Journal of Inherited Metabolic Disease

, Volume 37, Issue 1, pp 83–92 | Cite as

Human and mouse neuroinflammation markers in Niemann-Pick disease, type C1

  • Stephanie M. Cologna
  • Celine V. M. Cluzeau
  • Nicole M. Yanjanin
  • Paul S. Blank
  • Michelle K. Dail
  • Stephan Siebel
  • Cynthia L. Toth
  • Christopher A. Wassif
  • Andrew P. Lieberman
  • Forbes D. Porter
Original Article


Niemann-Pick disease, type C1 (NPC1) is an autosomal recessive lipid storage disorder in which a pathological cascade, including neuroinflammation occurs. While data demonstrating neuroinflammation is prevalent in mouse models, data from NPC1 patients is lacking. The current study focuses on identifying potential markers of neuroinflammation in NPC1 from both the Npc1 mouse model and NPC1 patients. We identified in the mouse model significant changes in expression of genes associated with inflammation and compared these results to the pattern of expression in human cortex and cerebellar tissue. From gene expression array analysis, complement 3 (C3) was increased in mouse and human post-mortem NPC1 brain tissues. We also characterized protein levels of inflammatory markers in cerebrospinal fluid (CSF) from NPC1 patients and controls. We found increased levels of interleukin 3, chemokine (C-X-C motif) ligand 5, interleukin 16 and chemokine ligand 3 (CCL3), and decreased levels of interleukin 4, 10, 13 and 12p40 in CSF from NPC1 patients. CSF markers were evaluated with respect to phenotypic severity. Miglustat treatment in NPC1 patients slightly decreased IL-3, IL-10 and IL-13 CSF levels; however, further studies are needed to establish a strong effect of miglustat on inflammation markers. The identification of inflammatory markers with altered levels in the cerebrospinal fluid of NPC1 patients may provide a means to follow secondary events in NPC1 disease during therapeutic trials.


NPC1 Patient Miglustat Cerebellar Tissue Sandhoff Disease Post Birth 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



Human tissue was obtained from the NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore, MD. This study was supported by the intramural research program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by the National Institute of Neurological Disorders and Stroke (R01 NS063967 to APL). Support for this work was also provided by Bench-to-Bedside awards from the NIH Clinical Center and Office of Rare Diseases. Research was supported in part by a grant from the National Niemann-Pick Disease Foundation to SMC. NMY was supported by the Ara Parseghian Medical Research Foundation (APMRF). APMRF also supported the collection of control CSF samples which were facilitated by the efforts of Dr. Cyndi Tifft. The authors would also like to acknowledge the contribution of the caretakers, the patients and their families, who participated in this study.

Conflict of interest


Supplementary material

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ESM 1 (DOCX 8.72 mb)
10545_2013_9610_MOESM2_ESM.xlsx (32 kb)
ESM 2 (XLSX 32 kb)


  1. Aqul A, Liu B, Ramirez CM et al (2011) Unesterified cholesterol accumulation in late endosomes/lysosomes causes neurodegeneration and is prevented by driving cholesterol export from this compartment. J Neurosci 31(25):9404–9413PubMedCentralPubMedCrossRefGoogle Scholar
  2. Baudry M, Yao Y, Simmons D, Liu J, Bi X (2003) Postnatal development of inflammation in a murine model of Niemann-Pick type C disease: immunohistochemical observations of microglia and astroglia. Exp Neurol 184(2):887–903PubMedCrossRefGoogle Scholar
  3. Carstea ED, Morris JA, Coleman KG et al (1997) Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. Science 277(5323):228–231PubMedCrossRefGoogle Scholar
  4. Chabot S, Williams G, Hamilton M, Sutherland G, Yong VW (1999) Mechanisms of IL-10 production in human microglia-T cell interaction. J Immunol 162(11):6819–6828PubMedGoogle Scholar
  5. Davidson CD, Ali NF, Micsenyi MC et al (2009) Chronic cyclodextrin treatment of murine Niemann-Pick C disease ameliorates neuronal cholesterol and glycosphingolipid storage and disease progression. PLoS One 4(9):e6951PubMedCentralPubMedCrossRefGoogle Scholar
  6. Eng LF, Ghirnikar RS, Lee YL (2000) Glial fibrillary acidic protein: GFAP-thirty-one years (1969–2000). Neurochem Res 25(9–10):1439–1451PubMedCrossRefGoogle Scholar
  7. Fu R, Yanjanin NM, Bianconi S, Pavan WJ, Porter FD (2010) Oxidative stress in Niemann-Pick disease, type C. Mol Genet Metab 101(2–3):214–218PubMedCentralPubMedCrossRefGoogle Scholar
  8. Ganser GH, Hewett P (2010) An accurate substitution method for analyzing censored data. J Occup Environ Hyg 7(4):233–244PubMedCrossRefGoogle Scholar
  9. Graeber MB, Li W, Rodriguez ML (2011) Role of microglia in CNS inflammation. FEBS Lett 585(23):3798–3805PubMedCrossRefGoogle Scholar
  10. Henry CJ, Huang Y, Wynne AM, Godbout JP (2009) Peripheral lipopolysaccharide (LPS) challenge promotes microglial hyperactivity in aged mice that is associated with exaggerated induction of both pro-inflammatory IL-1beta and anti-inflammatory IL-10 cytokines. Brain Behav Immun 23(3):309–317PubMedCentralPubMedCrossRefGoogle Scholar
  11. Klein A, Maldonado C, Vargas LM et al (2011) Oxidative stress activates the c-Abl/p73 proapoptotic pathway in Niemann-Pick type C neurons. Neurobiol Dis 41(1):209–218PubMedCrossRefGoogle Scholar
  12. Kunisch E, Fuhrmann R, Roth A, Winter R, Lungershausen W, Kinne RW (2004) Macrophage specificity of three anti-CD68 monoclonal antibodies (KP1, EBM11, and PGM1) widely used for immunohistochemistry and flow cytometry. Ann Rheum Dis 63(7):774–784PubMedCrossRefGoogle Scholar
  13. Langmade SJ, Gale SE, Frolov A et al (2006) Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci USA 103(37):13807–13812PubMedCrossRefGoogle Scholar
  14. Li H, Repa JJ, Valasek MA et al (2005) Molecular, anatomical, and biochemical events associated with neurodegeneration in mice with Niemann-Pick type C disease. J Neuropathol Exp Neurol 64(4):323–333PubMedGoogle Scholar
  15. Liao G, Wen Z, Irizarry K et al (2010) Abnormal gene expression in cerebellum of Npc1−/− mice during postnatal development. Brain Res 1325:128–140PubMedCrossRefGoogle Scholar
  16. Liu B, Ramirez CM, Miller AM, Repa JJ, Turley SD, Dietschy JM (2010) Cyclodextrin overcomes the transport defect in nearly every organ of NPC1 mice leading to excretion of sequestered cholesterol as bile acid. J Lipid Res 51(5):933–944PubMedCrossRefGoogle Scholar
  17. Liu B, Turley SD, Burns DK, Miller AM, Repa JJ, Dietschy JM (2009) Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1−/− mouse. Proc Natl Acad Sci USA 106(7):2377–2382PubMedCrossRefGoogle Scholar
  18. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods 25(4):402–408PubMedCrossRefGoogle Scholar
  19. Loftus SK, Morris JA, Carstea ED et al (1997) Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. Science 277(5323):232–235PubMedCrossRefGoogle Scholar
  20. Lopez ME, Klein AD, Hong J, Dimbil UJ, Scott MP (2012a) Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann-Pick C. Hum Mol Genet 21(13):2946–2960PubMedCrossRefGoogle Scholar
  21. Lopez ME, Klein AD, Scott MP (2012b) Complement is dispensable for neurodegeneration in Niemann-Pick disease type C. J Neuroinflamm 9(1):216CrossRefGoogle Scholar
  22. Love S, Bridges LR, Case CP (1995) Neurofibrillary tangles in Niemann-Pick disease type C. Brain 118(Pt 1):119–129PubMedCrossRefGoogle Scholar
  23. Marin-Teva JL, Cuadros MA, Martin-Oliva D, Navascues J (2012) Microglia and neuronal cell death. Neuron Glia Biol 7(1):25-40.CrossRefGoogle Scholar
  24. Ong WY, Kumar U, Switzer RC et al (2001) Neurodegeneration in Niemann-Pick type C disease mice. Exp Brain Res 141(2):218–231PubMedCrossRefGoogle Scholar
  25. Park KW, Lee DY, Joe EH, Kim SU, Jin BK (2005) Neuroprotective role of microglia expressing interleukin-4. J Neurosci Res 81(3):397–402PubMedCrossRefGoogle Scholar
  26. Parra J, Klein AD, Castro J et al (2011) Npc1 deficiency in the C57BL/6J genetic background enhances Niemann-Pick disease type C spleen pathology. Biochem Biophys Res Commun 413(3):400–406PubMedCrossRefGoogle Scholar
  27. Patterson MC, Vecchio D, Jacklin E et al (2010) Long-term miglustat therapy in children with Niemann-Pick disease type C. J Child Neurol 25(3):300–305PubMedCrossRefGoogle Scholar
  28. Patterson MC, Vecchio D, Prady H, Abel L, Wraith JE (2007) Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study. Lancet Neurol 6(9):765–772PubMedCrossRefGoogle Scholar
  29. Pentchev PG, Comly ME, Kruth HS et al (1987) Group C Niemann-Pick disease: faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts. FASEB J 1(1):40–45PubMedGoogle Scholar
  30. Pineda M, Wraith JE, Mengel E et al (2009) Miglustat in patients with Niemann-Pick disease Type C (NP-C): a multicenter observational retrospective cohort study. Mol Genet Metab 98(3):243–249PubMedCrossRefGoogle Scholar
  31. Porter FD, Scherrer DE, Lanier MH et al (2010) Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann-Pick C1 disease. Sci Trans Med 2(56):56ra81CrossRefGoogle Scholar
  32. Pressey SN, Smith DA, Wong AM, Platt FM, Cooper JD (2012) Early glial activation, synaptic changes and axonal pathology in the thalamocortical system of Niemann-Pick type C1 mice. Neurobiol Dis 45(3):1086–1100PubMedCentralPubMedCrossRefGoogle Scholar
  33. Ramirez CM, Liu B, Taylor AM et al (2010) Weekly cyclodextrin administration normalizes cholesterol metabolism in nearly every organ of the Niemann-Pick type C1 mouse and markedly prolongs life. Pediatr Res 68(4):309–315PubMedCentralPubMedCrossRefGoogle Scholar
  34. Ransohoff RM, Brown MA (2012) Innate immunity in the central nervous system. J Clin Invest 122(4):1164–1171PubMedCentralPubMedCrossRefGoogle Scholar
  35. Reddy JV, Ganley IG, Pfeffer SR (2006) Clues to neuro-degeneration in Niemann-Pick type C disease from global gene expression profiling. PLoS One 1:e19PubMedCentralPubMedCrossRefGoogle Scholar
  36. Repa JJ, Li H, Frank-Cannon TC et al (2007) Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse. J Neurosci 27(52):14470–14480PubMedCrossRefGoogle Scholar
  37. Rubio-Perez JM, Morillas-Ruiz JM (2012) A review: inflammatory process in Alzheimer’s disease, role of cytokines. SciWorld J 2012:756357Google Scholar
  38. Sarna JR, Larouche M, Marzban H, Sillitoe RV, Rancourt DE, Hawkes R (2003) Patterned Purkinje cell degeneration in mouse models of Niemann-Pick type C disease. J Comp Neurol 456(3):279–291PubMedCrossRefGoogle Scholar
  39. Smith D, Wallom KL, Williams IM, Jeyakumar M, Platt FM (2009) Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann-Pick disease type C1. Neurobiol Dis 36(2):242–251PubMedCrossRefGoogle Scholar
  40. Stein VM, Crooks A, Ding W et al (2012) Miglustat improves purkinje cell survival and alters microglial phenotype in feline Niemann-Pick disease type C. J Neuropathol Exp Neurol 71(5):434–448PubMedCentralPubMedCrossRefGoogle Scholar
  41. Suk K (2010) Combined analysis of the glia secretome and the CSF proteome: neuroinflammation and novel biomarkers. Expert Rev proteomics 7(2):263–274PubMedCrossRefGoogle Scholar
  42. Suzuki K, Parker CC, Pentchev PG et al (1995) Neurofibrillary tangles in Niemann-Pick disease type C. Acta Neuropathol 89(3):227–238PubMedCrossRefGoogle Scholar
  43. Vanier MT (2010) Niemann-Pick disease type C. Orphanet J Rare Dis 5:16PubMedCentralPubMedCrossRefGoogle Scholar
  44. Vanier MT, Millat G (2003) Niemann-Pick disease type C. Clin Genet 64(4):269–281PubMedCrossRefGoogle Scholar
  45. Vazquez MC, Del Pozo T, Robledo FA et al (2011) Alteration of gene expression profile in niemann-pick type C mice correlates with tissue damage and oxidative stress. PLoS One 6(12):e28777PubMedCentralPubMedCrossRefGoogle Scholar
  46. Veerhuis R, Nielsen HM, Tenner AJ (2011) Complement in the brain. Mol Immunol 48(14):1592–1603PubMedCentralPubMedCrossRefGoogle Scholar
  47. Ward S, O’Donnell P, Fernandez S, Vite CH (2010) 2-hydroxypropyl-beta-cyclodextrin raises hearing threshold in normal cats and in cats with Niemann-Pick type C disease. Pediatr Res 68(1):52–56PubMedCentralPubMedCrossRefGoogle Scholar
  48. Wraith JE, Vecchio D, Jacklin E et al (2010) Miglustat in adult and juvenile patients with Niemann-Pick disease type C: long-term data from a clinical trial. Mol Genet Metab 99(4):351–357PubMedCrossRefGoogle Scholar
  49. Wu YP, Mizukami H, Matsuda J, Saito Y, Proia RL, Suzuki K (2005) Apoptosis accompanied by up-regulation of TNF-alpha death pathway genes in the brain of Niemann-Pick type C disease. Mol Genet Metab 84(1):9–17PubMedCrossRefGoogle Scholar
  50. Wu YP, Proia RL (2004) Deletion of macrophage-inflammatory protein 1 alpha retards neurodegeneration in Sandhoff disease mice. Proc Natl Acad Sci USA 101(22):8425–8430PubMedCrossRefGoogle Scholar
  51. Yanjanin NM, Velez JI, Gropman A et al (2010) Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B Neuropsychiatr Genet 153B(1):132–140PubMedCentralPubMedGoogle Scholar
  52. Zampieri S, Mellon SH, Butters TD et al (2009) Oxidative stress in NPC1 deficient cells: protective effect of allopregnanolone. J Cell Mol Med 13(9B):3786–3796PubMedCentralPubMedCrossRefGoogle Scholar
  53. Zervas M, Dobrenis K, Walkley SU (2001) Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. J Neuropathol Exp Neurol 60(1):49–64PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg (outside the USA) 2013

Authors and Affiliations

  • Stephanie M. Cologna
    • 1
  • Celine V. M. Cluzeau
    • 1
  • Nicole M. Yanjanin
    • 1
  • Paul S. Blank
    • 2
  • Michelle K. Dail
    • 1
  • Stephan Siebel
    • 1
  • Cynthia L. Toth
    • 1
  • Christopher A. Wassif
    • 1
  • Andrew P. Lieberman
    • 3
  • Forbes D. Porter
    • 1
  1. 1.Program in Developmental Endocrinology and Genetics, Section on Molecular DysmorphologyNICHD, NIH, DHHSBethesdaUSA
  2. 2.Program in Physical Biology, Section on Membrane & Cellular BiophysicsNICHD, NIH, DHHSBethesdaUSA
  3. 3.Department of PathologyUniversity of MichiganAnn ArborUSA

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