Bexarotene therapy ameliorates behavioral deficits and induces functional and molecular changes in very-old Triple Transgenic Mice model of Alzheimer´s disease

Autoři: Jonathan Mauricio Muñoz-Cabrera aff001;  Adrián Gabriel Sandoval-Hernández aff002;  Andrea Niño aff002;  Tatiana Báez aff002;  Angie Bustos-Rangel aff002;  Gloria Patricia Cardona-Gómez aff003;  Alejandro Múnera aff001;  Gonzalo Arboleda aff002
Působiště autorů: Behavioral Neurophysiology Laboratory, School of Medicine, Universidad Nacional de Colombia, Bogotá, Colombia aff001;  Grupo de Muerte Celular, Instituto de Genética, Universidad Nacional de Colombia, Bogotá, Colombia aff002;  Área de Neurobiología Celular y Molecular, Grupo de Neurociencias de Antioquia, Facultad de Medicina, Universidad de Antioquia, Medellín, Colombia aff003
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: 10.1371/journal.pone.0223578



Bexarotene, a retinoid X receptor agonist, improves cognition in murine models of Alzheimer’s disease (AD). This study evaluated the effects of bexarotene on pathological and electrophysiological changes in very old triple transgenic AD mice (3xTg-AD mice).


24-month-old 3xTg-AD mice were treated with bexarotene (100 mg/kg/day for 30 days). The Morris water maze was used to evaluate spatial memory; immunofluorescence and confocal microscopy were used to evaluate pathological changes; and in vivo electrophysiological recordings were used to evaluate basal transmission and plasticity in the commissural CA3-CA1 pathway.


In addition to cognitive improvement, bexarotene-treated 3xTg-AD mice were found to have 1) reductions of astrogliosis and reactive microglia both in cortex and hippocampus; 2) increased ApoE expression restricted to CA1; 3) increased number of cells co-labeled with ApoE and NeuN; 4) recovery of NeuN expression, suggesting neuronal protection; and, 5) recovery of basal synaptic transmission and synaptic plasticity.


These results indicate that bexarotene-induced improvement in cognition is due to multiple changes that contribute to recovery of synaptic plasticity.

Klíčová slova:

Alzheimer's disease – Cognitive impairment – Hippocampus – Immunofluorescence – Learning – Mouse models – Quantitative analysis – Synaptic plasticity


1. Braak H, Braak E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59. doi: 10.1007/bf00308809 1759558.

2. Sandoval-Hernandez AG, Buitrago L, Moreno H, Cardona-Gomez GP, Arboleda G. Role of Liver X Receptor in AD Pathophysiology. PLoS One. 2015;10(12):e0145467. doi: 10.1371/journal.pone.0145467 26720273

3. Moreno H, Morfini G, Buitrago L, Ujlaki G, Choi S, Yu E, et al. Tau pathology-mediated presynaptic dysfunction. Neuroscience. 2016;325:30–8. doi: 10.1016/j.neuroscience.2016.03.044 27012611

4. Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science. 2002;297(5580):353–6. doi: 10.1126/science.1072994 12130773.

5. Jiang Q, Lee CY, Mandrekar S, Wilkinson B, Cramer P, Zelcer N, et al. ApoE promotes the proteolytic degradation of Abeta. Neuron. 2008;58(5):681–93. doi: 10.1016/j.neuron.2008.04.010 18549781

6. Bu G. Apolipoprotein E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10(5):333–44. doi: 10.1038/nrn2620 19339974

7. Evans RM, Mangelsdorf DJ. Nuclear Receptors, RXR, and the Big Bang. Cell. 2014;157(1):255–66. doi: 10.1016/j.cell.2014.03.012 24679540

8. Leblanc BP, Stunnenberg HG. 9-cis retinoic acid signaling: changing partners causes some excitement. Genes Dev. 1995;9(15):1811–6. doi: 10.1101/gad.9.15.1811 7649469.

9. Dheer Y, Chitranshi N, Gupta V, Sharma S, Pushpitha K, Abbasi M, et al. Retinoid x receptor modulation protects against ER stress response and rescues glaucoma phenotypes in adult mice. Exp Neurol. 2019;314:111–25. Epub 2019/02/01. doi: 10.1016/j.expneurol.2019.01.015 30703361.

10. Dickey AS, Sanchez DN, Arreola M, Sampat KR, Fan W, Arbez N, et al. PPARdelta activation by bexarotene promotes neuroprotection by restoring bioenergetic and quality control homeostasis. Sci Transl Med. 2017;9(419). Epub 2017/12/08. doi: 10.1126/scitranslmed.aal2332 29212711

11. Zhou HY, Zhong W, Zhang H, Bi MM, Wang S, Zhang WS. Potential role of nuclear receptor ligand all-trans retinoic acids in the treatment of fungal keratitis. Int J Ophthalmol. 2015;8(4):826–32. Epub 2015/08/27. doi: 10.3980/j.issn.2222-395.2015.04.32 26309886

12. Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med. 2008;14(8):837–42. Epub 2008/06/24. doi: 10.1038/nm1782 18568035

13. Cramer PE, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, et al. ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models. Science. 2012;335(6075):1503–6. Epub 2012/02/11. doi: 10.1126/science.1217697 22323736

14. Escribano L, Simon AM, Gimeno E, Cuadrado-Tejedor M, Lopez de Maturana R, Garcia-Osta A, et al. Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology. 2010;35(7):1593–604. doi: 10.1038/npp.2010.32 20336061

15. Skerrett R, Pellegrino MP, Casali BT, Taraboanta L, Landreth GE. Combined Liver X Receptor/Peroxisome Proliferator-activated Receptor gamma Agonist Treatment Reduces Amyloid beta Levels and Improves Behavior in Amyloid Precursor Protein/Presenilin 1 Mice. J Biol Chem. 2015;290(35):21591–602. doi: 10.1074/jbc.M115.652008 26163517

16. Mounier A, Georgiev D, Nam KN, Fitz NF, Castranio EL, Wolfe CM, et al. Bexarotene-Activated Retinoid X Receptors Regulate Neuronal Differentiation and Dendritic Complexity. J Neurosci. 2015;35(34):11862–76. Epub 2015/08/28. doi: 10.1523/JNEUROSCI.1001-15.2015 26311769

17. Nam KN, Mounier A, Fitz NF, Wolfe C, Schug J, Lefterov I, et al. RXR controlled regulatory networks identified in mouse brain counteract deleterious effects of Abeta oligomers. Sci Rep. 2016;6:24048. doi: 10.1038/srep24048 27051978

18. Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG. Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol. 2010;8(6):e1000412. doi: 10.1371/journal.pbio.1000412 20613859

19. Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003;39(3):409–21. Epub 2003/08/05. doi: 10.1016/s0896-6273(03)00434-3 12895417.

20. Paxinos G, Franklin KBJ. The mouse brain in stereotaxic coordinates. 2nd ed. San Diego: Academic Press; 2001.

21. Fitz NF, Cronican AA, Lefterov I, Koldamova R. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science. 2013;340(6135):924–c.

22. Landreth GE, Cramer PE, Lakner MM, Cirrito JR, Wesson DW, Brunden KR, et al. Response to comments on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science. 2013;340(6135):924–g. Epub 2013/05/25. doi: 10.1126/science.1234114 23704556

23. Price AR, Xu G, Siemienski ZB, Smithson LA, Borchelt DR, Golde TE, et al. Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science. 2013;340(6135):924–d. doi: 10.1126/science.1234089 23704553.

24. Tesseur I, Lo AC, Roberfroid A, Dietvorst S, Van Broeck B, Borgers M, et al. Comment on "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models". Science. 2013;340(6135):924–e. doi: 10.1126/science.1233937 23704554.

25. Veeraraghavalu K, Zhang C, Miller S, Hefendehl JK, Rajapaksha TW, Ulrich J, et al. Comment on “ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models”. Science. 2013;340(6135):924–f.

26. Caruso D, Barron AM, Brown MA, Abbiati F, Carrero P, Pike CJ, et al. Age-related changes in neuroactive steroid levels in 3xTg-AD mice. Neurobiol Aging. 2013;34(4):1080–9. doi: 10.1016/j.neurobiolaging.2012.10.007 23122920

27. Mastrangelo MA, Bowers WJ. Detailed immunohistochemical characterization of temporal and spatial progression of Alzheimer’s disease-related pathologies in male triple-transgenic mice. BMC Neurosci. 2008;9:81. doi: 10.1186/1471-2202-9-81 18700006

28. Combs CK, Johnson DE, Karlo JC, Cannady SB, Landreth GE. Inflammatory mechanisms in Alzheimer’s disease: inhibition of beta-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARgamma agonists. J Neurosci. 2000;20(2):558–67. 10632585.

29. Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, et al. Attenuation of neuroinflammation and Alzheimer’s disease pathology by liver x receptors. Proc Natl Acad Sci U S A. 2007;104(25):10601–6. doi: 10.1073/pnas.0701096104 17563384

30. Harris JA, Koyama A, Maeda S, Ho K, Devidze N, Dubal DB, et al. Human P301L-mutant tau expression in mouse entorhinal-hippocampal network causes tau aggregation and presynaptic pathology but no cognitive deficits. PLoS One. 2012;7(9):e45881. doi: 10.1371/journal.pone.0045881 23029293

31. LaFerla FM, Oddo S. Alzheimer’s disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005;11(4):170–6. doi: 10.1016/j.molmed.2005.02.009 15823755.

32. Palop JJ, Mucke L. Synaptic depression and aberrant excitatory network activity in Alzheimer’s disease: two faces of the same coin? Neuromolecular Med. 2010;12(1):48–55. doi: 10.1007/s12017-009-8097-7 19838821

33. Sheng M, Sabatini BL, Sudhof TC. Synapses and Alzheimer’s disease. Cold Spring Harb Perspect Biol. 2012;4(5). doi: 10.1101/cshperspect.a005777 22491782

34. Mullen RJ, Buck CR, Smith AM. NeuN, a neuronal specific nuclear protein in vertebrates. Development. 1992;116(1):201–11. 1483388.

35. Jawed SI, Myskowski PL, Horwitz S, Moskowitz A, Querfeld C. Primary cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome): part II. Prognosis, management, and future directions. J Am Acad Dermatol. 2014;70(2):223 e1–17; quiz 40–2. doi: 10.1016/j.jaad.2013.08.033 24438970.

36. Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes tangle formation in a triple transgenic model of Alzheimer’s disease. Neurobiol Aging. 2003;24(8):1063–70. Epub 2003/12/04. doi: 10.1016/j.neurobiolaging.2003.08.012 14643377.

37. Desai MK, Sudol KL, Janelsins MC, Mastrangelo MA, Frazer ME, Bowers WJ. Triple-transgenic Alzheimer’s disease mice exhibit region-specific abnormalities in brain myelination patterns prior to appearance of amyloid and tau pathology. Glia. 2009;57(1):54–65. Epub 2008/07/29. doi: 10.1002/glia.20734 18661556

38. Chawla A, Boisvert WA, Lee CH, Laffitte BA, Barak Y, Joseph SB, et al. A PPAR gamma-LXR-ABCA1 pathway in macrophages is involved in cholesterol efflux and atherogenesis. Mol Cell. 2001;7(1):161–71. doi: 10.1016/s1097-2765(01)00164-2 11172721.

39. Donkin JJ, 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(44):34144–54. doi: 10.1074/jbc.M110.108100 20739291

40. Zhong J, Cheng C, Liu H, Huang Z, Wu Y, Teng Z, et al. Bexarotene protects against traumatic brain injury in mice partially through apolipoprotein E. Neuroscience. 2017;343:434–48. doi: 10.1016/j.neuroscience.2016.05.033 27235741.

41. Terwel D, Steffensen KR, Verghese PB, Kummer MP, Gustafsson JA, Holtzman DM, et al. Critical role of astroglial apolipoprotein E and liver X receptor-alpha expression for microglial Abeta phagocytosis. J Neurosci. 2011;31(19):7049–59. doi: 10.1523/JNEUROSCI.6546-10.2011 21562267.

42. Lavezzi AM, Corna MF, Matturri L. Neuronal nuclear antigen (NeuN): a useful marker of neuronal immaturity in sudden unexplained perinatal death. J Neurol Sci. 2013;329(1–2):45–50. doi: 10.1016/j.jns.2013.03.012 23570982.

43. Wolf HK, Buslei R, Schmidt-Kastner R, Schmidt-Kastner PK, Pietsch T, Wiestler OD, et al. NeuN: a useful neuronal marker for diagnostic histopathology. J Histochem Cytochem. 1996;44(10):1167–71. doi: 10.1177/44.10.8813082 8813082.

44. Zhang QG, Wang RM, Scott E, Han D, Dong Y, Tu JY, et al. Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause. Brain. 2013;136(Pt 5):1432–45. doi: 10.1093/brain/awt046 23474850

45. Xu Q, Bernardo A, Walker D, Kanegawa T, Mahley RW, Huang Y. 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. 2006;26(19):4985–94. Epub 2006/05/12. doi: 10.1523/JNEUROSCI.5476-05.2006 16687490

46. Crespo-Biel N, Theunis C, Van Leuven F. Protein tau: prime cause of synaptic and neuronal degeneration in Alzheimer’s disease. Int J Alzheimers Dis. 2012;2012:251426. doi: 10.1155/2012/251426 22720188

47. Rapoport M, Dawson HN, Binder LI, Vitek MP, Ferreira A. Tau is essential to beta -amyloid-induced neurotoxicity. Proc Natl Acad Sci U S A. 2002;99(9):6364–9. doi: 10.1073/pnas.092136199 11959919

48. Combs CK, Bates P, Karlo JC, Landreth GE. Regulation of beta-amyloid stimulated proinflammatory responses by peroxisome proliferator-activated receptor alpha. Neurochem Int. 2001;39(5–6):449–57. doi: 10.1016/s0197-0186(01)00052-3 11578780.

49. Davis KE, Fox S, Gigg J. Increased hippocampal excitability in the 3xTgAD mouse model for Alzheimer’s disease in vivo. PLoS One. 2014;9(3):e91203. doi: 10.1371/journal.pone.0091203 24621690

50. Chakroborty S, Goussakov I, Miller MB, Stutzmann GE. Deviant ryanodine receptor-mediated calcium release resets synaptic homeostasis in presymptomatic 3xTg-AD mice. J Neurosci. 2009;29(30):9458–70. doi: 10.1523/JNEUROSCI.2047-09.2009 19641109.

51. Clark JK, Furgerson M, Crystal JD, Fechheimer M, Furukawa R, Wagner JJ. Alterations in synaptic plasticity coincide with deficits in spatial working memory in presymptomatic 3xTg-AD mice. Neurobiol Learn Mem. 2015;125:152–62. doi: 10.1016/j.nlm.2015.09.003 26385257

52. Sandoval-Hernandez AG, Hernandez HG, Restrepo A, Munoz JI, Bayon GF, Fernandez AF, et al. Liver X Receptor Agonist Modifies the DNA Methylation Profile of Synapse and Neurogenesis-Related Genes in the Triple Transgenic Mouse Model of Alzheimer’s Disease. J Mol Neurosci. 2016;58(2):243–53. Epub 2015/11/11. doi: 10.1007/s12031-015-0665-8 26553261.

53. Tachibana M, Shinohara M, Yamazaki Y, Liu CC, Rogers J, Bu G, et al. Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol. 2016;277:1–9. doi: 10.1016/j.expneurol.2015.12.003 26688581

54. Chen TJ, Wang DC, Chen SS. Amyloid-beta interrupts the PI3K-Akt-mTOR signaling pathway that could be involved in brain-derived neurotrophic factor-induced Arc expression in rat cortical neurons. J Neurosci Res. 2009;87(10):2297–307. doi: 10.1002/jnr.22057 19301428.

55. Hernandez-Ortega K, Garcia-Esparcia P, Gil L, Lucas JJ, Ferrer I. Altered Machinery of Protein Synthesis in Alzheimer’s: From the Nucleolus to the Ribosome. Brain Pathol. 2016;26(5):593–605. doi: 10.1111/bpa.12335 26512942.

56. Um JW, Kaufman AC, Kostylev M, Heiss JK, Stagi M, Takahashi H, et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer abeta oligomer bound to cellular prion protein. Neuron. 2013;79(5):887–902. doi: 10.1016/j.neuron.2013.06.036 24012003

57. Herz J, Beffert U. Apolipoprotein E receptors: linking brain development and Alzheimer’s disease. Nat Rev Neurosci. 2000;1(1):51–8. doi: 10.1038/35036221 11252768.

58. Huang Z. Molecular regulation of neuronal migration during neocortical development. Mol Cell Neurosci. 2009;42(1):11–22. doi: 10.1016/j.mcn.2009.06.003 19523518.

59. Paxinos G, Franklin KBJ. Paxinos and Franklin’s the mouse brain in stereotaxic coordinates. 4th ed. Amsterdam: Elsevier/AP; 2013.

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