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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?

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Abstract

There is mounting evidence linking Aβ42 generation in Alzheimer’s disease (AD) with sphingomyelin catabolism. Using microarray technology to study 17 brain regions from subjects with varying severity of AD and dementia we detected multiple gene expression abnormalities of the key enzymes that control sphingolipid metabolism. These changes were correlated with the progression of clinical dementia. The upregulation of gene expression of the enzymes controlling synthesis de novo of Cer and the downregulation of the enzymes involved in glycosphingolipid synthesis was evident as early in disease progression as in mild dementia. Together these changes suggest a shift in sphingolipid metabolism towards accumulation of Cer, depletion of glycosphingolipids and the reduction of synthesis of the anti-apoptosis signaling lipid—sphingosine 1-phosphate as a function of disease progression. This disrupted balance within the sphingolipid metabolism may trigger signaling events promoting neurodegeneration across cortical regions. This potential mechanism may provide a link between lipid metabolism disturbance and AD.

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References

  1. Glenner GG, Wong CW (1984) Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 120(3):885–890

    Article  PubMed  CAS  Google Scholar 

  2. Grundke-Iqbal I, Iqbal K, Tung YC et al (1986) Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 83(13):4913–4917

    Article  PubMed  CAS  Google Scholar 

  3. Davies P, Maloney AJ (1976) Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet 2(8000):1403

    Article  PubMed  CAS  Google Scholar 

  4. Hirai K, Aliev G, Nunomura A et al (2001) Mitochondrial abnormalities in Alzheimer’s disease. J Neurosci 21(9):3017–3023

    PubMed  CAS  Google Scholar 

  5. Landfield PW, Thibault O, Mazzanti ML et al (1992) Mechanisms of neuronal death in brain aging and Alzheimer’s disease: role of endocrine-mediated calcium dyshomeostasis. J Neurobiol 23(9):1247–1260

    Article  PubMed  CAS  Google Scholar 

  6. McGeer PL, Itagaki S, Boyes BE, McGeer EG (1988) Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson’s and Alzheimer’s disease brains. Neurology 38(8):1285–1291

    PubMed  CAS  Google Scholar 

  7. Arendt T, Bruckner MK, Bigl V, Marcova L (1995) Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer’s disease. II. Ageing, Korsakoff’s disease, Parkinson’s disease, and Alzheimer’s disease. J Comp Neurol 351(2):189–222

    Article  PubMed  CAS  Google Scholar 

  8. Saunders AM, Strittmatter WJ, Schmechel DE et al (1993) Association of apolipoprotein E allele epsilon 4 with late-onset familial and sporadic Alzheimer’s Disease. Neurology 43:1467–1472

    PubMed  CAS  Google Scholar 

  9. Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s Disease in late onset families. Science 261:921–923

    Article  PubMed  CAS  Google Scholar 

  10. Nassar BA, Dunn J, Title LM et al (1999) Relation of genetic polymorphisms of apolipoprotein E, angiotensin converting enzyme, apolipoprotein B-100, and glycoprotein IIIa and early-onset coronary heart disease. Clin Biochem 32(4):275–282

    Article  PubMed  CAS  Google Scholar 

  11. Holopainen JM, Medina OP, Metso AJ, Kinnunen PK (2000) Sphingomyelinase activity associated with human plasma low density lipoprotein. J Biol Chem 275(22):16484–16489

    Article  PubMed  CAS  Google Scholar 

  12. Ruvolo PP (2003) Intracellular signal transduction pathways activated by ceramide and its metabolites. Pharmacol Res 47(5):383–392

    Article  PubMed  CAS  Google Scholar 

  13. Hannun YA (1994) The sphingomyelin cycle and the second messenger function of ceramide. J Biol Chem 269(5):3125–3128

    PubMed  CAS  Google Scholar 

  14. Kurinna SM, Tsao CC, Nica AF et al (2004) Ceramide promotes apoptosis in lung cancer-derived A549 cells by a mechanism involving c-Jun NH2-terminal kinase. Cancer Res 64(21):7852–7856

    Article  PubMed  CAS  Google Scholar 

  15. Halliwell B (1989) Oxidants and the central nervous system: some fundamental questions. Is oxidant damage relevant to Parkinson’s disease, Alzheimer’s disease, traumatic injury or stroke? Acta Neurol Scand Suppl 126:23–33

    PubMed  CAS  Google Scholar 

  16. Binder LI, Guillozet-Bongaarts AL, Garcia-Sierra F, Berry RW (2005) Tau, tangles, and Alzheimer’s disease. Biochim Biophys Acta 1739(2–3):216–223

    PubMed  CAS  Google Scholar 

  17. Gamblin TC, Chen F, Zambrano A et al (2003) Caspase cleavage of tau: linking amyloid and neurofibrillary tangles in Alzheimer’s disease. Proc Natl Acad Sci USA 100(17):10032–10037

    Article  PubMed  CAS  Google Scholar 

  18. Butterfield DA, Griffin S, Munch G, Pasinetti GM (2002) Amyloid beta-peptide and amyloid pathology are central to the oxidative stress and inflammatory cascades under which Alzheimer’s disease brain exists. J Alzheimers Dis 4(3):193–201

    PubMed  CAS  Google Scholar 

  19. Pompl PN, Yemul S, Xiang Z et al (2003) Caspase gene expression in the brain as a function of the clinical progression of Alzheimer disease. Arch Neurol 60(3):369–376

    Article  PubMed  Google Scholar 

  20. Ross R (1993) The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362(6423):801–809

    Article  PubMed  CAS  Google Scholar 

  21. Schissel SL, Tweedie-Hardman J, Rapp JH et al (1996) Rabbit aorta and human atherosclerotic lesions hydrolyze the sphingomyelin of retained low-density lipoprotein. Proposed role for arterial-wall sphingomyelinase in subendothelial retention and aggregation of atherogenic lipoproteins. J Clin Invest 98(6):1455–1464

    Article  PubMed  CAS  Google Scholar 

  22. Jiang XC, Paultre F, Pearson TA et al (2000) Plasma sphingomyelin level as a risk factor for coronary artery disease. Arterioscler Thromb Vasc Biol 20(12):2614–2618

    PubMed  CAS  Google Scholar 

  23. Schlitt A, Blankenberg S, Yan D et al (2006) Further evaluation of plasma sphingomyelin levels as a risk factor for coronary artery disease. Nutr Metab (Lond) 3:5

    Article  CAS  Google Scholar 

  24. Han X, Holtzman DM, McKeel DW Jr et al (2002) Substantial sulfatide deficiency and ceramide elevation in very early Alzheimer’s disease: potential role in disease pathogenesis. J Neurochem 82(4):809–818

    Article  PubMed  CAS  Google Scholar 

  25. Satoi H, Tomimoto H, Ohtani R et al (2005) Astroglial expression of ceramide in Alzheimer’s disease brains: a role during neuronal apoptosis. Neuroscience 130(3):657–666

    Article  PubMed  CAS  Google Scholar 

  26. Cutler RG, Kelly J, Storie 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 USA 101(7):2070–2075

    Article  PubMed  CAS  Google Scholar 

  27. Beeri MS, Rapp M, Silverman JM et al (2006) Coronary artery disease is associated with Alzheimer’s disease neuropathology in APOE 4 carriers. Neurology 66(9):1399–1404

    Article  PubMed  CAS  Google Scholar 

  28. Costantini C, Scrable H, Puglielli L (2006) An aging pathway controls the TrkA to p75NTR receptor switch and amyloid beta-peptide generation. EMBO J 25(9):1997–2006

    Article  PubMed  CAS  Google Scholar 

  29. Puglielli L, Ellis BC, Saunders AJ, Kovacs DM (2003) Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis. J Biol Chem 278(22):19777–19783

    Article  PubMed  CAS  Google Scholar 

  30. Grimm MO, Grimm HS, Patzold AJ et al (2005) Regulation of cholesterol and sphingomyelin metabolism by amyloid-beta and presenilin. Nat Cell Biol 7(11):1118–1123

    Article  PubMed  CAS  Google Scholar 

  31. Tamboli IY, Prager K, Barth E et al (2005) Inhibition of glycosphingolipid biosynthesis reduces secretion of the beta amyloid precursor protein and amyloid beta peptide. J Biol Chem 280:28110–28117

    Article  PubMed  CAS  Google Scholar 

  32. Jana A, Pahan K (2004) Fibrillar amyloid-beta peptides kill human primary neurons via NADPH oxidase-mediated activation of neutral sphingomyelinase. Implications for Alzheimer’s disease. J Biol Chem 279(49):51451–51459

    Article  PubMed  CAS  Google Scholar 

  33. Zeng C, Lee JT, Chen H et al (2005) Amyloid-beta peptide enhances tumor necrosis factor-alpha-induced NOS through neutral sphingomyelinase/ceramide pathway in oligodendrocytes. J Neurochem 94(3):703–712

    Article  PubMed  CAS  Google Scholar 

  34. Chen S, Lee JM, Zeng C et al (2006) Amyloid beta peptide increases DP5 expression via activation of neutral sphingomyelinase and JNK in oligodendrocytes. J Neurochem 97(3):631–640

    Article  PubMed  CAS  Google Scholar 

  35. Lee JT, Xu J, Lee JM et al (2004) Amyloid-beta peptide induces oligodendrocyte death by activating the neutral sphingomyelinase-ceramide pathway. J Cell Biol 164(1):123–131

    Article  PubMed  CAS  Google Scholar 

  36. Tomiuk S, Hofmann K, Nix M et al (1998) Cloned mammalian neutral sphingomyelinase: functions in sphingolipid signaling?. Proc Natl Acad Sci USA 95(7):3638–3643

    Article  PubMed  CAS  Google Scholar 

  37. Okazaki T, Bielawska A, Domae N et al (1994) Characteristics and partial purification of a novel cytosolic, magnesium-independent, neutral sphingomyelinase activated in the early signal transduction of 1 alpha,25-dihydroxyvitamin D3-induced HL-60 cell differentiation. J Biol Chem 269(6):4070–4077

    PubMed  CAS  Google Scholar 

  38. Haroutunian V, Perl DP, Purohit DP et al (1998) Regional distribution of neuritic plaques in the nondemented elderly and subjects with very mild Alzheimer disease. Arch Neurol 55(9):1185–1191

    Article  PubMed  CAS  Google Scholar 

  39. Haroutunian V, Purohit DP, Perl DP et al (1999) Neurofibrillary tangles in nondemented elderly subjects and mild Alzheimer disease. Arch Neurol 56(6):713–718

    Article  PubMed  CAS  Google Scholar 

  40. Naslund J, Haroutunian V, Mohs R et al (2000) Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 283(12):1571–1577

    Article  PubMed  CAS  Google Scholar 

  41. Mirra SS, Heyman A, McKeel D et al (1991) The Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). Part II. Standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41:479–486

    PubMed  CAS  Google Scholar 

  42. Katsel P, Davis KL, Gorman JM, Haroutunian V (2005) Variations in differential gene expression patterns across multiple brain regions in schizophrenia. Schizo Res 79(2–3):157–173

    Article  Google Scholar 

  43. Katsel P, Davis KL, Gorman JM, Haroutunian V (2005) Variations in myelin and oligodendrocyte-related gene expression across multiple brain regions: a gene ontology study. Schizo Res 17(2–3):241–252

    Article  Google Scholar 

  44. Braak H, Braak E (1995) Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging 16(3):271–278

    Article  PubMed  CAS  Google Scholar 

  45. Morris JC (1993) The clinical dementia rating (CDR): current version and scoring rules. Neurology 43:2412–2414

    PubMed  CAS  Google Scholar 

  46. Budhraja V, Spitznagel E, Schaiff WT, Sadovsky Y (2003) Incorporation of gene-specific variability improves expression analysis using high-density DNA microarrays. BMC Biol 1(1):1

    Article  PubMed  Google Scholar 

  47. Mariani TJ, Budhraja V, Mecham BH et al (2003) A variable fold change threshold determines significance for expression microarrays. FASEB J 17(2):321–323

    PubMed  CAS  Google Scholar 

  48. Pavlidis P, Weston J, Cai J, Noble WS (2002) Learning gene functional classifications from multiple data types. J Comput Biol 9(2):401–411

    Article  PubMed  CAS  Google Scholar 

  49. Pavlidis P, Qin J, Arango V et al (2004) Using the gene ontology for microarray data mining: a comparison of methods and application to age effects in human prefrontal cortex. Neurochem Res 29(6):1213–1222

    Article  PubMed  CAS  Google Scholar 

  50. Yamaoka S, Miyaji M, Kitano T et al (2004) Expression cloning of a human cDNA restoring sphingomyelin synthesis and cell growth in sphingomyelin synthase-defective lymphoid cells. J Biol Chem 279(18):18688–18693

    Article  PubMed  CAS  Google Scholar 

  51. Huitema K, van den Dikkenberg J, Brouwers JF, Holthuis JC (2004) Identification of a family of animal sphingomyelin synthases. EMBO J 23(1):33–44

    Article  PubMed  CAS  Google Scholar 

  52. Kai M, Wada I, Imai S et al (1997) Cloning and characterization of two human isozymes of Mg2+-independent phosphatidic acid phosphatase. J Biol Chem 272(39):24572–24578

    Article  PubMed  CAS  Google Scholar 

  53. Mizutani Y, Kihara A, Igarashi Y (2005) Mammalian Lass6 and its related family members regulate synthesis of specific ceramides. Biochem J 390(Pt 1):263–271

    PubMed  CAS  Google Scholar 

  54. Mizutani Y, Kihara A, Igarashi Y (2006) LASS3 (longevity assurance homologue 3) is a mainly testis-specific (dihydro)ceramide synthase with relatively broad substrate specificity. Biochem J 398(3):531–538

    Article  PubMed  CAS  Google Scholar 

  55. Riebeling C, Allegood JC, Wang E et al (2003) Two mammalian longevity assurance gene (LAG1) family members, trh1 and trh4, regulate dihydroceramide synthesis using different fatty acyl-CoA donors. J Biol Chem 278(44):43452–43459

    Article  PubMed  CAS  Google Scholar 

  56. Venkataraman K, Riebeling C, Bodennec J et al (2002) Upstream of growth and differentiation factor 1 (uog1), a mammalian homolog of the yeast longevity assurance gene 1 (LAG1), regulates N-stearoyl-sphinganine (C18-(dihydro)ceramide) synthesis in a fumonisin B1-independent manner in mammalian cells. J Biol Chem 277(38):35642–35649

    Article  PubMed  CAS  Google Scholar 

  57. Panetti TS (2002) Differential effects of sphingosine 1-phosphate and lysophosphatidic acid on endothelial cells. Biochim Biophys Acta 1582(1–3):190–196

    PubMed  CAS  Google Scholar 

  58. Barrier L, Ingrand S, Piriou A et al (2005) Lactic acidosis stimulates ganglioside and ceramide generation without sphingomyelin hydrolysis in rat cortical astrocytes. Neurosci Lett 385(3):224–229

    Article  PubMed  CAS  Google Scholar 

  59. Ohtani R, Tomimoto H, Kondo T et al (2004) Upregulation of ceramide and its regulating mechanism in a rat model of chronic cerebral ischemia. Brain Res 1023(1):31–40

    Article  PubMed  CAS  Google Scholar 

  60. Takahashi K, Ginis I, Nishioka R et al (2004) Glucosylceramide synthase activity and ceramide levels are modulated during cerebral ischemia after ischemic preconditioning. J Cereb Blood Flow Metab 24(6):623–627

    Article  PubMed  CAS  Google Scholar 

  61. Sadowski M, Pankiewicz J, Scholtzova H et al (2004) Links between the pathology of Alzheimer’s disease and vascular dementia. Neurochem Res 29(6):1257–1266

    Article  PubMed  CAS  Google Scholar 

  62. Buckner RL (2004) Memory and executive function in aging and AD: multiple factors that cause decline and reserve factors that compensate. Neuron 44(1):195–208

    Article  PubMed  CAS  Google Scholar 

  63. Skoog I, Gustafson D (2006) Update on hypertension and Alzheimer’s disease. Neurol Res 28(6):605–611

    Article  PubMed  Google Scholar 

  64. Lesser G, Kandiah K, Libow LS et al (2001) Elevated serum total and LDL cholesterol in very old patients with Alzheimer’s disease. Dementia 12(2):138–145

    CAS  Google Scholar 

  65. Vermeer SE, Prins ND, den Heijer T et al (2003) Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348(13):1215–1222

    Article  PubMed  Google Scholar 

  66. Prins ND, van Dijk EJ, den Heijer T et al (2005) Cerebral small-vessel disease and decline in information processing speed, executive function and memory. Brain 128(Pt 9):2034–2041

    Article  PubMed  Google Scholar 

  67. Dressler KA, Mathias S, Kolesnick RN (1992) Tumor necrosis factor-alpha activates the sphingomyelin signal transduction pathway in a cell-free system. Science 255(5052):1715–1718

    Article  PubMed  CAS  Google Scholar 

  68. Xia Z, Dickens M, Raingeaud J et al (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270(5240):1326–1331

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

Supported by NIH AG02219 grant.

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Authors and Affiliations

  1. Department of Psychiatry, The Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY, 10029-6575, USA

    Pavel Katsel, Celeste Li & Vahram Haroutunian

  2. Department of Psychiatry, James J Peters VA Medical Center, 130 West Kingsbridge Road, Bronx, NY, 10468, USA

    Pavel Katsel, Celeste Li & Vahram Haroutunian

  3. Department of Psychiatry, Bronx VA Medical Center, Room 4F-20, 130 West Kingsbridge Road, Bronx, NY, 10468, USA

    Pavel Katsel

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  1. Pavel Katsel
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Correspondence to Pavel Katsel.

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Special issue dedicated to John P. Blass.

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Katsel, P., Li, C. & Haroutunian, V. 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 (2007). https://doi.org/10.1007/s11064-007-9297-x

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  • DOI: https://doi.org/10.1007/s11064-007-9297-x

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