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Sphingolipid metabolism correlates with cerebrospinal fluid Beta amyloid levels in Alzheimer's disease.

Authors: Alfred N Fonteh|||Cora Ormseth|||Jiarong Chiang|||Matthew Cipolla|||Xianghong Arakaki|||Michael G Harrington

Journal: PloS one

Publication Type: Journal Article

Date: 2015

DOI: PMC4418746

ID: 25938590

Affiliations:

Affiliations

    Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.|||Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.|||Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.|||Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.|||Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.|||Molecular Neurology Program, Huntington Medical Research Institutes, 99 N El Molino Ave, Pasadena, California, United Sates of America.

Abstract

Sphingolipids are important in many brain functions but their role in Alzheimer's disease (AD) is not completely defined. A major limit is availability of fresh brain tissue with defined AD pathology. The discovery that cerebrospinal fluid (CSF) contains abundant nanoparticles that include synaptic vesicles and large dense core vesicles offer an accessible sample to study these organelles, while the supernatant fluid allows study of brain interstitial metabolism. Our objective was to characterize sphingolipids in nanoparticles representative of membrane vesicle metabolism, and in supernatant fluid representative of interstitial metabolism from study participants with varying levels of cognitive dysfunction. We recently described the recruitment, diagnosis, and CSF collection from cognitively normal or impaired study participants. Using liquid chromatography tandem mass spectrometry, we report that cognitively normal participants had measureable levels of sphingomyelin, ceramide, and dihydroceramide species, but that their distribution differed between nanoparticles and supernatant fluid, and further differed in those with cognitive impairment. In CSF from AD compared with cognitively normal participants: a) total sphingomyelin levels were lower in nanoparticles and supernatant fluid; b) levels of ceramide species were lower in nanoparticles and higher in supernatant fluid; c) three sphingomyelin species were reduced in the nanoparticle fraction. Moreover, three sphingomyelin species in the nanoparticle fraction were lower in mild cognitive impairment compared with cognitively normal participants. The activity of acid, but not neutral sphingomyelinase was significantly reduced in the CSF from AD participants. The reduction in acid sphingomylinase in CSF from AD participants was independent of depression and psychotropic medications. Acid sphingomyelinase activity positively correlated with amyloid β42 concentration in CSF from cognitively normal but not impaired participants. In dementia, altered sphingolipid metabolism, decreased acid sphingomyelinase activity and its lost association with CSF amyloid β42 concentration, underscores the potential of sphingolipids as disease biomarkers, and acid sphingomyelinase as a target for AD diagnosis and/or treatment.


Chemical List

    Amyloid beta-Peptides|||Apolipoproteins E|||Biomarkers|||Sphingolipids|||tau Proteins|||Sphingomyelin Phosphodiesterase

Reference List

    Thies W, Bleiler L (2013) Alzheimer's disease facts and figures. Alzheimers Dement 9: 208–245. 10.1016/j.jalz.2013.02.003|||Takizawa C, Thompson PL, van WA, Faure C, Maier WC (2014) Epidemiological and Economic Burden of Alzheimer's Disease: A Systematic Literature Review of Data across Europe and the United States of America. J Alzheimers Dis. Pii: 9725561206716310. 10.3233/JAD-141134|||Braak H, Alafuzoff I, Arzberger T, Kretzschmar H, Del TK (2006) Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry. Acta Neuropathol 112: 389–404.|||Bazan NG, Molina MF, Gordon WC (2011) Docosahexaenoic acid signalolipidomics in nutrition: significance in aging, neuroinflammation, macular degeneration, Alzheimer's, and other neurodegenerative diseases. Annu Rev Nutr 31: 321–351. 10.1146/annurev.nutr.012809.104635|||Piomelli D, Astarita G, Rapaka R (2007) A neuroscientist's guide to lipidomics. Nat Rev Neurosci 8: 743–754.|||Fonteh AN, Harrington RJ, Huhmer AF, Biringer RG, Riggins JN, Harrington MG (2006) Identification of disease markers in human cerebrospinal fluid using lipidomic and proteomic methods. Dis Markers 22: 39–64.|||Pettus BJ, Chalfant CE, Hannun YA (2004) Sphingolipids in inflammation: roles and implications. Curr Mol Med 4: 405–418.|||Shimizu T (2009) Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu Rev Pharmacol Toxicol 49: 123–150. 10.1146/annurev.pharmtox.011008.145616|||Bazan NG (2005) Synaptic signaling by lipids in the life and death of neurons. Mol Neurobiol 31: 219–230.|||Farooqui AA, Horrocks LA (2001) Plasmalogens: workhorse lipids of membranes in normal and injured neurons and glia. Neuroscientist 7: 232–245.|||Fahy E, Subramaniam S, Brown HA, Glass CK, Merrill AH Jr, Murphy RC, et al. (2005) A comprehensive classification system for lipids. J Lipid Res 46: 839–861.|||Chan RB, Oliveira TG, Cortes EP, Honig LS, Duff KE, Small SA, et al. (2012) Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J Biol Chem 287: 2678–2688. 10.1074/jbc.M111.274142|||Muhle C, Reichel M, Gulbins E, Kornhuber J (2013) Sphingolipids in psychiatric disorders and pain syndromes. Handb Exp Pharmacol 431–456. 10.1007/978-3-7091-1511-4_22|||Jenkins RW, Canals D, Hannun YA (2009) Roles and regulation of secretory and lysosomal acid sphingomyelinase. Cell Signal 21: 836–846.|||Marchesini N, Hannun YA (2004) Acid and neutral sphingomyelinases: roles and mechanisms of regulation. Biochem Cell Biol 82: 27–44.|||Jenkins RW, Idkowiak-Baldys J, Simbari F, Canals D, Roddy P, Riner CD, et al. (2011) A novel mechanism of lysosomal acid sphingomyelinase maturation: requirement for carboxyl-terminal proteolytic processing. J Biol Chem 286: 3777–3788. 10.1074/jbc.M110.155234|||Adibhatla RM, Hatcher JF (2008) Altered lipid metabolism in brain injury and disorders. Subcell Biochem 49: 241–268. 10.1007/978-1-4020-8831-5_9|||Bartke N, Hannun YA (2009) Bioactive sphingolipids: metabolism and function. J Lipid Res 50 Suppl: S91–S96. 10.1194/jlr.R800080-JLR200|||Hannun YA, Obeid LM (1995) Ceramide: an intracellular signal for apoptosis. Trends Biochem Sci 20: 73–77.|||Alessenko AV, Bugrova AE, Dudnik LB (2004) Connection of lipid peroxide oxidation with the sphingomyelin pathway in the development of Alzheimer's disease. Biochem Soc Trans 32: 144–146.|||Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, et al. (2004) 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 101: 2070–2075.|||Wang G, Dinkins M, He Q, Zhu G, Poirier C, Campbell A, et al. (2012) 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 287: 21384–21395. 10.1074/jbc.M112.340513|||Zhang H, Ding J, Tian W, Wang L, Huang L, Ruan Y, et al. (2009) Ganglioside GM1 binding the N-terminus of amyloid precursor protein. Neurobiol Aging 30: 1245–1253.|||Martin V, Fabelo N, Santpere G, Puig B, Marin R, Ferrer I, et al. (2010) Lipid alterations in lipid rafts from Alzheimer's disease human brain cortex. J Alzheimers Dis 19: 489–502. pii: F38201J2N5132MRX. 10.3233/JAD-2010-1242|||Yu RK, Tsai YT, Ariga T (2012) Functional roles of gangliosides in neurodevelopment: an overview of recent advances. Neurochem Res 37: 1230–1244. 10.1007/s11064-012-0744-y|||Young MM, Kester M, Wang HG (2013) Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res 54: 5–19 10.1194/jlr.R031278|||Babenko NA, Shakhova EG (2014) Long-term food restriction prevents aging-associated sphingolipid turnover dysregulation in the brain. Arch Gerontol Geriatr 58: 420–426. 10.1016/j.archger.2013.12.005|||Mielke MM, Bandaru VV, McArthur JC, Chu M, Haughey NJ (2010) Disturbance in cerebral spinal fluid sphingolipid content is associated with memory impairment in subjects infected with the human immunodeficiency virus. J Neurovirol 16: 445–456. 10.3109/13550284.2010.525599|||Satoi H, Tomimoto H, Ohtani R, Kitano T, Kondo T, Watanabe M, et al. (2005) Astroglial expression of ceramide in Alzheimer's disease brains: a role during neuronal apoptosis. Neuroscience 130: 657–666.|||Kosicek M, Kirsch S, Bene R, Trkanjec Z, Titlic M, Bindila L, et al. (2010) Nano-HPLC-MS analysis of phospholipids in cerebrospinal fluid of Alzheimer's disease patients-a pilot study. Anal Bioanal Chem 398: 2929–2937. 10.1007/s00216-010-4273-8|||Kosicek M, Zetterberg H, Andreasen N, Peter-Katalinic J, Hecimovic S (2012) Elevated cerebrospinal fluid sphingomyelin levels in prodromal Alzheimer's disease. Neurosci Lett 516: 302–305. 10.1016/j.neulet.2012.04.019|||Mielke MM, Haughey NJ, Bandaru VV, Zetterberg H, Blennow K, Andreasson U, et al. (2014) Cerebrospinal fluid sphingolipids, beta-amyloid, and tau in adults at risk for Alzheimer’s disease. Neurobiol Aging 35: 2486–2494. 10.1016/j.neurobiolaging.2014.05.019|||Harrington MG, Fonteh AN, Oborina E, Liao P, Cowan RP, McComb G, et al. (2009) The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid. Cerebrospinal Fluid Res 6: 10 pii: 1743-8454-6-10. 10.1186/1743-8454-6-10|||Berg L, Miller JP, Storandt M, Duchek J, Morris JC, Rubin EH, et al. (1988) Mild senile dementia of the Alzheimer type: 2. Longitudinal assessment. Ann Neurol 23: 477–484.|||Harrington MG, Chiang J, Pogoda JM, Gomez M, Thomas K, Marion SD, et al. (2013) Executive function changes before memory in preclinical Alzheimer's pathology: a prospective, cross-sectional, case control study. PLoS One 8: e79378 pii: PONE-D-13-28931. 10.1371/journal.pone.0079378|||Petersen RC, Aisen P, Boeve BF, Geda YE, Ivnik RJ, Knopman DS, et al. (2013) Criteria for mild cognitive impairment due to alzheimer's disease in the community. Ann Neurol. 10.1002/ana.23931|||McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR Jr, Kawas CH, et al. (2011) The diagnosis of dementia due to Alzheimer's disease: recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease. Alzheimers Dement 7: 263–269. 10.1016/j.jalz.2011.03.005|||Morris JC (1996) Classification of dementia and Alzheimer's disease. Acta Neurol Scand Suppl 165: 41–50.|||Saunders AM, Strittmatter WJ, Schmechel D, George-Hyslop PH, Pericak-Vance MA, Joo SH, et al. (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer's disease. Neurology 43: 1467–1472.|||Bligh EG, Dyer WJ (1959) A rapid method of total lipid extraction and purification. Can J Biochem Physiol 37: 911–917.|||Fonteh AN, Chiang J, Cipolla M, Hale J, Diallo F, Chirino A, et al. (2013) Alterations in cerebrospinal fluid glycerophospholipids and phospholipase A2 activity in Alzheimer's disease. J Lipid Res 54: 2884–2897. 10.1194/jlr.M037622|||Shaner RL, Allegood JC, Park H, Wang E, Kelly S, Haynes CA, et al. (2009) Quantitative analysis of sphingolipids for lipidomics using triple quadrupole and quadrupole linear ion trap mass spectrometers. J Lipid Res 50: 1692–1707. 10.1194/jlr.D800051-JLR200|||Roe CM, Fagan AM, Grant EA, Marcus DS, Benzinger TL, Mintun MA, et al.(2011) Cerebrospinal fluid biomarkers, education, brain volume, and future cognition. Arch Neurol 68: 1145–1151. 10.1001/archneurol.2011.192|||Shaner RL, Allegood JC, Park H, Wang E, Kelly S, Haynes CA, et al. (2009) Quantitative analysis of sphingolipids for lipidomics using triple quadrupole and quadrupole linear ion trap mass spectrometers. J Lipid Res 50: 1692–1707. 10.1194/jlr.D800051-JLR200|||Malaplate-Armand C, Florent-Bechard S, Youssef I, Koziel V, Sponne I, Kriem B, et al. (2006) Soluble oligomers of amyloid-beta peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol Dis 23: 178–189.|||Muller CP, Reichel M, Muhle C, Rhein C, Gulbins E, Kornhuber J (2014) Brain membrane lipids in major depression and anxiety disorders. Biochim Biophys Acta. pii: S1388-1981(14)00266-2. 10.1016/j.bbalip.2014.12.014|||Kornhuber J, Medlin A, Bleich S, Jendrossek V, Henkel AW, Wiltfang J, et al. (2005) High activity of acid sphingomyelinase in major depression. J Neural Transm 112: 1583–1590.|||Hannun YA, Obeid LM (2011) Many ceramides. J Biol Chem 286: 27855–27862. 10.1074/jbc.R111.254359|||Katsel P, Li C, Haroutunian V (2007) Gene expression alterations in the sphingolipid metabolism pathways during progression of dementia and Alzheimer's disease: a shift toward ceramide accumulation at the earliest recognizable stages of Alzheimer's disease? Neurochem Res 32: 845–856.|||Cowart LA, Okamoto Y, Pinto FR, Gandy JL, Almeida JS, Hannun YA (2003) Roles for sphingolipid biosynthesis in mediation of specific programs of the heat stress response determined through gene expression profiling. J Biol Chem 278: 30328–30338.|||Han X, Holtzman M, McKeel DW Jr, Kelley J, Morris JC (2002) Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer's disease: potential role in disease pathogenesis. J Neurochem 82(4): 809–818.|||Mielke MM, Lyketsos CG (2010) Alterations of the sphingolipid pathway in Alzheimer's disease: new biomarkers and treatment targets? Neuromolecular Med 12: 331–340. 10.1007/s12017-010-8121-y|||Haughey NJ, Bandaru VV, Bae M, Mattson MP (2010) Roles for dysfunctional sphingolipid metabolism in Alzheimer's disease neuropathogenesis. Biochim Biophys Acta 1801: 878–886. 10.1016/j.bbalip.2010.05.003|||Tamboli IY, Hampel H, Tien NT, Tolksdorf K, Breiden B, Mathews PM, et al. (2011) Sphingolipid storage affects autophagic metabolism of the amyloid precursor protein and promotes Abeta generation. J Neurosci 31: 1837–1849. 10.1523/JNEUROSCI.2954-10.2011|||van Echten-Deckert G, Walter J (2012) Sphingolipids: critical players in Alzheimer's disease. Prog Lipid Res 51: 378–393. 10.1016/j.plipres.2012.07.001|||Han X (2007) Potential mechanisms contributing to sulfatide depletion at the earliest clinically recognizable stage of Alzheimer's disease: a tale of shotgun lipidomics. J Neurochem 103 Suppl 1: 171–179.|||Yuyama K, Sun H, Mitsutake S, Igarashi Y (2012) Sphingolipid-modulated exosome secretion promotes clearance of amyloid-beta by microglia. J Biol Chem 287: 10977–10989. 10.1074/jbc.M111.324616|||Mencarelli C, Martinez-Martinez P (2013) Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 70: 181–203. 10.1007/s00018-012-1038-x|||Chen SD, Yin JH, Hwang CS, Tang CM, Yang DI (2012) Anti-apoptotic and anti-oxidative mechanisms of minocycline against sphingomyelinase/ceramide neurotoxicity: implication in Alzheimer's disease and cerebral ischemia. Free Radic Res 46: 940–950. 10.3109/10715762.2012.674640|||Clarke CJ, Hannun YA (2006) Neutral sphingomyelinases and nSMase2: bridging the gaps. Biochim Biophys Acta 1758: 1893–1901.|||Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, et al. (2011) Identification of novel functional inhibitors of acid sphingomyelinase. PLoS One 6: e23852 pii: PONE-D-11-09881. 10.1371/journal.pone.0023852|||Kornhuber J, Muller CP, Becker KA, Reichel M, Gulbins E (2014) The ceramide system as a novel antidepressant target. Trends Pharmacol Sci 35: 293–304. 10.1016/j.tips.2014.04.003|||Hsiao JH, Fu Y, Hill AF, Halliday GM, Kim WS (2013) Elevation in sphingomyelin synthase activity is associated with increases in amyloid-beta peptide generation. PLoS One 8: e74016 pii: PONE-D-13-17775. 10.1371/journal.pone.0074016|||Subathra M, Qureshi A, Luberto C (2011) Sphingomyelin synthases regulate protein trafficking and secretion. PLoS One 6: e23644 pii: PONE-D-10-02888. 10.1371/journal.pone.0023644|||Idkowiak-Baldys J, Apraiz A, Li L, Rahmaniyan M, Clarke CJ, Kraveka JM, et al. (2010) Dihydroceramide desaturase activity is modulated by oxidative stress. Biochem J 427: 265–274. 10.1042/BJ20091589|||Tam C, Idone V, Devlin C, Fernandes MC, Flannery A, He X, et al. (2010) Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis and plasma membrane repair. J Cell Biol 189: 1027–1038. 10.1083/jcb.201003053|||Gabande-Rodriguez E, Boya P, Labrador V, Dotti CG, Ledesma MD (2014) High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A. Cell Death Differ. pii: cdd20144. 10.1038/cdd.2014.4|||Li X, Gulbins E, Zhang Y (2012) Oxidative stress triggers Ca-dependent lysosome trafficking and activation of acid sphingomyelinase. Cell Physiol Biochem 30: 815–826. 10.1159/000341460|||Herz J, Pardo J, Kashkar H, Schramm M, Kuzmenkina E, Bos E, et al. (2009) Acid sphingomyelinase is a key regulator of cytotoxic granule secretion by primary T lymphocytes. Nat Immunol 10: 761–768. 10.1038/ni.1757|||Rohrbough J, Rushton E, Palanker L, Woodruff E, Matthies HJ, Acharya U, et al. (2004) Ceramidase regulates synaptic vesicle exocytosis and trafficking. J Neurosci 24: 7789–7803. 1|||Ma MT, Yeo JF, Farooqui AA, Zhang J, Chen P, Ong WY (2010) Differential effects of lysophospholipids on exocytosis in rat PC12 cells. J Neural Transm 117: 301–308. 10.1007/s00702-009-0355-1|||Wei S, Ong WY, Thwin MM, Fong CW, Farooqui AA, Gopalakrishnakone P, et al. (2003) Group IIA secretory phospholipase A2 stimulates exocytosis and neurotransmitter release in pheochromocytoma-12 cells and cultured rat hippocampal neurons. Neuroscience 121: 891–898.|||Juhl K, Hoy M, Olsen HL, Bokvist K, Efanov AM, Hoffmann EK, et al. (2003) cPLA2alpha-evoked formation of arachidonic acid and lysophospholipids is required for exocytosis in mouse pancreatic beta-cells. Am J Physiol Endocrinol Metab 285: E73–E81.|||Galvan C, Camoletto PG, Cristofani F, Van Veldhoven PP, Ledesma MD (2008) Anomalous surface distribution of glycosyl phosphatidyl inositol-anchored proteins in neurons lacking acid sphingomyelinase. Mol Biol Cell 19: 509–522.|||He X, Huang Y, Li B, Gong CX, Schuchman EH (2010) Deregulation of sphingolipid metabolism in Alzheimer's disease. Neurobiol Aging 31: 398–408. 10.1016/j.neurobiolaging.2008.05.010|||Li X, Xu M, Pitzer AL, Xia M, Boini KM, Li PL, et al. (2014) Control of autophagy maturation by acid sphingomyelinase in mouse coronary arterial smooth muscle cells: protective role in atherosclerosis. J Mol Med (Berl). 10.1007/s00109-014-1120-y|||Fiala JC (2007) Mechanisms of amyloid plaque pathogenesis. Acta Neuropathol 114: 551–571.|||Sagare AP, Bell RD, Zhao Z, Ma Q, Winkler EA, Ramanathan A, et al. (2013) Pericyte loss influences Alzheimer-like neurodegeneration in mice. Nat Commun 4: 2932 pii: ncomms3932. 10.1038/ncomms3932|||Young MM, Kester M, Wang HG (2013) Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res 54: 5–19. 10.1194/jlr.R031278|||Fagan AM, Shaw LM, Xiong C, Vanderstichele H, Mintun MA, Trojanowski JQ, et al. (2011) Comparison of analytical platforms for cerebrospinal fluid measures of beta-amyloid 1–42, total tau, and p-tau181 for identifying Alzheimer disease amyloid plaque pathology. Arch Neurol 68: 1137–1144. 10.1001/archneurol.2011.105|||Leventhal AR, Chen W, Tall AR, Tabas I (2001) Acid sphingomyelinase-deficient macrophages have defective cholesterol trafficking and efflux. J Biol Chem 276: 44976–44983.|||Dodge JC, Clarke J, Treleaven CM, Taksir TV, Griffiths DA, Yang W, et al. (2009) Intracerebroventricular infusion of acid sphingomyelinase corrects CNS manifestations in a mouse model of Niemann-Pick A disease. Exp Neurol 215: 349–357. 10.1016/j.expneurol.2008.10.021