46]. Aβ peptide efflux across the BBB is commonly associated with the low density lipoprotein receptor-related protein 1 (LRP1) and other members of the low density lipoprotein receptor (LDLR) family [34,47,48]. Some ABC transporters have been described to take part in this efflux process such as ABCC1 (also named multidrug resistance associated protein 1 or MRP1) [49] and ABCG4 [50]. Very few studies focused on the effects of LXR or RXR stimulation in terms of amyloid metabolism at the BBB level, the latter therefore appears as the forgotten partner in LXR/ RXR approaches in AD. This lack of data is surprising knowing that oxysterols such as 24S-OHC and 27-OHC cross daily this barrier [19] and promote cholesterol efflux from BBB cells [51-54]. A study led by Panzenboeck’s team demonstrated in vitro that both 24S-OHC and 27- OHC induced the non-amyloidogenic cleavage of APP in BCECs and reduced Aβ secretion and oligomerisation in abluminal (i.e. cerebral) compartment [40]. Furthermore, we demonstrated in vitro in BCECs and in brain pericytes that ABCA1 expression is increased after LXR stimulation with 24S-OHC and 27-OHC but is not directly involved in accumulation or transport of soluble Aβ peptides [53,54]. The latter point highlights that ABCA1 is not able to transport Aβ peptides as previously described [55], however this transport is modified after LXR stimulation. Indeed, 24S-OHC and 27-OHC decreased Aβ peptide influx across BCECs that is associated with the increased expression and functionality of ABCB1 [53]. Even if ABCB1 is not a LXR target gene, a previous study in C57BL/6 mice has also shown that T0901317 and GW3965 induced its expression [56]. Knowing that ABCB1 expression and functionality are drastically decreased in brain microvessels of AD patients [57-60], these data suggest that LXR stimulation at the BBB level could restore/optimize ABCB1 expression and function by restricting the entry of Aβ peptides into the brain following an ABCB1-mediated process, and could therefore limit their deposition in perivascular spaces. In addition to our previous results on the LXR-based approach, the first studies focused on the RXR stimulation at the BBB level demonstrated promising effects in terms of Aβ peptide exchanges. In fact, bexarotene enhanced Aβ peptide clearance from brain to blood across the BBB following an ApoE and probably a LRP1-mediated process in a human in vitro BBB model [61,62]. Thus, the LXR/RXR stimulation studies at the BBB level reinforce the therapeutical interest of both nuclear receptors in AD by restricting Aβ peptide entry in brain and by optimizing the Aβ peptide clearance from brain.

Altogether, these observations underline the complementarity and the need of both brain- and BBB-focused studies in the LXR/RXR therapeutic approaches, and highlight once again how underestimated the BBB is in this disease.

References

1. Morris JC, Aisen PS, Bateman RJ, Benzinger TL, Cairns NJ, et al. (2012) Developing an international network for Alzheimer research: The Dominantly Inherited Alzheimer Network. Clin Investig (Lond) 2: 975-984.
2. Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, et al. (2010) Decreased clearance of CNS beta-amyloid in Alzheimer's disease. Science 330: 1774.
3. Alzheimer's Disease International (2013) World Alzheimer Report 2013 Journey of Caring, an analysis of long-term care for dementia.
4. Ducheix S, Lobaccaro JM, Martin PG, Guillou H (2011) Liver X Receptor: an oxysterol sensor and a major player in the control of lipogenesis. Chem Phys Lipids 164: 500-514.
5. Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, et al. (2007) Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci U S A 104: 10601-10606.
6. Hu YW, Zheng L, Wang Q (2010) Regulation of cholesterol homeostasis by liver X receptors. Clin Chim Acta 411: 617-625.
7. Hirsch-Reinshagen V, Wellington CL (2007) Cholesterol metabolism, apolipoprotein E, adenosine triphosphate-binding cassette transporters, and Alzheimer's disease. Curr Opin Lipidol 18: 325-332.
8. Fitz NF, Cronican AA, Saleem M, Fauq AH, Chapman R, et al. (2012) Abca1 deficiency affects Alzheimer's disease-like phenotype in human ApoE4 but not in ApoE3-targeted replacement mice. J Neurosci 32: 13125-13136.
9. Hirsch-Reinshagen V, Maia LF, Burgess BL, Blain JF, Naus KE, et al. (2005) The absence of ABCA1 decreases soluble ApoE levels but does not diminish amyloid deposition in two murine models of Alzheimer disease. J Biol Chem 280: 43243-43256.
10. Koldamova R, Staufenbiel M, Lefterov I (2005) Lack of ABCA1 considerably decreases brain ApoE level and increases amyloid deposition in APP23 mice. J Biol Chem 280: 43224-43235.
11. Wahrle SE, Jiang H, Parsadanian M, Hartman RE, Bales KR, et al. (2005) Deletion of Abca1 increases Abeta deposition in the PDAPP transgenic mouse model of Alzheimer disease. J Biol Chem 280: 43236-43242.
12. Wahrle SE, Jiang H, Parsadanian M, Kim J, Li A, et al. (2008) Overexpression of ABCA1 reduces amyloid deposition in the PDAPP mouse model of Alzheimer disease. J Clin Invest 118: 671-682.
13. Burns MP, Vardanian L, Pajoohesh-Ganji A, Wang L, Cooper M, et al. (2006) The effects of ABCA1 on cholesterol efflux and Abeta levels in vitro and in vivo. J Neurochem 98: 792-800.
14. Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, et al. (2010) 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 285: 34144-34154.
15. Fitz NF, Cronican A, Pham T, Fogg A, Fauq AH, et al. (2010) Liver X receptor agonist treatment ameliorates amyloid pathology and memory deficits caused by high-fat diet in APP23 mice. J Neurosci 30: 6862-6872.
16. Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, et al. (2005) 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.
17. Riddell DR, Zhou H, Comery TA, Kouranova E, Lo CF, 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.
18. Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JÅ, et al. (2011) Critical role of astroglial apolipoprotein E and liver X receptor-ÃŽ± expression for microglial AÃŽ² phagocytosis. J Neurosci 31: 7049-7059.
19. Björkhem I, Cedazo-Minguez A, Leoni V, Meaney S (2009) Oxysterols and neurodegenerative diseases. Mol Aspects Med 30: 171-179.
20. Brown J 3rd, Theisler C, Silberman S, Magnuson D, Gottardi-Littell N, et al. (2004) Differential expression of cholesterol hydroxylases in Alzheimer's disease. J Biol Chem 279: 34674-34681.
21. Jeitner TM, Voloshyna I, Reiss AB (2011) Oxysterol derivatives of cholesterol in neurodegenerative disorders. Curr Med Chem 18: 1515-1525.
22. Germain P, Chambon P, Eichele G, Evans RM, Lazar MA, et al. (2006) International Union of Pharmacology. LXIII. Retinoid X receptors. Pharmacol Rev 58: 760-772.
23. Lefebvre P, Benomar Y, Staels B (2010) Retinoid X receptors: common heterodimerization partners with distinct functions. Trends Endocrinol Metab 21: 676-683.
24. Mandrekar-Colucci S, Landreth GE (2011) Nuclear receptors as therapeutic targets for Alzheimer's disease. Expert Opin Ther Targets 15: 1085-1097.
25. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, et al. (2012) ApoE-directed therapeutics rapidly clear ÃŽ²-amyloid and reverse deficits in AD mouse models. Science 335: 1503-1506.
26. Fitz NF, Cronican AA, Lefterov I, Koldamova R (2013) Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science 340: 924-c.
27. LaClair KD, Manaye KF, Lee DL, Allard JS, Savonenko AV, et al. (2013) Treatment with bexarotene, a compound that increases apolipoprotein-E, provides no cognitive benefit in mutant APP/PS1 mice. Mol Neurodegener 8: 18.
28. Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, et al. (2013) Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science 340: 924-924d.
29. Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B, et al. (2013) Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science 340: 924-924e.
30. Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW, et al. (2013) Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science 340: 924-f.
31. Food and Drug Administration (2011) Targretin (bexarotene) capsules, 75 mg. http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/0210055s006lbl.pdf.
32. Tesseur I, De Strooper B (2013) When the dust settles: what did we learn from the bexarotene discussion? Alzheimers Res Ther 5: 54.
33. Gosselet F, Saint-Pol J, Candela P, Fenart L (2013) Amyloid-beta Peptides, Alzheimer's Disease and the Blood-Brain Barrier. Curr Alzheimer Res.
34. Zlokovic BV (2008) The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 57: 178-201.
35. Bourasset F, Ouellet M, Tremblay C, Julien C, Do TM, et al. (2009) Reduction of the cerebrovascular volume in a transgenic mouse model of Alzheimer's disease. Neuropharmacology 56: 808-813.
36. Ujiie M, Dickstein DL, Carlow DA, Jefferies WA (2003) Blood-brain barrier permeability precedes senile plaque formation in an Alzheimer disease model. Microcirculation 10: 463-470.
37. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ (2010) Structure and function of the blood-brain barrier. Neurobiol Dis 37: 13-25.
38. Cecchelli R, Berezowski V, Lundquist S, Culot M, Renftel M, et al. (2007) Modelling of the blood-brain barrier in drug discovery and development. Nat Rev Drug Discov 6: 650-661.
39. Forloni G, Demicheli F, Giorgi S, Bendotti C, Angeretti N (1992) Expression of amyloid precursor protein mRNAs in endothelial, neuronal and glial cells: modulation by interleukin-1. Brain Res Mol Brain Res 16: 128-134.
40. Schweinzer C, Kober A, Lang I, Etschmaier K, Scholler M, et al. (2011) Processing of endogenous AÃŽ²PP in blood-brain barrier endothelial cells is modulated by liver-X receptor agonists and altered cellular cholesterol homeostasis. J Alzheimers Dis 27: 341-360.
41. Simons ER, Marshall DC, Long HJ, Otto K, Billingslea A, et al. (1998) Blood brain barrier endothelial cells express candidate amyloid precursor protein-cleaving secretases. Amyloid 5: 153-162.
42. Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, et al. (2003) Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences of the United States of America 100: 4162-4167.
43. Candela P, Gosselet F, Saint-Pol J, Sevin E, Boucau MC, et al. (2010) Apical-to-basolateral transport of amyloid-beta peptides through blood-brain barrier cells is mediated by the receptor for advanced glycation end-products and is restricted by P-glycoprotein. J Alzheimers Dis 22: 849-859.
44. Deane R, Du Yan S, Submamaryan RK, LaRue B, Jovanovic S, et al. (2003) RAGE mediates amyloid-beta peptide transport across the blood-brain barrier and accumulation in brain. Nat Med 9: 907-913.
45. Tai LM, Loughlin AJ, Male DK, Romero IA (2009) P-glycoprotein and breast cancer resistance protein restrict apical-to-basolateral permeability of human brain endothelium to amyloid-beta. J Cereb Blood Flow Metab 29: 1079-1083.
46. Tai LM, Reddy PS, Lopez-Ramirez MA, Davies HA, Male DK, et al. (2009) Polarized P-glycoprotein expression by the immortalised human brain endothelial cell line, hCMEC/D3, restricts apical-to-basolateral permeability to rhodamine 123. Brain Res 1292: 14-24.
47. Bell RD, Sagare AP, Friedman AE, Bedi GS, Holtzman DM, et al. (2007) Transport pathways for clearance of human Alzheimer's amyloid beta-peptide and apolipoproteins E and J in the mouse central nervous system. J Cereb Blood Flow Metab 27: 909-918.
48. Castellano JM, Kim J, Stewart FR, Jiang H, DeMattos RB, et al. (2011) Human apoE isoforms differentially regulate brain amyloid-beta peptide clearance. Sci Transl Med 3: 89ra57.
49. Krohn M, Lange C, Hofrichter J, Scheffler K, Stenzel J, et al. (2011) Cerebral amyloid-beta proteostasis is regulated by the membrane transport protein ABCC1 in mice. J Clin Invest 121: 3924-3931.
50. Do TM, Noel-Hudson MS, Ribes S, Besengez C, Smirnova M, et al. (2012) ABCG2- and ABCG4-mediated efflux of amyloid-beta peptide 1-40 at the mouse blood-brain barrier. J Alzheimers Dis 30: 155-166.
51. Panzenboeck U, Balazs Z, Sovic A, Hrzenjak A, Levak-Frank S, et al. (2002) ABCA1 and scavenger receptor class B, type I, are modulators of reverse sterol transport at an in vitro blood-brain barrier constituted of porcine brain capillary endothelial cells. J Biol Chem 277: 42781-42789.
52. Panzenboeck U, Kratzer I, Sovic A, Wintersperger A, Bernhart E, et al. (2006) 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 38: 1314-1329.
53. Saint-Pol J, Candela P, Boucau MC, Fenart L, Gosselet F (2013) Oxysterols decrease apical-to-basolateral transport of Ass peptides via an ABCB1-mediated process in an in vitro Blood-brain barrier model constituted of bovine brain capillary endothelial cells. Brain Res 1517: 1-15.
54. Saint-Pol J, Vandenhaute E, Boucau MC, Candela P, Dehouck L, et al. (2012) Brain pericytes ABCA1 expression mediates cholesterol efflux but not cellular amyloid-beta peptide accumulation. J Alzheimers Dis 30: 489-503.
55. Akanuma S, Ohtsuki S, Doi Y, Tachikawa M, Ito S, et al. (2008) ATP-binding cassette transporter A1 (ABCA1) deficiency does not attenuate the brain-to-blood efflux transport of human amyloid-beta peptide (1-40) at the blood-brain barrier. Neurochem Int 52: 956-961.
56. Elali A, Hermann DM (2012) Liver X receptor activation enhances blood-brain barrier integrity in the ischemic brain and increases the abundance of ATP-binding cassette transporters ABCB1 and ABCC1 on brain capillary cells. Brain Pathol 22: 175-187.
57. Vogelgesang S, Cascorbi I, Schroeder E, Pahnke J, Kroemer HK, et al. (2002) Deposition of Alzheimer's beta-amyloid is inversely correlated with P-glycoprotein expression in the brains of elderly non-demented humans. Pharmacogenetics 12: 535-541.
58. Vogelgesang S, Jedlitschky G, Brenn A, Walker LC (2011) The role of the ATP-binding cassette transporter P-glycoprotein in the transport of beta-amyloid across the blood-brain barrier. Curr Pharm Des 17: 2778-2786.
59. Wijesuriya HC, Bullock JY, Faull RL, Hladky SB, Barrand MA (2010) ABC efflux transporters in brain vasculature of Alzheimer's subjects. Brain Res 1358: 228-238.
60. van Assema DM, Lubberink M, Boellaard R, Schuit RC, Windhorst AD, et al. (2012) P-glycoprotein function at the blood-brain barrier: effects of age and gender. Mol Imaging Biol 14: 771-776.
61. Bachmeier C, Beaulieu-Abdelahad D, Crawford F, Mullan M, Paris D (2013) Stimulation of the retinoid X receptor facilitates beta-amyloid clearance across the blood-brain barrier. J Mol Neurosci 49: 270-276.
62. Bachmeier C, Paris D, Beaulieu-Abdelahad D, Mouzon B, Mullan M, et al. (2013) A multifaceted role for apoE in the clearance of beta-amyloid across the blood-brain barrier. Neurodegener Dis 11: 13-21.