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Open Access 01-12-2014 | Research

Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer’s disease pathogenesis

Authors: Timothy A Couttas, Nupur Kain, Benjamin Daniels, Xin Ying Lim, Claire Shepherd, Jillian Kril, Russell Pickford, Hongyun Li, Brett Garner, Anthony S Don

Published in: Acta Neuropathologica Communications | Issue 1/2014

Abstract

Background

The greatest genetic risk factor for late-onset Alzheimer's disease (AD) is the ϵ4 allele of Apolipoprotein E (ApoE). ApoE regulates secretion of the potent neuroprotective signaling lipid Sphingosine 1-phosphate (S1P). S1P is derived by phosphorylation of sphingosine, catalysed by sphingosine kinases 1 and 2 (SphK1 and 2), and SphK1 positively regulates glutamate secretion and synaptic strength in hippocampal neurons. S1P and its receptor family have been subject to intense pharmacological interest in recent years, following approval of the immunomodulatory drug Fingolimod, an S1P mimetic, for relapsing multiple sclerosis.

Results

We quantified S1P levels in six brain regions that are differentially affected by AD pathology, in a cohort of 34 post-mortem brains, divided into four groups based on Braak neurofibrillary tangle staging. S1P declined with increasing Braak stage, and this was most pronounced in brain regions most heavily affected by AD pathology. The S1P/sphingosine ratio was 66% and 64% lower in Braak stage III/IV hippocampus (p = 0.010) and inferior temporal cortex (p = 0.014), respectively, compared to controls. In accordance with this change, both SphK1 and SphK2 activity declined with increasing Braak pathology in the hippocampus (p = 0.032 and 0.047, respectively). S1P/sphingosine ratio was 2.5-fold higher in hippocampus of ApoE2 carriers compared to ApoE4 carriers, and multivariate regression showed a significant association between APOE genotype and hippocampal S1P/sphingosine (p = 0.0495), suggesting a new link between APOE genotype and pre-disposition to AD.

Conclusions

This study demonstrates loss of S1P and sphingosine kinase activity early in AD pathogenesis, and prior to AD diagnosis. Our findings establish a rationale for further exploring S1P receptor pharmacology in the context of AD therapy.

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Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP: The global prevalence of dementia: a systematic review and metaanalysis. Alzheimers Dement 2013, 9: 63–75. e2 10.1016/j.jalz.2012.11.007CrossRefPubMed

Thies W, Bleiler L, Alzheimer's A: Alzheimer's disease facts and figures. Alzheimers Dement 2013, 2013(9):208–245.

Holtzman DM, Morris JC, Goate AM: Alzheimer's disease: the challenge of the second century. Sci Transl Med 2011, 3: 77sr1.PubMedPubMedCentral

DeKosky ST, Scheff SW: Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann Neurol 1990, 27: 457–464. 10.1002/ana.410270502CrossRefPubMed

Scheff SW, Price DA, Schmitt FA, Mufson EJ: Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment. Neurobiol Aging 2006, 27: 1372–1384. 10.1016/j.neurobiolaging.2005.09.012CrossRefPubMed

Braak H, Braak E: Staging of Alzheimer's disease-related neurofibrillary changes. Neurobiol Aging 1995, 16: 271–278. discussion 78–84 10.1016/0197-4580(95)00021-6CrossRefPubMed

Krstic D, Knuesel I: The airbag problem-a potential culprit for bench-to-bedside translational efforts: relevance for Alzheimer's disease. Acta Neuropathol Commun 2013, 1: 62. 10.1186/2051-5960-1-62CrossRefPubMedPubMedCentral

Crews L, Masliah E: Molecular mechanisms of neurodegeneration in Alzheimer's disease. Hum Mol Genet 2010, 19: R12-R20. 10.1093/hmg/ddq160CrossRefPubMedPubMedCentral

Corbett A, Ballard C: New and emerging treatments for Alzheimer's disease. Expert Opin Emerg Drugs 2012, 17: 147–156. 10.1517/14728214.2012.675327CrossRefPubMed

10.

Lane RM, Farlow MR: Lipid homeostasis and apolipoprotein E in the development and progression of Alzheimer's disease. J Lipid Res 2005, 46: 949–968. 10.1194/jlr.M400486-JLR200CrossRefPubMed

11.

Vance JE, Hayashi H: Formation and function of apolipoprotein E-containing lipoproteins in the nervous system. Biochim Biophys Acta 1801, 2010: 806–818.

12.

Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small GW, Roses AD, Haines JL, Pericak-Vance MA: Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993, 261: 921–923. 10.1126/science.8346443CrossRefPubMed

13.

Corder EH, Saunders AM, Risch NJ, Strittmatter WJ, Schmechel DE, Gaskell PC Jr, Rimmler JB, Locke PA, Conneally PM, Schmader KE, et al.: Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet 1994, 7: 180–184. 10.1038/ng0694-180CrossRefPubMed

14.

Harold D, et al.: Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 2009, 41: 1088–1093. 10.1038/ng.440CrossRefPubMedPubMedCentral

15.

Lambert JC, et al.: Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 2009, 41: 1094–1099. 10.1038/ng.439CrossRefPubMed

16.

Hollingworth P, et al.: Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease. Nat Genet 2011, 43: 429–435. 10.1038/ng.803CrossRefPubMedPubMedCentral

17.

Sato K, Malchinkhuu E, Horiuchi Y, Mogi C, Tomura H, Tosaka M, Yoshimoto Y, Kuwabara A, Okajima F: Critical role of ABCA1 transporter in sphingosine 1-phosphate release from astrocytes. J Neurochem 2007, 103: 2610–2619.PubMed

18.

Sato K, Malchinkhuu E, Horiuchi Y, Mogi C, Tomura H, Tosaka M, Yoshimoto Y, Kuwabara A, Okajima F: HDL-like lipoproteins in cerebrospinal fluid affect neural cell activity through lipoprotein-associated sphingosine 1-phosphate. Biochem Biophys Res Commun 2007, 359: 649–654. 10.1016/j.bbrc.2007.05.131CrossRefPubMed

19.

Maceyka M, Harikumar KB, Milstien S, Spiegel S: Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 2012, 22: 50–60. 10.1016/j.tcb.2011.09.003CrossRefPubMed

20.

Choi JW, Chun J: Lysophospholipids and their receptors in the central nervous system. Biochim Biophys Acta 1831, 2013: 20–32.

21.

Mizugishi K, Yamashita T, Olivera A, Miller GF, Spiegel S, Proia RL: Essential role for sphingosine kinases in neural and vascular development. Mol Cell Biol 2005, 25: 11113–11121. 10.1128/MCB.25.24.11113-11121.2005CrossRefPubMedPubMedCentral

22.

Cuvillier O, Pirianov G, Kleuser B, Vanek PG, Coso OA, Gutkind JS, Spiegel S: Suppression of ceramide-mediated programmed cell death by sphingosine-1-phosphate. Nature 1996, 381: 800–803. 10.1038/381800a0CrossRefPubMed

23.

Malaplate-Armand C, Florent-Bechard S, Youssef I, Koziel V, Sponne I, Kriem B, Leininger-Muller B, Olivier JL, Oster T, Pillot T: Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis 2006, 23: 178–189. 10.1016/j.nbd.2006.02.010CrossRefPubMed

24.

Kajimoto T, Okada T, Yu H, Goparaju SK, Jahangeer S, Nakamura S: Involvement of sphingosine-1-phosphate in glutamate secretion in hippocampal neurons. Mol Cell Biol 2007, 27: 3429–3440. 10.1128/MCB.01465-06CrossRefPubMedPubMedCentral

25.

Kanno T, Nishizaki T, Proia RL, Kajimoto T, Jahangeer S, Okada T, Nakamura S: Regulation of synaptic strength by sphingosine 1-phosphate in the hippocampus. Neuroscience 2010, 171: 973–980. 10.1016/j.neuroscience.2010.10.021CrossRefPubMed

26.

Chan JP, Hu Z, Sieburth D: Recruitment of sphingosine kinase to presynaptic terminals by a conserved muscarinic signaling pathway promotes neurotransmitter release. Genes Dev 2012, 26: 1070–1085. 10.1101/gad.188003.112CrossRefPubMedPubMedCentral

27.

Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H: Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 2002, 296: 346–349. 10.1126/science.1070238CrossRefPubMed

28.

Scott LJ: Fingolimod: a review of its use in the management of relapsing-remitting multiple sclerosis. CNS Drugs 2011, 25: 673–698. 10.2165/11207350-000000000-00000CrossRefPubMed

29.

Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR: The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 2002, 277: 21453–21457. 10.1074/jbc.C200176200CrossRefPubMed

30.

Rosen H, Gonzalez-Cabrera P, Marsolais D, Cahalan S, Don AS, Sanna MG: Modulating tone: the overture of S1P receptor immunotherapeutics. Immunol Rev 2008, 223: 221–235. 10.1111/j.1600-065X.2008.00645.xCrossRefPubMed

31.

Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K, Teo ST, Yung YC, Lu M, Kennedy G, Chun J: FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 2011, 108: 751–756. 10.1073/pnas.1014154108CrossRefPubMed

32.

Doi Y, Takeuchi H, Horiuchi H, Hanyu T, Kawanokuchi J, Jin S, Parajuli B, Sonobe Y, Mizuno T, Suzumura A: Fingolimod phosphate attenuates oligomeric amyloid beta-induced neurotoxicity via increased brain-derived neurotrophic factor expression in neurons. PLoS One 2013, 8: e61988. 10.1371/journal.pone.0061988CrossRefPubMedPubMedCentral

33.

Asle-Rousta M, Kolahdooz Z, Oryan S, Ahmadiani A, Dargahi L: FTY720 (fingolimod) attenuates beta-amyloid peptide (Abeta42)-induced impairment of spatial learning and memory in rats. J Mol Neurosci 2013, 50: 524–532. 10.1007/s12031-013-9979-6CrossRefPubMed

34.

Takasugi N, Sasaki T, Ebinuma I, Osawa S, Isshiki H, Takeo K, Tomita T, Iwatsubo T: FTY720/fingolimod, a sphingosine analogue, reduces amyloid-beta production in neurons. PLoS One 2013, 8: e64050. 10.1371/journal.pone.0064050CrossRefPubMedPubMedCentral

35.

He X, Huang Y, Li B, Gong CX, Schuchman EH: Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging 2010, 31: 398–408. 10.1016/j.neurobiolaging.2008.05.010CrossRefPubMed

36.

Harding AJ, Kril JJ, Halliday GM: Practical measures to simplify the Braak tangle staging method for routine pathological screening. Acta Neuropathol 2000, 99: 199–208. 10.1007/PL00007425CrossRefPubMed

37.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS, Nelson PT, Schneider JA, Thal DR, Thies B, Trojanowski JQ, Vinters HV, Montine TJ: National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement 2012, 8: 1–13. 10.1016/j.jalz.2011.10.007CrossRefPubMedPubMedCentral

38.

Bhatia S, Jenner AM, Li H, Ruberu K, Spiro AS, Shepherd CE, Kril JJ, Kain N, Don A, Garner B: Increased apolipoprotein D dimer formation in Alzheimer's disease hippocampus is associated with lipid conjugated diene levels. J Alzheimers Dis 2013, 35: 475–486.PubMed

39.

Wong JWH, Abuhusain HJ, McDonald KL, Don AS: MMSAT: automated quantification of metabolites in selected reaction monitoring experiments. Anal Chem 2012, 84: 470–474. 10.1021/ac2026578CrossRefPubMed

40.

Don AS, Martinez-Lamenca C, Webb WR, Proia RL, Roberts E, Rosen H: Essential requirement for sphingosine kinase 2 in a sphingolipid apoptosis pathway activated by FTY720 analogues. J Biol Chem 2007, 282: 15833–15842. 10.1074/jbc.M609124200CrossRefPubMed

41.

Mechtcheriakova D, Wlachos A, Sobanov J, Bornancin F, Zlabinger G, Baumruker T, Billich A: FTY720-phosphate is dephosphorylated by lipid phosphate phosphatase 3. FEBS Lett 2007, 581: 3063–3068. 10.1016/j.febslet.2007.05.069CrossRefPubMed

42.

Laemmli UK: Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 1970, 227: 680–685. 10.1038/227680a0CrossRefPubMed

43.

Towbin H, Staehelin T, Gordon J: Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A 1979, 76: 4350–4354. 10.1073/pnas.76.9.4350CrossRefPubMedPubMedCentral

44.

Filippov V, Song MA, Zhang K, Vinters HV, Tung S, Kirsch WM, Yang J, Duerksen-Hughes PJ: Increased ceramide in brains with Alzheimer's and other neurodegenerative diseases. J Alzheimers Dis 2012, 29: 537–547.PubMedPubMedCentral

45.

Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP: Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci U S A 2004, 101: 2070–2075. 10.1073/pnas.0305799101CrossRefPubMedPubMedCentral

46.

Liu H, Sugiura M, Nava VE, Edsall LC, Kono K, Poulton S, Milstien S, Kohama T, Spiegel S: Molecular cloning and functional characterization of a novel mammalian sphingosine kinase type 2 isoform. J Biol Chem 2000, 275: 19513–19520. 10.1074/jbc.M002759200CrossRefPubMed

47.

Johnson KR, Johnson KY, Becker KP, Bielawski J, Mao C, Obeid LM: Role of human sphingosine-1-phosphate phosphatase 1 in the regulation of intra- and extracellular sphingosine-1-phosphate levels and cell viability. J Biol Chem 2003, 278: 34541–34547. 10.1074/jbc.M301741200CrossRefPubMed

48.

Ogawa C, Kihara A, Gokoh M, Igarashi Y: Identification and characterization of a novel human sphingosine-1-phosphate phosphohydrolase, hSPP2. J Biol Chem 2003, 278: 1268–1272. 10.1074/jbc.M209514200CrossRefPubMed

49.

Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR: Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 2004, 13: 159–170.CrossRefPubMed

50.

Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L: High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000, 20: 4050–4058.PubMed

51.

Yuyama K, Mitsutake S, Igarashi Y: Pathological roles of ceramide and its metabolites in metabolic syndrome and Alzheimer's disease. Biochim Biophys Acta 2013. in press

52.

Wang G, Dinkins M, He Q, Zhu G, Poirier C, Campbell A, Mayer-Proschel M, Bieberich E: Astrocytes secrete exosomes enriched with proapoptotic ceramide and prostate apoptosis response 4 (PAR-4): potential mechanism of apoptosis induction in Alzheimer disease (AD). J Biol Chem 2012, 287: 21384–21395. 10.1074/jbc.M112.340513CrossRefPubMedPubMedCentral

53.

Han X, MH D, McKeel DW Jr, Kelley J, Morris JC: Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J Neurochem 2002, 82: 809–818. 10.1046/j.1471-4159.2002.00997.xCrossRefPubMed

54.

Xiong Y, Lee HJ, Mariko B, Lu YC, Dannenberg AJ, Haka AS, Maxfield FR, Camerer E, Proia RL, Hla T: Sphingosine kinases are not required for inflammatory responses in macrophages. J Biol Chem 2013, 288: 32563–32573. 10.1074/jbc.M113.483750CrossRefPubMedPubMedCentral

55.

Kharel Y, Raje M, Gao M, Gellett AM, Tomsig JL, Lynch KR, Santos WL: Sphingosine kinase type 2 inhibition elevates circulating sphingosine 1-phosphate. Biochem J 2012, 447: 149–157. 10.1042/BJ20120609CrossRefPubMedPubMedCentral

56.

Fischer I, Alliod C, Martinier N, Newcombe J, Brana C, Pouly S: Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLoS One 2011, 6: e23905. 10.1371/journal.pone.0023905CrossRefPubMedPubMedCentral

57.

Blondeau N, Lai Y, Tyndall S, Popolo M, Topalkara K, Pru JK, Zhang L, Kim H, Liao JK, Ding K, Waeber C: Distribution of sphingosine kinase activity and mRNA in rodent brain. J Neurochem 2007, 103: 509–517. 10.1111/j.1471-4159.2007.04755.xCrossRefPubMedPubMedCentral

58.

Allende ML, Sasaki T, Kawai H, Olivera A, Mi Y, van Echten-Deckert G, Hajdu R, Rosenbach M, Keohane CA, Mandala S, Spiegel S, Proia RL: Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720. J Biol Chem 2004, 279: 52487–52492. 10.1074/jbc.M406512200CrossRefPubMed

59.

Takasugi N, Sasaki T, Suzuki K, Osawa S, Isshiki H, Hori Y, Shimada N, Higo T, Yokoshima S, Fukuyama T, Lee VM, Trojanowski JQ, Tomita T, Iwatsubo T: BACE1 activity is modulated by cell-associated sphingosine-1-phosphate. J Neurosci 2011, 31: 6850–6857. 10.1523/JNEUROSCI.6467-10.2011CrossRefPubMedPubMedCentral

60.

Theilmeier G, Schmidt C, Herrmann J, Keul P, Schafers M, Herrgott I, Mersmann J, Larmann J, Hermann S, Stypmann J, Schober O, Hildebrand R, Schulz R, Heusch G, Haude M, von Wnuck Lipinski K, Herzog C, Schmitz M, Erbel R, Chun J, Levkau B: High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation 2006, 114: 1403–1409. 10.1161/CIRCULATIONAHA.105.607135CrossRefPubMed

Title: Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer’s disease pathogenesis
Authors: Timothy A Couttas
Nupur Kain
Benjamin Daniels
Xin Ying Lim
Claire Shepherd
Jillian Kril
Russell Pickford
Hongyun Li
Brett Garner
Anthony S Don
Publication date: 01-12-2014
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2014
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/2051-5960-2-9

At a glance: The STEP trials

Springer Medicine

Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer’s disease pathogenesis

Abstract

Background

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Results

Conclusions

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