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TREM2 in Alzheimer’s disease

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Abstract

Recent works have demonstrated a rare functional variant (R47H) in triggering receptor expressed on myeloid cells (TREM) 2 gene, encoding TREM2 protein, increase susceptibility to late-onset Alzheimer’s disease (AD), with an odds ratio similar to that of the apolipoprotein E ε4 allele. The reduced function of TREM2 was speculated to be the main cause in the pathogenic effects of this risk variant, and TREM2 is highly expressed in white matter, as well as in the hippocampus and neocortex, which is partly consistent with the pathological features reported in AD brain, indicating the possible involvement of TREM2 in AD pathogenesis. Emerging evidence has demonstrated that TREM2 could suppress inflammatory response by repression of microglia-mediated cytokine production and secretion, which may prevent inflammation-induced bystander damage of neurons. TREM2 also participates in the regulation of phagocytic pathways that are responsible for the removal of neuronal debris. In this article, we review the recent epidemiological findings of TREM2 that related with late-onset AD and speculate the possible roles of TREM2 in progression of this disease. Based on the potential protective actions of TREM2 in AD pathogenesis, targeting TREM2 might provide new opportunities for AD treatment.

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References

  1. Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297(5580):353–356. doi:10.1126/science.1072994

    Article  PubMed  CAS  Google Scholar 

  2. Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14(10):1227–1235. doi:10.1038/nn.2923

    Article  PubMed  CAS  Google Scholar 

  3. Streit WJ, Mrak RE, Griffin WS (2004) Microglia and neuroinflammation: a pathological perspective. J Neuroinflammation 1(1):14. doi:10.1186/1742-2094-1-14

    Article  PubMed  Google Scholar 

  4. Jones B (2012) Alzheimer disease: TREM2 linked to late-onset AD. Nat Rev Neurol 9(1):5. doi:10.1038/nrneurol.2012.254

    Article  PubMed  Google Scholar 

  5. Niemitz E (2012) TREM2 and Alzheimer’s disease. Nat Genet 45(1):11. doi:10.1038/ng.2513

    Article  Google Scholar 

  6. Neumann H, Daly MJ (2013) Variant TREM2 as risk factor for Alzheimer’s disease. N Engl J Med 368(2):182–184. doi:10.1056/NEJMe1213157

    Article  PubMed  CAS  Google Scholar 

  7. 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(2):117–127. doi:10.1056/NEJMoa1211851

    Article  PubMed  CAS  Google Scholar 

  8. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2):107–116. doi:10.1056/NEJMoa1211103

    Article  PubMed  CAS  Google Scholar 

  9. Colonna M (2003) TREMs in the immune system and beyond. Nat Rev Immunol 3(6):445–453. doi:10.1038/nri1106

    Article  PubMed  CAS  Google Scholar 

  10. Bouchon A, Dietrich J, Colonna M (2000) Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 164(10):4991–4995

    PubMed  CAS  Google Scholar 

  11. Bouchon A, Hernandez-Munain C, Cella M, Colonna M (2001) A DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194(8):1111–1122

    Article  PubMed  CAS  Google Scholar 

  12. N’Diaye EN, Branda CS, Branda SS, Nevarez L, Colonna M, Lowell C et al (2009) TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol 184(2):215–223. doi:10.1083/jcb.200808080

    Article  PubMed  Google Scholar 

  13. Stefano L, Racchetti G, Bianco F, Passini N, Gupta RS, Panina Bordignon P et al (2009) The surface-exposed chaperone, Hsp60, is an agonist of the microglial TREM2 receptor. J Neurochem 110(1):284–294. doi:10.1111/j.1471-4159.2009.06130.x

    Article  PubMed  CAS  Google Scholar 

  14. Ito H, Hamerman JA (2012) TREM-2, triggering receptor expressed on myeloid cell-2, negatively regulates TLR responses in dendritic cells. Eur J Immunol 42(1):176–185. doi:10.1002/eji.201141679

    Article  PubMed  CAS  Google Scholar 

  15. Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC et al (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109(4):1144–1156. doi:10.1111/j.1471-4159.2009.06042.x

    Article  PubMed  CAS  Google Scholar 

  16. Bajramovic JJ (2011) Regulation of innate immune responses in the central nervous system. CNS Neurol Disord Drug Targets 10(1):4–24

    Article  PubMed  CAS  Google Scholar 

  17. Sun GY, Guan CX, Zhou Y, Liu YP, Li SF, Zhou HF et al (2011) Vasoactive intestinal peptide re-balances TREM-1/TREM-2 ratio in acute lung injury. Regul Pept 167(1):56–64. doi:10.1016/j.regpep.2010.11.008

    Article  PubMed  CAS  Google Scholar 

  18. Takahashi K, Rochford CD, Neumann H (2005) Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med 201(4):647–657. doi:10.1084/jem.20041611

    Article  PubMed  CAS  Google Scholar 

  19. Fenoglio C, Galimberti D, Piccio L, Scalabrini D, Panina P, Buonsanti C et al (2007) Absence of TREM2 polymorphisms in patients with Alzheimer’s disease and Frontotemporal Lobar Degeneration. Neurosci Lett 411(2):133–137. doi:10.1016/j.neulet.2006.10.029

    Article  PubMed  CAS  Google Scholar 

  20. Guerreiro RJ, Lohmann E, Bras JM, Gibbs JR, Rohrer JD, Gurunlian N, et al (2012) Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. Arch Neurol :1–7. doi:10.1001/archneurol.2013.579

  21. Frank S, Burbach GJ, Bonin M, Walter M, Streit W, Bechmann I et al (2008) TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56(13):1438–1447. doi:10.1002/glia.20710

    Article  PubMed  Google Scholar 

  22. Melchior B, Garcia AE, Hsiung BK, Lo KM, Doose JM, Thrash JC et al (2010) Dual induction of TREM2 and tolerance-related transcript, Tmem176b, in amyloid transgenic mice: implications for vaccine-based therapies for Alzheimer’s disease. ASN Neuro 2(3):e00037. doi:10.1042/AN20100010

    Article  PubMed  Google Scholar 

  23. Bianchin MM, Lima JE, Natel J, Sakamoto AC (2006) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 66(4):615–616. doi:10.1212/01.wnl.0000216105.11788.0f, author reply −6

    Article  PubMed  Google Scholar 

  24. Verloes A, Maquet P, Sadzot B, Vivario M, Thiry A, Franck G (1997) Nasu–Hakola syndrome: polycystic lipomembranous osteodysplasia with sclerosing leucoencephalopathy and presenile dementia. J Med Genet 34(9):753–757

    Article  PubMed  CAS  Google Scholar 

  25. 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

    PubMed  CAS  Google Scholar 

  26. Madry H, Prudlo J, Grgic A, Freyschmidt J (2007) Nasu–Hakola disease (PLOSL): report of five cases and review of the literature. Clin Orthop Relat Res 454:262–269. doi:10.1097/01.blo.0000229364.57985.df

    Article  PubMed  Google Scholar 

  27. Chouery E, Delague V, Bergougnoux A, Koussa S, Serre JL, Megarbane A (2008) Mutations in TREM2 lead to pure early-onset dementia without bone cysts. Hum Mutat 29(9):E194–E204. doi:10.1002/humu.20836

    Article  PubMed  Google Scholar 

  28. 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(2):71–75

    PubMed  Google Scholar 

  29. Sessa G, Podini P, Mariani M, Meroni A, Spreafico R, Sinigaglia F et al (2004) Distribution and signaling of TREM2/DAP12, the receptor system mutated in human polycystic lipomembraneous osteodysplasia with sclerosing leukoencephalopathy dementia. Eur J Neurosci 20(10):2617–2628. doi:10.1111/j.1460-9568.2004.03729.x

    Article  PubMed  Google Scholar 

  30. Thrash JC, Torbett BE, Carson MJ (2009) Developmental regulation of TREM2 and DAP12 expression in the murine CNS: implications for Nasu–Hakola disease. Neurochem Res 34(1):38–45. doi:10.1007/s11064-008-9657-1

    Article  PubMed  CAS  Google Scholar 

  31. Vom Berg J, Prokop S, Miller KR, Obst J, Kalin RE, Lopategui-Cabezas I et al (2012) Inhibition of IL-12/IL-23 signaling reduces Alzheimer’s disease-like pathology and cognitive decline. Nat Med 18(12):1812–1819. doi:10.1038/nm.2965

    Article  PubMed  CAS  Google Scholar 

  32. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A et al (2012) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. doi:10.1038/nature11729

  33. Varnum MM, Ikezu T (2012) The classification of microglial activation phenotypes on neurodegeneration and regeneration in Alzheimer’s disease brain. Arch Immunol Ther Exp 60(4):251–266. doi:10.1007/s00005-012-0181-2

    Article  CAS  Google Scholar 

  34. Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL (2006) Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12. J Immunol 177(4):2051–2055

    PubMed  CAS  Google Scholar 

  35. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L et al (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177(6):3520–3524

    PubMed  CAS  Google Scholar 

  36. Hamerman JA, Tchao NK, Lowell CA, Lanier LL (2005) Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12. Nat Immunol 6(6):579–586. doi:10.1038/ni1204

    Article  PubMed  CAS  Google Scholar 

  37. Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H (2007) TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4(4):e124. doi:10.1371/journal.pmed.0040124

    Article  PubMed  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(5):1290–1301. doi:10.1002/eji.200636837

    Article  PubMed  CAS  Google Scholar 

  39. Singaraja RR (2013) TREM2: a new risk factor for Alzheimer’s Disease. Clin Genet. doi:10.1111/cge.12108

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Acknowledgments

This work was supported by grants from the National Natural Science Foundation of China (81000544, 81171209), the Shandong Provincial Natural Science Foundation, China (ZR2010HQ004, ZR2011HZ001), and the Shandong Provincial Outstanding Medical Academic Professional Program.

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Correspondence to Jin-Tai Yu or Lan Tan.

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Jiang, T., Yu, JT., Zhu, XC. et al. TREM2 in Alzheimer’s disease. Mol Neurobiol 48, 180–185 (2013). https://doi.org/10.1007/s12035-013-8424-8

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  • DOI: https://doi.org/10.1007/s12035-013-8424-8

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