Abstract
Alzheimer’s disease (AD) is a devastating neurodegenerative disease characterized by beta-amyloid (Aβ) accumulation and neurofibrillary tangles formation in the brain which are associated to synaptic deficits and dementia. Liver X receptor (LXR) agonists have been demonstrated to revert of pathologic and cognitive defects in murine models of AD through the regulation of Apolipoprotein E, ATP-Binding Cassette A1 (ABCA1), by dampening neuroinflammation and also by reducing the levels of amyloid-β (Aβ) accumulation in the brain. However, the role of LXR with regard to the regulation of synaptic function remains relatively understudied. In the present paper, we analyzed the in-vitro effect of the LXR agonist GW3965 on synaptic function upon exposure of primary hippocampal cultures to oligomeric amyloid-β (oAβ(1–42)). We showed that oAβ(1–42) exposure significantly decreased the density of mature (mushroom shaped) dendritic spines density and synaptic contacts number. oAβ(1–42) also modulates the expression of pre- (VGlut1, SYT1, SV2A) and post-synaptic (SHANK2, NMDA) proteins, it decreases the expression of PINK1, and increases ROCKII, and activates of caspase-3; these changes were prevented by the pre-treating neuronal cultures with GW3965. These results show further support the role of the LXR agonist GW3965 in synaptic physiology and highlight its potential as an alternative pharmacological strategy for AD.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Alberdi E, Sáncer-Gómez MV, Cavaliere F, Pérez-Samartín A, Zugaza JL, Trullas R, Domercq M, Matute C (2010) Amyloid β oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47(3):264–272. https://doi.org/10.1016/j.ceca.2009.12.010
Arellano JI, Benavides-Piccione R, Defelipe J, Yuste R (2007) Ultrastructure of dendritic spines: correlation between synaptic and spine morphologies. Front Neurosci 1(1):131–143. https://doi.org/10.3389/neuro.01.1.1.010.2007
Armstrong RA (2011) The pathogenesis of Alzheimer’s disease: a reevaluation of the “amyloid cascade hypothesis”. Int J Alzheimers Dis 2011:630865. https://doi.org/10.4061/2011/630865
Beaudoin G, Lee SH, Singh D, Yuan Y, Ng YG, Reichardt LF, Arikkath J (2012) Culturing pyramidal neurons from the early postnatal mouse hippocampus and cortex. Nat Protoc 7:1741–1754
Beilina A, Cookson MR (2015) Genes associated to Parkinson’s disease: regulation of autophagy and beyond. J Neurochem 139:91–107
Bittner T, Fuhrmann M, Burgold S, Ochs SM, Hoffmann N, Mitteregger G, Kretzschmar H, LaFerla FM, Herms J (2010) Multiple events lead to dendritic spine loss in triple transgenic Alzheimer’s disease mice. PLoS One 5(11):e15477. https://doi.org/10.1371/journal.pone.0015477
Canas PM, Simões AP, Rodrigues RJ, Cunha RA (2014) Predominant loss of glutamatergic terminal markers in a β-amyloid peptide model of Alzheimer’s disease. Neuropharmacology 76:51–56. https://doi.org/10.1016/j.neuropharm.2013.08.026
Chen J, Zacharek A, Cui X, Shehadah A, Jiang H, Roberts C, Lu M, Chopp M (2010) Treatment of stroke with a synthetic liver X receptor agonist, TO901317, promotes synaptic plasticity and axonal regeneration in mice. J Cereb Blood Flow Metab Off J Int Soc Cereb Blood Flow Metab 30(1):102–109. https://doi.org/10.1038/jcbfm.2009.187
Chen KH, Reese EA, Kim HW, Rapoport SI, Rao JS (2011) Disturbed neurotransmitter transporter expression in alzheimer disease brain. J Alzheimers Dis 26(4):755–766. https://doi.org/10.3233/JAD-2011-110002
Cingolani LA, Goda Y (2008) Actin in action: the interplay between the actin cytoskeleton and synaptic efficacy. Nat Rev Neurosci 9(5):344–356. https://doi.org/10.1038/nrn2373
Citron M (2010) Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 9(5):387–398. https://doi.org/10.1038/nrd2896
Contreras-Zárate MJ, Niño A, Rojas L, Arboleda H, Arboleda G (2015) Silencing of PINK1 inhibits insulin-like growth Factor-1-mediated receptor activation and neuronal survival. J Mol Neurosci 56:188–197
Cui X, Chopp M, Zhang Z, Li R, Zacharek A, Landschoot-Ward J, Venkat P, Chen J (2013) The neurorestorative benefit of GW3965 treatment of stroke in mice. Stroke 44(1):153–161. https://doi.org/10.1161/STROKEAHA.112.677682
Cullen WK, Suh YH, Anwyl R, Rowan MJ (1997) Block of LTP in rat hippocampus in vivo by beta-amyloid precursor protein fragments. Neuroreport 8(15):3213–3217. https://doi.org/10.1097/00001756-199710200-00006
Dai Y, Tan XJ, WF W, Warner M, Gustafsson JÅ (2012) Liver X receptor β protects dopaminergic neurons in a mouse model of Parkinson disease. Proc Natl Acad Sci U S A 109(32):13112–13117. https://doi.org/10.1073/pnas.1210833109
DeKosky ST, Scheff SW (1990) Synapse loss in frontal cortex biopsies in Alzheimer’s disease: correlation with cognitive severity. Ann Neurol 27(5):457–464. https://doi.org/10.1002/ana.410270502
Dewar D, Chalmers DT, Graham DI, McCulloch J (1991) Glutamate metabotropic and AMPA binding sites are reduced in Alzheimer’s disease: an autoradiographic study of the hippocampus. Brain Res 553(1):58–64. https://doi.org/10.1016/0006-8993(91)90230-S
Donkin JJ, Stukas S, Hirsch-Reinshagen V, Namjoshi D, Wilkinson A, May S, Chan J, Fan J, Collins J, Wellington CL (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(44):34144–34154. https://doi.org/10.1074/jbc.M110.108100
Du F, Yu Q, Yan S, Hu G, Lue LF, Walker DG, Wu L, Yan SF, Tieu K, Yan SS (2017) PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease. Brain. https://doi.org/10.1093/brain/awx258
Frassoni C, Inverardi F, Coco S, Ortino B, Grumelli C, Pozzi D, Verderio C, Matteoli M (2005) Analysis of SNAP-25 immunoreactivity in hippocampal inhibitory neurons during development in culture and in situ. Neuroscience 131(4):813–823
Gong Y, Lippa CF, Zhu J, Lin Q, Rosso AL (2009) Disruption of glutamate receptors at shank-postsynaptic platform in Alzheimer’s disease. Brain Res 1292:191–198. https://doi.org/10.1016/j.brainres.2009.07.056
Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer’s amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112. https://doi.org/10.1038/nrm2101
Hardy J, Allsop D (1991) Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends Pharmacol Sci 12:383–388
Hering H, Sheng M (2001) Dendritic spines: structure, dynamics and regulation. Nat Rev Neurosci 2(12):880–888. https://doi.org/10.1038/35104061
Jacob CP, Koutsilieri E, Bartl J, Neuen-Jacob E, Arzberger T, Zander N, Ravid R, Roggendorf W, Riederer P, Grünblatt E (2007) Alterations in expression of glutamatergic transporters and receptors in sporadic Alzheimer’s disease. J Alzheimers Dis 11:97–116
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 Abeta. Neuron 58:681–693
Kabogo D, Rauw G, Amritraj A, Baker G, Kar S (2010) Beta-amyloid-related peptides potentiate K+−evoked glutamate release from adult rat hippocampal slices. Neurobiol Aging 31:1164–1172
Kashani A, Lepicard E, Poirel O, Videau C, David JP, Fallet-Bianco C, Simon A, Delacourte A, Giros B, Epelbaum J, Betancur C, El Mestikawy S (2008) Loss of VGLUT1 and VGLUT2 in the prefrontal cortex is correlated with cognitive decline in Alzheimer disease. Neurobiol Aging 29:1619–1630
Kilkenny C, Browne WJ, Cuthill IC, Emerson M, Altman DG (2010) Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research. PLoS Biol 8(6):e1000412. https://doi.org/10.1371/journal.pbio.1000412
Kirvell SL, Esiri M, Francis PT (2006) Down-regulation of vesicular glutamate transporters precedes cell loss and pathology in Alzheimer’s disease. J Neurochem 98(3):939–950. https://doi.org/10.1111/j.1471-4159.2006.03935.x
Knobloch M, Mansuy I (2008) Dendritic spine loss and synaptic alterations in Alzheimer’s disease. Mol Neurobiol 37(1):73–82. https://doi.org/10.1007/s12035-008-8018-z
Koldamova RP, Lefterov IM, Staufenbiel M, Wolfe D, Huang S, Glorioso JC, Walter M, Roth MG, Lazo JS (2005) The liver X receptor ligand T0901317 decreases amyloid Î2 production and in a mouse model of Alzheimer's disease. J Biol Chem 280:4079–4088
Korobova F, Svitkina T (2010) Molecular architecture of synaptic actin cytoskeleton in hippocampal neurons reveals a mechanism of dendritic spine morphogenesis. Mol Biol Cell 21(1):165–176. https://doi.org/10.1091/mbc.E09-07-0596
Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L, Larson EB (2002) Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol 59(11):1737–1746. https://doi.org/10.1001/archneur.59.11.1737
Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL (2007) Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci Off J Soc Neurosci 27(4):796–807. https://doi.org/10.1523/JNEUROSCI.3501-06.2007
Lai Y, Lou X, Wang C, Xia T, Tong J (2014) Synaptotagmin 1 and ca(2+) drive trans SNARE zippering. Sci Rep 4:4575. https://doi.org/10.1038/srep04575
Laurén J, Gimbel DA, Nygaard HB, Gilbert JW, Strittmatter SM (2009) Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457(7233):1128–1132. https://doi.org/10.1038/nature07761
Li S, Hong S, Shepardson N, Walsh D, Shankar G, Selkoe D (2009) Soluble oligomers of amyloid β-protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62(6):788–801. https://doi.org/10.1016/j.neuron.2009.05.012
Li S, Shankar G, Selkoe D (2010) How do soluble oligomers of amyloid beta-protein impair hippocampal synaptic plasticity? Front Cell Neurosci 4:5. https://doi.org/10.3389/fncel.2010.00005
Pearlstein E, Michel FJ, Save L, Ferrari DC, Hammond C (2016) Abnormal development of glutamatergic synapses afferent to dopaminergic neurons of the Pink1(−/−) mouse model of Parkinson’s disease. Front Cell Neurosci 23:168
Penzes P, Cahill ME, Jones KA, VanLeeuwen JE, Woolfrey KM (2011) Dendritic spine pathology in neuropsychiatric disorders. Nat Neurosci 14(3):285–293. https://doi.org/10.1038/nn.2741
Sandoval-Hernández AG, Buitrago L, Moreno H, Cardona-Gómez GP, Arboleda G (2015) Role of liver X receptor in AD pathophysiology. PLoS One 10(12):e0145467. https://doi.org/10.1371/journal.pone.0145467
Sandoval-Hernández AG, Hernández HG, Restrepo A, Muñoz JI, Bayon GF, Fernández AF, Fraga MF, Cardona-Gómez GP, Arboleda H, Arboleda G (2016) 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 58(2):243–253. https://doi.org/10.1007/s12031-015-0665-8
Shan Y, Liu B, Li L, Chang N, Li L, Wang H, Wang D, Feng H, Cheung C, Liao M, Cui T, Sugita S, Wan Q (2009) Regulation of PINK1 by NR2B-containing NMDA receptors in ischemic neuronal injury. J Neurochem 111(5):1149–1160. https://doi.org/10.1111/j.1471-4159.2009.06398.x
Sorra KE, Harris KM (2000) Overview on the structure, composition, function, development, and plasticity of hippocampal dendritic spines. Hippocampus 10:501–511
Sze C-I, Bi H, Kleinschmidt-DeMasters B, Filley C, Martin L (2000) Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J Neurol Sci 175(2):81–90. https://doi.org/10.1016/S0022-510X(00)00285-9
Tachibana M, Shinohara M, Yamazaki Y, Liu CC, Rogers J, Bu G, Kanekiyo T (2016) Rescuing effects of RXR agonist bexarotene on aging-related synapse loss depend on neuronal LRP1. Exp Neurol 277:1–9. https://doi.org/10.1007/s12640-017-9845-3
Tashiro A, Yuste R (2003) Structure and molecular organization of dendritic spines. Histol Histopathol 18(2):617–634. https://doi.org/10.14670/HH-18.617
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, Lütjohann D, Mulder M (2011) Liver X receptor activation restores memory in aged AD mice without reducing amyloid. Neurobiol Aging 32:1262–1272
Yuste R (2015) The discovery of dendritic spines. Front Neuroanat 9:2–7
Zelcer N, Khanlou N, Clare R, Jiang Q, Reed-Geaghan EG, Landreth GE, Vinters HV, Tontonoz P (2007) Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors. Proc Natl Acad Sci 104:10601–10606
Funding
This study was funded by COLCIENCIAS (110161538259) and DIEB (37405) and Facultad de Medicina, Universidad Nacional de Colombia, Bogotá.
Author information
Authors and Affiliations
Contributions
Báez-Becerra C: performed most experiments and contributed to manuscript writing.
Filipello F: performed dendritic spine analysis.
Sandoval-Hernández A: performed western blott experiments.
Arboleda H: contributed to desing of the experiments and writing of the manuscript.
Arboleda G: desing the experiments and wrote the manuscript.
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical Approval
All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.
Rights and permissions
About this article
Cite this article
Báez-Becerra, C., Filipello, F., Sandoval-Hernández, A. et al. Liver X Receptor Agonist GW3965 Regulates Synaptic Function upon Amyloid Beta Exposure in Hippocampal Neurons. Neurotox Res 33, 569–579 (2018). https://doi.org/10.1007/s12640-017-9845-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-017-9845-3