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Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status

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Abstract

Low frequency coding variants in TREM2 are associated with increased Alzheimer disease (AD) risk, while loss of functions mutations in the gene lead to an autosomal recessive early-onset dementia, named Nasu-Hakola disease (NHD). TREM2 can be detected as a soluble protein in cerebrospinal fluid (CSF) and plasma, and its CSF levels are elevated in inflammatory CNS diseases. We measured soluble TREM2 (sTREM2) in the CSF of a large AD case–control dataset (n = 180) and 40 TREM2 risk variant carriers to determine whether CSF sTREM2 levels are associated with AD status or mutation status. We also performed genetic studies to identify genetic variants associated with CSF sTREM2 levels. CSF, but not plasma, sTREM2 was highly correlated with CSF total tau and phosphorylated-tau levels (r = 0.35, P < 1×10−4; r = 0.40, P < 1×10−4, respectively), but not with CSF Aβ42. AD cases presented higher CSF sTREM2 levels than controls (P = 0.01). Carriers of NHD-associated TREM2 variants presented significantly lower CSF sTREM2 levels, supporting the hypothesis that these mutations lead to reduced protein production/function (R136Q, D87N, Q33X or T66M; P = 1×10−3). In contrast, CSF sTREM2 levels were significantly higher in R47H carriers compared to non-carriers (P = 6×10−3), suggesting that this variant does not impact protein expression and increases AD risk through a different pathogenic mechanism than NHD variants. In GWAS analyses for CSF sTREM2 levels the most significant signal was located on the MS4A gene locus (P = 5.45 × 10−07) corresponding to one of the SNPs reported to be associated with AD risk in this locus. Furthermore, SNPs involved in pathways related to virus cellular entry and vesicular trafficking were overrepresented, suggesting that CSF sTREM2 levels could be an informative phenotype for AD.

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References

  1. Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H et al (2015) Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 290:26043–26050. doi:10.1074/jbc.M115.679043

    Article  CAS  PubMed  Google Scholar 

  2. Bailey CC, DeVaux LB, Farzan M (2015) The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J Biol Chem 290:26033–26042. doi:10.1074/jbc.M115.677286

    Article  CAS  PubMed  Google Scholar 

  3. Benitez BA, Cooper B, Pastor P, Jin SC, Lorenzo E, Cervantes S et al (2013) TREM2 is associated with the risk of Alzheimer’s disease in Spanish population. Neurobiol Aging 34(1711):e1715–1717. doi:10.1016/j.neurobiolaging.2012.12.018

    Google Scholar 

  4. Benitez BA, Cruchaga C (2013) TREM2 and neurodegenerative disease. N Engl J Med 369:1567–1568. doi:10.1056/NEJMc1306509#SA4

    PubMed  PubMed Central  Google Scholar 

  5. Benitez BA, Jin SC, Guerreiro R, Graham R, Lord J, Harold D et al (2014) Missense variant in TREML2 protects against Alzheimer’s disease. Neurobiol Aging 35(1510):e1519–1526. doi:10.1016/j.neurobiolaging.2013.12.010

    Google Scholar 

  6. Cady J, Koval ED, Benitez BA, Zaidman C, Jockel-Balsarotti J, Allred P et al (2014) TREM2 variant p. R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol 71:449–453. doi:10.1001/jamaneurol.2013.6237

    Article  PubMed  PubMed Central  Google Scholar 

  7. Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R et al (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129:429–447. doi:10.1007/s00401-015-1388-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ (2015) Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience 4:7. doi:10.1186/s13742-015-0047-8

    Article  PubMed  PubMed Central  Google Scholar 

  9. Colonna M (2003) TREMs in the immune system and beyond. Nat Rev Immunol 3:445–453. doi:10.1038/nri1106

    Article  CAS  PubMed  Google Scholar 

  10. Craig-Schapiro R, Perrin RJ, Roe CM, Xiong C, Carter D, Cairns NJ et al (2010) YKL-40: a novel prognostic fluid biomarker for preclinical Alzheimer’s disease. Biol Psychiatry 68:903–912. doi:10.1016/j.biopsych.2010.08.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cruchaga C, Haller G, Chakraverty S, Mayo K, Vallania FL, Mitra RD et al (2012) Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer’s disease families. PLoS One 7:e31039. doi:10.1371/journal.pone.0031039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cruchaga C, Kauwe JS, Nowotny P, Bales K, Pickering EH, Mayo K et al (2012) Cerebrospinal fluid APOE levels: an endophenotype for genetic studies for Alzheimer’s disease. Hum Mol Genet. doi:10.1093/hmg/dds296

  13. Cruchaga C, Kauwe JS, Harari O, Jin SC, Cai Y, Karch CM et al (2013) GWAS of cerebrospinal fluid tau levels identifies risk variants for Alzheimer’s disease. Neuron. doi:10.1016/j.neuron.2013.02.026

  14. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J et al (2014) Investigating the role of rare heterozygous TREM2 variants in Alzheimer’s disease and frontotemporal dementia. Neurobiol Aging 35(726):e711–729. doi:10.1016/j.neurobiolaging.2013.09.009

    Google Scholar 

  15. Doragna D, Tupler R, Ratti MT, Montalbetti L, Papi L, Sestim R (2003) An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. J Neurol Neurosurg Psychiatry 74:825–826

    Article  Google Scholar 

  16. Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR et al (2006) Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol 59:512–519

    Article  CAS  PubMed  Google Scholar 

  17. Guerreiro R, Bilgic B, Guven G, Bras J, Rohrer J, Lohmann E et al (2013) Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiol Aging 34(2890):e2891–2895. doi:10.1016/j.neurobiolaging.2013.06.005

    Google Scholar 

  18. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127. doi:10.1056/NEJMoa1211851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Guerreiro RJ, Lohmann E, Bras JM, Gibbs JR, Rohrer JD, Gurunlian N et al (2013) Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol 70:78–84. doi:10.1001/jamaneurol.2013.579

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hakola HP (1972) Neuropsychiatric and genetic aspects of a new hereditary disease characterized by progressive dementia and lipomembranous polycystic osteodysplasia. Acta Psychiatr Scand Suppl 232:1–173

    CAS  PubMed  Google Scholar 

  21. Jin SC, Pastor P, Cooper B, Cervantes S, Benitez BA, Razquin C et al (2012) Pooled-DNA sequencing identifies novel causative variants in PSEN1, GRN and MAPT in a clinical early-onset and familial Alzheimer’s disease Ibero-American cohort. Alzheimers Res Ther 4:34. doi:10.1186/alzrt137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D et al (2014) Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum Mol Genet. doi:10.1093/hmg/ddu277

  23. Jin SC, Carrasquillo MM, Benitez BA, Skorupa T, Carrell D, Patel D et al (2015) TREM2 is associated with increased risk for Alzheimer’s disease in African Americans. Mol Neurodegener 10:19. doi:10.1186/s13024-015-0016-9

    Article  PubMed  PubMed Central  Google Scholar 

  24. Jonsson T, Stefansson H, Ph DS, Jonsdottir I, Jonsson PV, Snaedal Jet al (2012) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med. doi:10.1056/NEJMoa1211103

  25. Jonsson T, Stefansson K (2013) TREM2 and neurodegenerative disease. N Engl J Med 369:1568–1569. doi:10.1056/NEJMc1306509

    CAS  PubMed  Google Scholar 

  26. Kauwe JS, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL et al (2014) Genome-wide association study of CSF levels of 59 Alzheimer’s disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet 10:e1004758. doi:10.1371/journal.pgen.1004758

    Article  PubMed  PubMed Central  Google Scholar 

  27. Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E et al (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6:243ra286. doi:10.1126/scitranslmed.3009093

  28. Klunemann HH, Ridha H, Magy L, Wherrett JR, Hemelsoet DM, Keen RW et al (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts DAP12 and TREM2. Neurology 64:1502–1507. doi:10.1212/01.Wnl.0000160304.00003.Ca

    Article  CAS  PubMed  Google Scholar 

  29. Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C et al (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer’s disease. Nat Genet. doi:10.1038/ng.2802

  30. Lill CM, Rengmark A, Pihlstrom L, Fogh I, Shatunov A, Sleiman PM et al (2015) The role of TREM2 R47H as a risk factor for Alzheimer’s disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson’s disease. Alzheimers Dement. doi:10.1016/j.jalz.2014.12.009

  31. Luis EO, Ortega-Cubero S, Lamet I, Razquin C, Cruchaga C, Benitez BA et al (2014) Frontobasal gray matter loss is associated with the TREM2 p.R47H variant. Neurobiol Aging. doi:10.1016/j.neurobiolaging.2014.06.007

  32. Ma J, Yu JT, Tan L (2015) MS4A cluster in Alzheimer’s disease. Mol Neurobiol 51:1240–1248. doi:10.1007/s12035-014-8800-z

    Article  CAS  PubMed  Google Scholar 

  33. McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM (1984) Clinical diagnosis of Alzheimer’s disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer’s Disease. Neurology 34:939–944

    Article  CAS  PubMed  Google Scholar 

  34. Montalbetti L, Ratti MT, Greco B, Aprile C, Moglia A, Soragna D (2005) Neuropsychological tests and functional nuclear neuroimaging provide evidence of subclinical impairment in Nasu-Hakola disease heterozygotes. Funct Neurol 20:71–75

    PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  36. Numasawa Y, Yamaura C, Ishihara S, Shintani S, Yamazaki M, Tabunoki H et al (2011) Nasu-Hakola disease with a splicing mutation of TREM2 in a Japanese family. Eur J Neurol 18:1179–1183. doi:10.1111/j.1468-1331.2010.03311.x

    Article  CAS  PubMed  Google Scholar 

  37. Paloneva J, Manninen T, Christman G, Hovanes K, Mandelin J, Adolfsson R et al (2002) Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am J Hum Genet 71:656–662. doi:10.1086/342259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Piccio L, Buonsanti C, Mariani M, Cella M, Gilfillan S, Cross AH et al (2007) Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur J Immunol 37:1290–1301. doi:10.1002/eji.200636837

    Article  CAS  PubMed  Google Scholar 

  39. Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C et al (2008) Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain 131:3081–3091. doi:10.1093/brain/awn217

    Article  PubMed  PubMed Central  Google Scholar 

  40. Tarawneh R, Lee JM, Ladenson JH, Morris JC, Holtzman DM (2012) CSF VILIP-1 predicts rates of cognitive decline in early Alzheimer disease. Neurology 78:709–719. doi:10.1212/WNL.0b013e318248e568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vallania FL, Druley TE, Ramos E, Wang J, Borecki I, Province M et al (2010) High-throughput discovery of rare insertions and deletions in large cohorts. Genome Res 20:1711–1718. doi:10.1101/gr.109157.110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML et al (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160:1061–1071. doi:10.1016/j.cell.2015.01.049

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang J, Manolio TA, Pasquale LR, Boerwinkle E, Caporaso N, Cunningham JM et al (2011) Genome partitioning of genetic variation for complex traits using common SNPs. Nat Genet 43:519–525. doi:10.1038/ng.823

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929–11947. doi:10.1523/JNEUROSCI.1860-14.2014

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

We thank Dr. Marco Colonna for providing the antibodies used in the sTREM2 ELISA. This work was supported by a Knight-ADRC pilot grant (to LP and CC) and grants from the National Institutes of Health (R01-AG044546, P01-AG003991, P50-AG005681), and Alzheimer Association (NIRG-11-200110). LP is a Harry Weaver Neuroscience Scholar of the National Multiple Sclerosis Society (NMSS, JF 2144A2/1) and supported by Fondazione Italiana Sclerosi Multipla (2014/R/15). CC was a recipient of a New Investigator Award in Alzheimer’s disease from the American Federation for Aging Research. CC is a recipient of a Bright Focus Foundation Alzheimer’s Disease Research Grant (A2013359S). The recruitment and clinical characterization of research participants at Washington University were supported by NIH P50 AG05681, P01 AG03991, and P01 AG026276. This work was performed by accessing equipment available in the Hope Center for Neurological Disorders and the Departments of Neurology and Psychiatry at Washington University School of Medicine.

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    Authors and Affiliations

    1. Department of Neurology, Washington University School of Medicine, Campus Box 8111, 660 S. Euclid Avenue, Saint Louis, MO, 63110, USA

      Laura Piccio, Laura Ghezzi, David M. Holtzman & Anne M. Fagan

    2. Department of Psychiatry, Washington University School of Medicine, 660 South Euclid Avenue B8134, Saint Louis, MO, 63110, USA

      Yuetiva Deming, Jorge L. Del-Águila & Carlos Cruchaga

    3. Hope Center for Neurological Disorders, Washington University School of Medicine, Saint Louis, MO, USA

      Laura Piccio, David M. Holtzman, Anne M. Fagan & Carlos Cruchaga

    4. Knight Alzheimer’s disease Research Center, Washington University School of Medicine, Saint Louis, MO, USA

      David M. Holtzman, Anne M. Fagan & Carlos Cruchaga

    5. Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Policlinico, Milan, Italy

      Laura Ghezzi, Chiara Fenoglio & Daniela Galimberti

    6. Neurology Unit, University of Brescia, Piazza Spedali Civili 1, 25100, Brescia, Italy

      Barbara Borroni

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    1. Laura Piccio
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    Correspondence to Laura Piccio or Carlos Cruchaga.

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    L. Piccio and C. Cruchaga contributed equally.

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    401_2016_1533_MOESM1_ESM.tif

    Supplementary material 1 Supplementary Fig. 1. Correlation between CSF sTREM2, and CSF Aβ, tau, ptau181 and plasma TREM2. All the samples, including outliers were included in these analyses. a CSF sTREM2 levels are correlated with age and b they are higher in males compared females. c CSF and plasma TREM2 levels are not correlated. d CSF sTREM2 levels are not correlated with CSF Aβ42, but they are significantly correlated with e CSF tau and f p-tau. Pearson correlation was used for correlation analyses. Mann–Whitney test was used for two group comparison. Association of the CSF TREM2 levels with age and gender was performed using samples from Ospedale Maggiore Policlinico and the Knight-ADRC, and the association with CSF Aβ42, tau and p-tau only includes samples from the Knight ADRC (TIFF 19422 kb)

    401_2016_1533_MOESM2_ESM.tif

    Supplementary material 2 Supplementary Fig. 2. CSF and blood sTREM2 levels in AD cases and controls. All the samples, including outliers were included in these analyses. a sTREM2 levels were measured in CSF and b plasma by ELISA in control and AD cases. Values are medians ± interquartile range. Mann–Whitney test was used for two group comparison (TIFF 13044 kb)

    401_2016_1533_MOESM3_ESM.tif

    Supplementary material 3 Supplementary Fig. 3. CSF sTREM2 levels in AD, FTD cases and controls. sTREM2 levels were measured in CSF by ELISA in cognitively normal subjects, AD and FTD cases. Values are medians ± interquartile range. Multi-group statistical analysis was done by Kruskal–Wallis test (TIFF 6754 kb)

    401_2016_1533_MOESM4_ESM.tif

    Supplementary material 4 Supplementary Fig. 4 CSF sTREM2 levels in TREM2 variant carriers. All the samples, including outliers were included in these analyses. sTREM2 was measured in the CSF of cognitively normal (CDR 0) participants who were non-carriers for TREM2 genetic variants, carriers of the TREM2 AD-associated risk variants R47H (n = 9), R62H (n = 10), T96K/L211/W191X (n = 16) and NHD-pathogenic variants (R136Q, D87N, Q33X, T66M; n = 5 heterozygous carriers) which in homozygosis cause NHD. Values are medians ± interquartile range. Multi-group statistical analysis was done by Kruskal–Wallis test (TIFF 6782 kb)

    401_2016_1533_MOESM5_ESM.xlsx

    Supplementary material 5 Supplementary Table 1 Summary statistics for all the SNPs with a P value <10−5 for CSF TREM2 (XLSX 77 kb)

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    Piccio, L., Deming, Y., Del-Águila, J.L. et al. Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol 131, 925–933 (2016). https://doi.org/10.1007/s00401-016-1533-5

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