Advertisement

Acta Neuropathologica

, Volume 132, Issue 5, pp 667–683 | Cite as

TREM1 facilitates microglial phagocytosis of amyloid beta

  • Teng Jiang
  • Ying-Dong ZhangEmail author
  • Qing Gao
  • Jun-Shan Zhou
  • Xi-Chen Zhu
  • Huan Lu
  • Jian-Quan Shi
  • Lan TanEmail author
  • Qi Chen
  • Jin-Tai YuEmail author
Original Paper

Abstract

As the most common type of neurodegenerative disease, Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β peptide (Aβ) within the brain. Triggering receptor expressed on myeloid cells (TREM) 1 is an immune receptor expressed by mononuclear phagocytes including monocytes and microglia, coupling with TYRO protein tyrosine kinase binding protein to regulate immune reactions. Emerging evidence indicates that rs6910730G, an intronic variant of TREM1, is associated with an increased Aβ neuropathology in the brains of elderly subjects, but the underlying mechanisms remain unclear. Here, using two independent cohorts of healthy individuals, we provided evidence that rs6910730G reduced the ability of human monocytes for Aβ phagocytosis, and this reduction was likely attributed to a decreased monocytic TREM1 expression. By knockdown and overexpression of Trem1 in mouse primary microglia, we showed that TREM1 facilitated microglial phagocytosis of Aβ. In support of this finding, knockdown of Trem1 in the brains of APP/PSEN1 mice increased Aβ1–42 levels and total amyloid burden, whereas selective overexpression of Trem1 on microglia or activation of Trem1 signaling by an agonistic antibody ameliorated Aβ neuropathology and rescued AD-related spatial cognitive impairments. Altogether, these findings uncover the role of TREM1 in microglial Aβ clearance, and establish TREM1 as a potential therapeutic target for AD.

Keywords

TREM1 Alzheimer’s disease Amyloid-β Microglia Monocytes Phagocytosis 

Notes

Acknowledgments

This work was supported by National Natural Science Foundation of China (81501092, 81500916), China Postdoctoral Science Foundation (2015M580448, 2016T90480), Natural Science Foundation of Jiangsu Province (BK20150091), and “Six Talent Summit” Foundation of Jiangsu Province (2016-WSN-180).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

All procedures performed in this study involving human participants were in accordance with the ethical standards of Nanjing First Hospital and Qingdao Municipal Hospital and with the declaration of Helsinki. A written informed consent was obtained from each participant. Meanwhile, all procedures performed in this study involving animals were in accordance with the ethical standards of Nanjing First Hospital and Qingdao Municipal Hospital.

Supplementary material

401_2016_1622_MOESM1_ESM.pdf (1019 kb)
Supplementary material 1 (PDF 1019 kb)

References

  1. 1.
    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–e1526. doi: 10.1016/j.neurobiolaging.2013.12.010 Google Scholar
  2. 2.
    Bliederhaeuser C, Grozdanov V, Speidel A, Zondler L, Ruf WP, Bayer H et al (2016) Age-dependent defects of alpha-synuclein oligomer uptake in microglia and monocytes. Acta Neuropathol 131:379–391. doi: 10.1007/s00401-015-1504-2 CrossRefPubMedGoogle Scholar
  3. 3.
    Burgess N, Maguire EA, O’Keefe J (2002) The human hippocampus and spatial and episodic memory. Neuron 35:625–641CrossRefPubMedGoogle Scholar
  4. 4.
    Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR et al (2015) CD33 modulates TREM2: convergence of Alzheimer loci. Nat Neurosci 18:1556–1558. doi: 10.1038/nn.4126 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Colonna M (2003) TREMs in the immune system and beyond. Nat Rev Immunol 3:445–453. doi: 10.1038/nri1106 CrossRefPubMedGoogle Scholar
  6. 6.
    Doens D, Fernandez PL (2014) Microglia receptors and their implications in the response to amyloid beta for Alzheimer’s disease pathogenesis. J Neuroinflammation 11:48. doi: 10.1186/1742-2094-11-48 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Gaikwad S, Larionov S, Wang Y, Dannenberg H, Matozaki T, Monsonego A et al (2009) Signal regulatory protein-beta1: a microglial modulator of phagocytosis in Alzheimer’s disease. Am J Pathol 175:2528–2539. doi: 10.2353/ajpath.2009.090147 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Geumann C, Gronborg M, Hellwig M, Martens H, Jahn R (2010) A sandwich enzyme-linked immunosorbent assay for the quantification of insoluble membrane and scaffold proteins. Anal Biochem 402:161–169. doi: 10.1016/j.ab.2010.03.037 CrossRefPubMedGoogle Scholar
  9. 9.
    Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K et al (2013) Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78:631–643. doi: 10.1016/j.neuron.2013.04.014 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    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 CrossRefPubMedGoogle Scholar
  11. 11.
    Hardy J, Bogdanovic N, Winblad B, Portelius E, Andreasen N, Cedazo-Minguez A et al (2014) Pathways to Alzheimer’s disease. J Intern Med 275:296–303. doi: 10.1111/joim.12192 CrossRefPubMedGoogle Scholar
  12. 12.
    Hardy J, Selkoe DJ (2002) The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297:353–356. doi: 10.1126/science.1072994 CrossRefPubMedGoogle Scholar
  13. 13.
    Harry GJ (2013) Microglia during development and aging. Pharmacol Ther 139:313–326. doi: 10.1016/j.pharmthera.2013.04.013 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Hommes TJ, Hoogendijk AJ, Dessing MC, Van’t Veer C, Florquin S, Colonna M et al (2014) Triggering receptor expressed on myeloid cells-1 (TREM-1) improves host defence in pneumococcal pneumonia. J Pathol 233:357–367. doi: 10.1002/path.4361 CrossRefPubMedGoogle Scholar
  15. 15.
    Ingersoll MA, Spanbroek R, Lottaz C, Gautier EL, Frankenberger M, Hoffmann R et al (2010) Comparison of gene expression profiles between human and mouse monocyte subsets. Blood 115:e10–e19. doi: 10.1182/blood-2009-07-235028 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Jiang T, Tan L, Zhu XC, Zhang QQ, Cao L, Tan MS et al (2014) Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer’s disease. Neuropsychopharmacology 39:2949–2962. doi: 10.1038/npp.2014.164 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Jiang T, Tan L, Zhu XC, Zhou JS, Cao L, Tan MS et al (2015) Silencing of TREM2 exacerbates tau pathology, neurodegenerative changes, and spatial learning deficits in P301S tau transgenic mice. Neurobiol Aging 36:3176–3186. doi: 10.1016/j.neurobiolaging.2015.08.019 CrossRefPubMedGoogle Scholar
  18. 18.
    Jiang T, Wan Y, Zhang YD, Zhou JS, Gao Q, Zhu XC et al (2016) TREM2 overexpression has no improvement on neuropathology and cognitive impairment in aging APPswe/PS1dE9 mice. Mol Neurobiol. doi: 10.1007/s12035-016-9704-x Google Scholar
  19. 19.
    Jiang T, Wan Y, Zhou JS, Tan MS, Huang Q, Zhu XC et al (2016) A missense variant in TREML2 reduces risk of Alzheimer’s disease in a han chinese population. Mol Neurobiol. doi: 10.1007/s12035-016-9706-8 Google Scholar
  20. 20.
    Jiang T, Yu JT, Tian Y, Tan L (2013) Epidemiology and etiology of alzheimer’s disease: from genetic to non-genetic factors. Curr Alzheimer Res 10:852–867CrossRefPubMedGoogle Scholar
  21. 21.
    Jiang T, Zhang YD, Chen Q, Gao Q, Zhu XC, Zhou JS et al (2016) TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105:196–206. doi: 10.1016/j.neuropharm.2016.01.028 CrossRefPubMedGoogle Scholar
  22. 22.
    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 368:107–116. doi: 10.1056/NEJMoa1211103 CrossRefPubMedGoogle Scholar
  23. 23.
    Klesney-Tait J, Turnbull IR, Colonna M (2006) The TREM receptor family and signal integration. Nat Immunol 7:1266–1273. doi: 10.1038/ni1411 CrossRefPubMedGoogle Scholar
  24. 24.
    Kuhlmann T, Wendling U, Nolte C, Zipp F, Maruschak B, Stadelmann C et al (2002) Differential regulation of myelin phagocytosis by macrophages/microglia, involvement of target myelin, Fc receptors and activation by intravenous immunoglobulins. J Neurosci Res 67:185–190CrossRefPubMedGoogle Scholar
  25. 25.
    Li H, Hong F, Pan S, Lei L, Yan F (2016) Silencing triggering receptors expressed on myeloid cells-1 impaired the inflammatory response to oxidized low-density lipoprotein in macrophages. Inflammation 39:199–208. doi: 10.1007/s10753-015-0239-5 CrossRefPubMedGoogle Scholar
  26. 26.
    Liang S, Domon H, Hosur KB, Wang M, Hajishengallis G (2009) Age-related alterations in innate immune receptor expression and ability of macrophages to respond to pathogen challenge in vitro. Mech Ageing Dev 130:538–546. doi: 10.1016/j.mad.2009.06.006 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Mahe D, Fisson S, Montoni A, Morel A, Couez D (2001) Identification and IFNgamma-regulation of differentially expressed mRNAs in murine microglial and CNS-associated macrophage subpopulations. Mol Cell Neurosci 18:363–380. doi: 10.1006/mcne.2001.1038 CrossRefPubMedGoogle Scholar
  28. 28.
    Malm T, Koistinaho M, Muona A, Magga J, Koistinaho J (2010) The role and therapeutic potential of monocytic cells in Alzheimer’s disease. Glia 58:889–900. doi: 10.1002/glia.20973 PubMedGoogle Scholar
  29. 29.
    Mawuenyega KG, Sigurdson W, Ovod V, Munsell L, Kasten T, Morris JC et al (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease. Science 330:1774. doi: 10.1126/science.1197623 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    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:e00037. doi: 10.1042/AN20100010 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Murakami Y, Akahoshi T, Aoki N, Toyomoto M, Miyasaka N, Kohsaka H (2009) Intervention of an inflammation amplifier, triggering receptor expressed on myeloid cells 1, for treatment of autoimmune arthritis. Arthritis Rheum 60:1615–1623. doi: 10.1002/art.24554 CrossRefPubMedGoogle Scholar
  32. 32.
    Ornatowska M, Azim AC, Wang X, Christman JW, Xiao L, Joo M et al (2007) Functional genomics of silencing TREM-1 on TLR4 signaling in macrophages. Am J Physiol Lung Cell Mol Physiol 293:L1377–L1384. doi: 10.1152/ajplung.00140.2007 CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Radsak MP, Salih HR, Rammensee HG, Schild H (2004) Triggering receptor expressed on myeloid cells-1 in neutrophil inflammatory responses: differential regulation of activation and survival. J Immunol 172:4956–4963CrossRefPubMedGoogle Scholar
  34. 34.
    Replogle JM, Chan G, White CC, Raj T, Winn PA, Evans DA et al (2015) A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology. Ann Neurol 77:469–477. doi: 10.1002/ana.24337 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Rogers J, Strohmeyer R, Kovelowski CJ, Li R (2002) Microglia and inflammatory mechanisms in the clearance of amyloid beta peptide. Glia 40:260–269. doi: 10.1002/glia.10153 CrossRefPubMedGoogle Scholar
  36. 36.
    Scheltens P, Blennow K, Breteler MM, de Strooper B, Frisoni GB, Salloway S et al (2016) Alzheimer’s disease. Lancet. doi: 10.1016/S0140-6736(15)01124-1 Google Scholar
  37. 37.
    Tan MS, Yu JT, Jiang T, Zhu XC, Guan HS, Tan L (2014) IL12/23 p40 inhibition ameliorates Alzheimer’s disease-associated neuropathology and spatial memory in SAMP8 mice. J Alzheimers Dis 38:633–646. doi: 10.3233/JAD-131148 PubMedGoogle Scholar
  38. 38.
    Walsh DM, Selkoe DJ (2004) Deciphering the molecular basis of memory failure in Alzheimer’s disease. Neuron 44:181–193. doi: 10.1016/j.neuron.2004.09.010 CrossRefPubMedGoogle Scholar
  39. 39.
    Yu JT, Jiang T, Wang YL, Wang HF, Zhang W, Hu N et al (2014) Triggering receptor expressed on myeloid cells 2 variant is rare in late-onset Alzheimer’s disease in Han Chinese individuals. Neurobiol Aging 35(937):e931–e933. doi: 10.1016/j.neurobiolaging.2013.10.075 Google Scholar
  40. 40.
    Zondler L, Muller K, Khalaji S, Bliederhauser C, Ruf WP, Grozdanov V et al (2016) Peripheral monocytes are functionally altered and invade the CNS in ALS patients. Acta Neuropathol. doi: 10.1007/s00401-016-1548-y Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  1. 1.Department of Neurology, Nanjing First HospitalNanjing Medical UniversityNanjingPeople’s Republic of China
  2. 2.Department of Neurology, Qingdao Municipal HospitalSchool of Medicine, Qingdao UniversityQingdaoPeople’s Republic of China
  3. 3.Department of PathophysiologyNanjing Medical UniversityNanjingPeople’s Republic of China

Personalised recommendations