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Does Soluble TREM2 Protect Against Alzheimer's Disease?

Brown, Guy C., St George-Hyslop, Peter·2022·Frontiers in Aging Neuroscience
DOI 10.3389/fnagi.2021.834697PMC PMC8831327
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Abstract

Triggering Receptor Expressed in Myeloid Cells 2 (TREM2) is a pattern recognition receptor on myeloid cells, and is upregulated on microglia surrounding amyloid plaques in Alzheimer's disease (AD). Rare, heterozygous mutations in TREM2 (e.g., R47H) increase AD risk several fold. TREM2 can be cleaved at the plasma membrane by metalloproteases to release the ectodomain as soluble TREM2 (sTREM2). Wild-type sTREM2 binds oligomeric amyloid beta (Aβ) and acts as an extracellular chaperone, blocking and reversing Aβ oligomerization and fibrillization, and preventing Aβ-induced neuronal loss in vitro. Whereas, R47H sTREM2 increases Aβ fibrillization and neurotoxicity. AD brains expressing R47H TREM2 have more fibrous plaques with more neuritic pathology around these plaques, consistent with R47H sTREM2 promoting Aβ fibrillization relative to WT sTREM2. Brain expression or injection of wild-type sTREM2 reduces pathology in amyloid models of AD in mice, indicating that wild-type sTREM2 is protective against amyloid pathology. Levels of sTREM2 in cerebrospinal fluid (CSF) fall prior to AD, rise in early AD, and fall again in late AD. People with higher sTREM2 levels in CSF progress more slowly into and through AD than do people with lower sTREM2 levels, suggesting that sTREM2 protects against AD. However, some of these experiments can be interpreted as full-length TREM2 protecting rather than sTREM2, and to distinguish between these two possibilities, we need more experiments testing whether sTREM2 itself protects in AD and AD models, and at what stage of disease. If sTREM2 is protective, then treatments could be designed to elevate sTREM2 in AD.

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  1. Bekris, 2018, Soluble TREM2 and biomarkers of central and peripheral inflammation in neurodegenerative disease, J. Neuroimmunol, 319, 19, 10.1016/j.jneuroim.2018.03.003 · DOI
  2. Berner, 2020, Meprin β cleaves TREM2 and controls its phagocytic activity on macrophages, FASEB J, 34, 6675, 10.1096/fj.201902183R · DOI
  3. Condello, 2015, Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques, Nat. Commun, 6, 6176, 10.1038/ncomms7176 · DOI · Paper page
  4. Deczkowska, 2020, The physiology, pathology, and potential therapeutic applications of the TREM2 signaling pathway, Cell, 181, 1207, 10.1016/j.cell.2020.05.003 · DOI · Paper page
  5. Del-Aguila, 2019, TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers, Mol. Neurodegener, 14, 18, 10.1186/s13024-019-0319-3 · DOI
  6. Edwin, 2020, A high cerebrospinal fluid soluble TREM2 level is associated with slow clinical progression of Alzheimer's disease, Alzheimers Dement., 12, e12128, 10.1002/dad2.12128 · DOI
  7. Fassler, 2021, Engagement of TREM2 by a novel monoclonal antibody induces activation of microglia and improves cognitive function in Alzheimer's disease models, J. Neuroinflamm, 18, 19, 10.1186/s12974-020-01980-5 · DOI
  8. Franzmeier, 2020, Higher CSF sTREM2 attenuates ApoE4-related risk for cognitive decline and neurodegeneration, Mol. Neurodegener, 15, 57, 10.1186/s13024-020-00407-2 · DOI
  9. Giraldo, 2013, Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease, Neurobiol. Aging, 34, 2077, 10.1016/j.neurobiolaging.2013.02.016 · DOI · Paper page
  10. Gisslén, 2018, CSF concentrations of soluble TREM2 as a marker of microglial activation in HIV-1 infection, Neurol. Neuroimmunol. Neuroinflamm, 6, e512, 10.1212/NXI.0000000000000512 · DOI
  11. Guerreiro, 2012, TREM2 variants in Alzheimer's disease, N. Engl. J. Med, 368, 117, 10.1056/NEJMoa1211851 · DOI · Paper page
  12. Henjum, 2016, Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease, Alzheimers. Res. Ther, 8, 17, 10.1186/s13195-016-0182-1 · DOI
  13. Hou, 2019, Genome-wide association study identifies Alzheimer's risk variant in MS4A6A influencing cerebrospinal fluid sTREM2 levels, Neurobiol. Aging, 84, 241, 10.1016/j.neurobiolaging.2019.05.008 · DOI
  14. Jonsson, 2013, Variant of TREM2 associated with the risk of Alzheimer's disease, N. Engl. J. Med, 368, 107, 10.1056/NEJMoa1211103 · DOI · Paper page
  15. Keren-Shaul, 2017, A unique microglia type associated with restricting development of Alzheimer's disease, Cell, 169, 1276, 10.1016/j.cell.2017.05.018 · DOI · Paper page
  16. Kober, 2021, Functional insights from biophysical study of TREM2 interactions with apoE and Aβ1-42, Alzheimers Dement, 17, 475, 10.1101/2020.02.24.963264 · DOI
  17. Kulkarni, 2021, Role of TREM2 in Alzheimer's disease: a long road ahead, Mol. Neurobiol, 58, 5239, 10.1007/s12035-021-02477-9 · DOI
  18. Lessard, 2018, High-affinity interactions and signal transduction between Aβ oligomers and TREM2, EMBO Mol. Med, 10, e9027, 10.15252/emmm.201809027 · DOI
  19. Liu, 2018, Soluble TREM2 changes during the clinical course of Alzheimer's disease: a meta-analysis, Neurosci. Lett, 686, 10, 10.1016/j.neulet.2018.08.038 · DOI
  20. Ma, 2016, Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer's disease brains, Mol. Neurodegener, 11, 72, 10.1186/s13024-016-0137-9 · DOI · Paper page
  21. Ma, 2020, Dynamic changes of CSF sTREM2 in preclinical Alzheimer's disease: the CABLE study, Mol. Neurodegener, 15, 25, 10.1186/s13024-020-00374-8 · DOI
  22. Nordengen, 2019, Glial activation and inflammation along the Alzheimer's disease continuum, J. Neuroinflamm, 16, 46, 10.1186/s12974-019-1399-2 · DOI · Paper page
  23. Pascoal, 2021, Microglial activation and tau propagate jointly across braak stages, Nat. Med, 27, 1592, 10.1038/s41591-021-01456-w · DOI · Paper page
  24. Piccio, 2008, Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation, Brain, 131, 3081, 10.1093/brain/awn217 · DOI
  25. Piccio, 2016, Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status, Acta Neuropathol, 131, 925, 10.1007/s00401-016-1533-5 · DOI · Paper page
  26. Rauchmann, 2020, Soluble TREM2 and inflammatory proteins in Alzheimer's disease cerebrospinal fluid, J. Alzheimers. Dis, 73, 1615, 10.3233/JAD-191120 · DOI
  27. Rauchmann, 2019, CSF soluble TREM2 as a measure of immune response along the Alzheimer's disease continuum, Neurobiol. Aging, 74, 182, 10.1016/j.neurobiolaging.2018.10.022 · DOI
  28. Schlepckow, 2017, An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function, EMBO Mol. Med, 9, 1356, 10.15252/emmm.201707672 · DOI
  29. Sheng, 2021, Identification of the minimal active soluble TREM2 sequence for modulating microglial phenotypes and amyloid pathology, J. Neuroinflamm, 18, 286, 10.1186/s12974-021-02340-7 · DOI
  30. Vilalta, 2021, Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation, J. Biol. Chem, 296, 100631, 10.1016/j.jbc.2021.100631 · DOI · Paper page
  31. Wang, 2020, Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer's disease model, J. Exp. Med, 217, e20200785, 10.1084/jem.20200785 · DOI · Paper page
  32. Yuan, 2016, TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy, Neuron, 90, 724, 10.1016/j.neuron.2016.05.003 · DOI · Paper page
  33. Zhao, 2018, TREM2 is a receptor for beta-amyloid that mediates microglial function, Neuron, 97, 1023, 10.1016/j.neuron.2018.01.031 · DOI · Paper page
  34. Zhong, 2019, The emerging roles and therapeutic potential of soluble TREM2 in Alzheimer's disease, Front. Aging Neurosci, 11, 328, 10.3389/fnagi.2019.00328 · DOI
  35. Zhong, 2017, Soluble TREM2 induces inflammatory responses and enhances microglial survival, J. Exp. Med, 214, 597, 10.1084/jem.20160844 · DOI
  36. Zhong, 2018, Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2), Mol. Neurodegener, 13, 15, 10.1186/s13024-018-0247-7 · DOI
  37. Zhong, 2019, Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer's disease model, Nat. Commun, 10, 1365, 10.1038/s41467-019-09118-9 · DOI · Paper page

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Metadata

Authors
Brown, G. C., & St George-Hyslop, P.
Venue
Frontiers in Aging Neuroscience
Publisher
Frontiers Media SA
Published
2022-01-28
Volume
13
ISSN
1663-4365
DOI
10.3389/fnagi.2021.834697
PMC
PMC8831327
Cited by
39
References
16
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Innovative Medicines Initiative
  • Wellcome Trust

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