Elucidating the Role of TREM2 in Alzheimer's Disease

Neuron

Volumn 94, Issue 2, 2017, Pages 237-248

  Ulrich, Jason D ^a   Ulland, Tyler K ^a   Colonna, Marco ^a   Holtzman, David M ^a  

^a WASHINGTON UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Alzheimer's disease; microglia; TREM2

Indexed keywords

AMYLOID BETA PROTEIN; TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; BIOLOGICAL MARKER; IMMUNOGLOBULIN RECEPTOR; MEMBRANE PROTEIN; TREM2 PROTEIN, HUMAN;

ALZHEIMER DISEASE; BINDING AFFINITY; DEGENERATIVE DISEASE; GENETIC RISK; GENETIC VARIABILITY; HUMAN; IMMUNOPATHOGENESIS; IMMUNOREGULATION; INFLAMMATION; INNATE IMMUNITY; NERVE INJURY; NONHUMAN; PROTEIN ANALYSIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; REVIEW; ANIMAL; DISEASE MODEL; METABOLISM; MICROGLIA; PATHOLOGY;

ALZHEIMER DISEASE; AMYLOID BETA-PEPTIDES; ANIMALS; BIOMARKERS; DISEASE MODELS, ANIMAL; HUMANS; MEMBRANE GLYCOPROTEINS; MICROGLIA; RECEPTORS, IMMUNOLOGIC;

EID: 85018557303     PISSN: 08966273     EISSN: 10974199     Source Type: Journal    
DOI: 10.1016/j.neuron.2017.02.042     Document Type: Review

References (84)

1. Atagi, Y., Liu, C.-C., Painter, M.M., Chen, X.-F., Verbeeck, C., Zheng, H., Li, X., Rademakers, R., Kang, S.S., Xu, H., et al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J. Biol. Chem. 290 (2015), 26043–26050.
2. Bailey, C.C., DeVaux, L.B., Farzan, M., The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J. Biol. Chem. 290 (2015), 26033–26042.
3. Bateman, R.J., Xiong, C., Benzinger, T.L.S., Fagan, A.M., Goate, A., Fox, N.C., Marcus, D.S., Cairns, N.J., Xie, X., Blazey, T.M., et al., Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367 (2012), 795–804.
4. Benitez, B.A., Jin, S.C., Guerreiro, R., Graham, R., Lord, J., Harold, D., Sims, R., Lambert, J.-C., Gibbs, J.R., Bras, J., et al. Missense variant in TREML2 protects against Alzheimer's disease. Neurobiol. Aging 35 (2014), 1510.e19–1510.e26.
5. Blennow, K., Zetterberg, H., Fagan, A.M., Fluid biomarkers in Alzheimer disease. Cold Spring Harb. Perspect. Med., 2, 2012, a006221.
6. Borroni, B., Ferrari, F., Galimberti, D., Nacmias, B., Barone, C., Bagnoli, S., Fenoglio, C., Piaceri, I., Archetti, S., Bonvicini, C., et al. Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol. Aging 35 (2014), 934.e7–934.e10.
7. Bouchon, A., Dietrich, J., Colonna, M., Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J. Immunol. 164 (2000), 4991–4995.
8. Bradshaw, E.M., Chibnik, L.B., Keenan, B.T., Ottoboni, L., Raj, T., Tang, A., Rosenkrantz, L.L., Imboywa, S., Lee, M., Von Korff, A., et al., Alzheimer Disease Neuroimaging Initiative. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat. Neurosci. 16 (2013), 848–850.
9. Brier, M.R., Gordon, B., Friedrichsen, K., McCarthy, J., Stern, A., Christensen, J., Owen, C., Aldea, P., Su, Y., Hassenstab, J., et al. Tau and Aβ imaging, CSF measures, and cognition in Alzheimer's disease. Sci. Transl. Med., 8, 2016, 338ra66.
10. Butovsky, O., Jedrychowski, M.P., Moore, C.S., Cialic, R., Lanser, A.J., Gabriely, G., Koeglsperger, T., Dake, B., Wu, P.M., Doykan, C.E., et al. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat. Neurosci. 17 (2014), 131–143.
11. Butovsky, O., Jedrychowski, M.P., Cialic, R., Krasemann, S., Murugaiyan, G., Fanek, Z., Greco, D.J., Wu, P.M., Doykan, C.E., Kiner, O., et al. Targeting miR-155 restores abnormal microglia and attenuates disease in SOD1 mice. Ann. Neurol. 77 (2015), 75–99.
12. Cady, J., Koval, E.D., Benitez, B.A., Zaidman, C., Jockel-Balsarotti, J., Allred, P., Baloh, R.H., Ravits, J., Simpson, E., Appel, S.H., et al. TREM2 variant p.R47H as a risk factor for sporadic amyotrophic lateral sclerosis. JAMA Neurol. 71 (2014), 449–453.
13. Cannon, J.P., O'Driscoll, M., Litman, G.W., Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 64 (2012), 39–47.
14. Cantoni, C., Bollman, B., Licastro, D., Xie, M., Mikesell, R., Schmidt, R., Yuede, C.M., Galimberti, D., Olivecrona, G., Klein, R.S., et al. TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol. 129 (2015), 429–447.
15. Chakrabarty, P., Li, A., Ceballos-Diaz, C., Eddy, J.A., Funk, C.C., Moore, B., DiNunno, N., Rosario, A.M., Cruz, P.E., Verbeeck, C., et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85 (2015), 519–533.
16. Colonna, M., TREMs in the immune system and beyond. Nat. Rev. Immunol. 3 (2003), 445–453.
17. Colonna, M., Wang, Y., TREM2 variants: new keys to decipher Alzheimer disease pathogenesis. Nat. Rev. Neurosci. 17 (2016), 201–207.
18. Condello, C., Yuan, P., Schain, A., Grutzendler, J., Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat. Commun., 6, 2015, 6176.
19. Dagher, N.N., Najafi, A.R., Kayala, K.M., Elmore, M.R., White, T.E., Medeiros, R., West, B.L., Green, K.N., Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J. Neuroinflammation, 12, 2015, 139.
20. Daws, M.R., Sullam, P.M., Niemi, E.C., Chen, T.T., Tchao, N.K., Seaman, W.E., Pattern recognition by TREM-2: binding of anionic ligands. J. Immunol. 171 (2003), 594–599.
21. Elmore, M.R., Najafi, A.R., Koike, M.A., Dagher, N.N., Spangenberg, E.E., Rice, R.A., Kitazawa, M., Matusow, B., Nguyen, H., West, B.L., Green, K.N., Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82 (2014), 380–397.
22. Fagan, A.M., Xiong, C., Jasielec, M.S., Bateman, R.J., Goate, A.M., Benzinger, T.L.S., Ghetti, B., Martins, R.N., Masters, C.L., Mayeux, R., et al., Dominantly Inherited Alzheimer Network. Longitudinal change in CSF biomarkers in autosomal-dominant Alzheimer's disease. Sci. Transl. Med., 6, 2014, 226ra30.
23. Griciuc, A., Serrano-Pozo, A., Parrado, A.R., Lesinski, A.N., Asselin, C.N., Mullin, K., Hooli, B., Choi, S.H., Hyman, B.T., Tanzi, R.E., Alzheimer's disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78 (2013), 631–643.
24. Guan, Z., Kuhn, J.A., Wang, X., Colquitt, B., Solorzano, C., Vaman, S., Guan, A.K., Evans-Reinsch, Z., Braz, J., Devor, M., et al. Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19 (2016), 94–101.
25. Guerreiro, R.J., Lohmann, E., Brás, J.M., Gibbs, J.R., Rohrer, J.D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol. 70 (2013), 78–84.
26. Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J.S.K., Younkin, S., et al., Alzheimer Genetic Analysis Group. TREM2 variants in Alzheimer's disease. N. Engl. J. Med. 368 (2013), 117–127.
27. Guillot-Sestier, M.-V., Doty, K.R., Gate, D., Rodriguez, J. Jr., Leung, B.P., Rezai-Zadeh, K., Town, T., Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85 (2015), 534–548.
28. Heneka, M.T., Kummer, M.P., Latz, E., Innate immune activation in neurodegenerative disease. Nat. Rev. Immunol. 14 (2014), 463–477.
29. Henjum, K., Almdahl, I.S., Årskog, V., Minthon, L., Hansson, O., Fladby, T., Nilsson, L.N.G., Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease. Alzheimers Res. Ther., 8, 2016, 17.
30. Heslegrave, A., Heywood, W., Paterson, R., Magdalinou, N., Svensson, J., Johansson, P., Öhrfelt, A., Blennow, K., Hardy, J., Schott, J., et al. Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease. Mol. Neurodegener., 11, 2016, 3.
31. Jack, C.R. Jr., Holtzman, D.M., Biomarker modeling of Alzheimer's disease. Neuron 80 (2013), 1347–1358.
32. + inflammatory macrophages and ameliorates pathology in Alzheimer's disease mouse models. J. Exp. Med. 212 (2015), 287–295.
33. Jay, T.R., Hirsch, A.M., Broihier, M.L., Miller, C.M., Neilson, L.E., Ransohoff, R.M., Lamb, B.T., Landreth, G.E., Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer's disease. J. Neurosci. 37 (2017), 637–647.
34. Jin, S.C., Benitez, B.A., Karch, C.M., Cooper, B., Skorupa, T., Carrell, D., Norton, J.B., Hsu, S., Harari, O., Cai, Y., et al. Coding variants in TREM2 increase risk for Alzheimer's disease. Hum. Mol. Genet. 23 (2014), 5838–5846.
35. Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P.V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A.I., Lah, J.J., et al. Variant of TREM2 associated with the risk of Alzheimer's disease. N. Engl. J. Med. 368 (2013), 107–116.
36. Karch, C.M., Goate, A.M., Alzheimer's disease risk genes and mechanisms of disease pathogenesis. Biol. Psychiatry 77 (2015), 43–51.
37. Kawabori, M., Kacimi, R., Kauppinen, T., Calosing, C., Kim, J.Y., Hsieh, C.L., Nakamura, M.C., Yenari, M.A., Triggering receptor expressed on myeloid cells 2 (TREM2) deficiency attenuates phagocytic activities of microglia and exacerbates ischemic damage in experimental stroke. J. Neurosci. 35 (2015), 3384–3396.
38. Kleinberger, G., Yamanishi, Y., Suárez-Calvet, M., Czirr, E., Lohmann, E., Cuyvers, E., Struyfs, H., Pettkus, N., Wenninger-Weinzierl, A., Mazaheri, F., et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci. Transl. Med., 6, 2014, 243ra86.
39. Kobayashi, M., Konishi, H., Sayo, A., Takai, T., Kiyama, H., TREM2/DAP12 signal elicits proinflammatory response in microglia and exacerbates neuropathic pain. J. Neurosci. 36 (2016), 11138–11150.
40. Kober, D.L., Alexander-Brett, J.M., Karch, C.M., Cruchaga, C., Colonna, M., Holtzman, M.J., Brett, T.J., Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife, 5, 2016, e20391.
41. Lefterov, I., Schug, J., Mounier, A., Nam, K.N., Fitz, N.F., Koldamova, R., RNA-sequencing reveals transcriptional up-regulation of Trem2 in response to bexarotene treatment. Neurobiol. Dis. 82 (2015), 132–140.
42. Li, T., Braunstein, K.E., Zhang, J., Lau, A., Sibener, L., Deeble, C., Wong, P.C., The neuritic plaque facilitates pathological conversion of tau in an Alzheimer's disease mouse model. Nat. Commun., 7, 2016, 12082.
43. Lill, C.M., Rengmark, A., Pihlstrøm, L., Fogh, I., Shatunov, A., Sleiman, P.M., Wang, L.-S., Liu, T., Lassen, C.F., Meissner, E., et al., SLAGEN Consortium. 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. 11 (2015), 1407–1416.
44. Ma, L., Allen, M., Sakae, N., Ertekin-Taner, N., Graff-Radford, N.R., Dickson, D.W., Younkin, S.G., Sevlever, D., Expression and processing analyses of wild type and p.R47H TREM2 variant in Alzheimer's disease brains. Mol. Neurodegener., 11, 2016, 72.
45. Maphis, N., Xu, G., Kokiko-Cochran, O.N., Jiang, S., Cardona, A., Ransohoff, R.M., Lamb, B.T., Bhaskar, K., Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138 (2015), 1738–1755.
46. Matarin, M., Salih, D.A., Yasvoina, M., Cummings, D.M., Guelfi, S., Liu, W., Nahaboo Solim, M.A., Moens, T.G., Paublete, R.M., Ali, S.S., et al. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep. 10 (2015), 633–644.
47. Musiek, E.S., Holtzman, D.M., Three dimensions of the amyloid hypothesis: time, space and ‘wingmen’. Nat. Neurosci. 18 (2015), 800–806.
48. Oakley, H., Cole, S.L., Logan, S., Maus, E., Shao, P., Craft, J., Guillozet-Bongaarts, A., Ohno, M., Disterhoft, J., Van Eldik, L., et al. Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J. Neurosci. 26 (2006), 10129–10140.
49. Öhrfelt, A., Axelsson, M., Malmeström, C., Novakova, L., Heslegrave, A., Blennow, K., Lycke, J., Zetterberg, H., Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult. Scler. 22 (2016), 1587–1595.
50. Paloneva, J., Autti, T., Raininko, R., Partanen, J., Salonen, O., Puranen, M., Hakola, P., Haltia, M., CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts. Neurology 56 (2001), 1552–1558.
51. Paloneva, J., Manninen, T., Christman, G., Hovanes, K., Mandelin, J., Adolfsson, R., Bianchin, M., Bird, T., Miranda, R., Salmaggi, A., et al. Mutations in two genes encoding different subunits of a receptor signaling complex result in an identical disease phenotype. Am. J. Hum. Genet. 71 (2002), 656–662.
52. Piccio, L., Buonsanti, C., Mariani, M., Cella, M., Gilfillan, S., Cross, A.H., Colonna, M., Panina-Bordignon, P., Blockade of TREM-2 exacerbates experimental autoimmune encephalomyelitis. Eur. J. Immunol. 37 (2007), 1290–1301.
53. Piccio, L., Buonsanti, C., Cella, M., Tassi, I., Schmidt, R.E., Fenoglio, C., Rinker, J. 2nd, Naismith, R.T., Panina-Bordignon, P., Passini, N., et al. Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain 131 (2008), 3081–3091.
54. Piccio, L., Deming, Y., Del-Águila, J.L., Ghezzi, L., Holtzman, D.M., Fagan, A.M., Fenoglio, C., Galimberti, D., Borroni, B., Cruchaga, C., Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol. 131 (2016), 925–933.
55. Poliani, P.L., Wang, Y., Fontana, E., Robinette, M.L., Yamanishi, Y., Gilfillan, S., Colonna, M., TREM2 sustains microglial expansion during aging and response to demyelination. J. Clin. Invest. 125 (2015), 2161–2170.
56. Prokop, S., Miller, K.R., Drost, N., Handrick, S., Mathur, V., Luo, J., Wegner, A., Wyss-Coray, T., Heppner, F.L., Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer's disease-like mice. J. Exp. Med. 212 (2015), 1811–1818.
57. Radde, R., Bolmont, T., Kaeser, S.A., Coomaraswamy, J., Lindau, D., Stoltze, L., Calhoun, M.E., Jäggi, F., Wolburg, H., Gengler, S., et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep. 7 (2006), 940–946.
58. Rademakers, R., Baker, M., Nicholson, A.M., Rutherford, N.J., Finch, N., Soto-Ortolaza, A., Lash, J., Wider, C., Wojtas, A., DeJesus-Hernandez, M., et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44 (2011), 200–205.
59. Rayaprolu, S., Mullen, B., Baker, M., Lynch, T., Finger, E., Seeley, W.W., Hatanpaa, K.J., Lomen-Hoerth, C., Kertesz, A., Bigio, E.H., et al. TREM2 in neurodegeneration: evidence for association of the p.R47H variant with frontotemporal dementia and Parkinson's disease. Mol. Neurodegener., 8, 2013, 19.
60. Replogle, J.M., Chan, G., White, C.C., Raj, T., Winn, P.A., Evans, D.A., Sperling, R.A., Chibnik, L.B., Bradshaw, E.M., Schneider, J.A., et al. A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology. Ann. Neurol. 77 (2015), 469–477.
61. Saber, M., Kokiko-Cochran, O., Puntambekar, S.S., Lathia, J.D., Lamb, B.T., Triggering receptor expressed on myeloid cells 2 deficiency alters acute macrophage distribution and improves recovery after traumatic brain injury. J. Neurotrauma 34 (2017), 423–435.
62. Saito, T., Matsuba, Y., Mihira, N., Takano, J., Nilsson, P., Itohara, S., Iwata, N., Saido, T.C., Single App knock-in mouse models of Alzheimer's disease. Nat. Neurosci. 17 (2014), 661–663.
63. Savage, J.C., Jay, T., Goduni, E., Quigley, C., Mariani, M.M., Malm, T., Ransohoff, R.M., Lamb, B.T., Landreth, G.E., Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer's disease. J. Neurosci. 35 (2015), 6532–6543.
64. Sieber, M.W., Jaenisch, N., Brehm, M., Guenther, M., Linnartz-Gerlach, B., Neumann, H., Witte, O.W., Frahm, C., Attenuated inflammatory response in triggering receptor expressed on myeloid cells 2 (TREM2) knock-out mice following stroke. PLoS ONE, 8, 2013, e52982.
65. Song, W., Hooli, B., Mullin, K., Jin, S.C., Cella, M., Ulland, T.K., Wang, Y., Tanzi, R., Colonna, M., Alzheimer's disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement., 2016, 10.1016/j.alz.2016.07.004 Published online August 9, 2016.
66. Soragna, D., Papi, L., Ratti, M.T., Sestini, R., Tupler, R., Montalbetti, L., An Italian family affected by Nasu-Hakola disease with a novel genetic mutation in the TREM2 gene. J. Neurol. Neurosurg. Psychiatry 74 (2003), 825–826.
67. Spangenberg, E.E., Lee, R.J., Najafi, A.R., Rice, R.A., Elmore, M.R.P., Blurton-Jones, M., West, B.L., Green, K.N., Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139 (2016), 1265–1281.
68. Srinivasan, K., Friedman, B.A., Larson, J.L., Lauffer, B.E., Goldstein, L.D., Appling, L.L., Borneo, J., Poon, C., Ho, T., Cai, F., et al. Untangling the brain's neuroinflammatory and neurodegenerative transcriptional responses. Nat. Commun., 7, 2016, 11295.
69. Suárez-Calvet, M., Araque Caballero, M.Á., Kleinberger, G., Bateman, R.J., Fagan, A.M., Morris, J.C., Levin, J., Danek, A., Ewers, M., Haass, C., Dominantly Inherited Alzheimer Network. Early changes in CSF sTREM2 in dominantly inherited Alzheimer's disease occur after amyloid deposition and neuronal injury. Sci. Transl. Med., 8, 2016, 369ra178.
70. Suárez-Calvet, M., Kleinberger, G., Araque Caballero, M.Á., Brendel, M., Rominger, A., Alcolea, D., Fortea, J., Lleó, A., Blesa, R., Gispert, J.D., et al. sTREM2 cerebrospinal fluid levels are a potential biomarker for microglia activity in early-stage Alzheimer's disease and associate with neuronal injury markers. EMBO Mol. Med. 8 (2016), 466–476.
71. Takahashi, K., Rochford, C.D.P., Neumann, H., Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J. Exp. Med. 201 (2005), 647–657.
72. Ulrich, J.D., Finn, M.B., Wang, Y., Shen, A., Mahan, T.E., Jiang, H., Stewart, F.R., Piccio, L., Colonna, M., Holtzman, D.M., Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol. Neurodegener., 9, 2014, 20.
73. Varvel, N.H., Grathwohl, S.A., Degenhardt, K., Resch, C., Bosch, A., Jucker, M., Neher, J.J., Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer's disease. J. Exp. Med. 212 (2015), 1803–1809.
74. Wang, Y., Szretter, K.J., Vermi, W., Gilfillan, S., Rossini, C., Cella, M., Barrow, A.D., Diamond, M.S., Colonna, M., IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat. Immunol. 13 (2012), 753–760.
75. Wang, Y., Cella, M., Mallinson, K., Ulrich, J.D., Young, K.L., Robinette, M.L., Gilfillan, S., Krishnan, G.M., Sudhakar, S., Zinselmeyer, B.H., et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160 (2015), 1061–1071.
76. Wang, Y., Ulland, T.K., Ulrich, J.D., Song, W., Tzaferis, J.A., Hole, J.T., Yuan, P., Mahan, T.E., Shi, Y., Gilfillan, S., et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J. Exp. Med. 213 (2016), 667–675.
77. Wu, K., Byers, D.E., Jin, X., Agapov, E., Alexander-Brett, J., Patel, A.C., Cella, M., Gilfilan, S., Colonna, M., Kober, D.L., et al. TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J. Exp. Med. 212 (2015), 681–697.
78. Xiang, X., Werner, G., Bohrmann, B., Liesz, A., Mazaheri, F., Capell, A., Feederle, R., Knuesel, I., Kleinberger, G., Haass, C., TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance. EMBO Mol. Med. 8 (2016), 992–1004.
79. Yeh, F.L., Wang, Y., Tom, I., Gonzalez, L.C., Sheng, M., TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91 (2016), 328–340.
80. Yoshiyama, Y., Higuchi, M., Zhang, B., Huang, S.-M., Iwata, N., Saido, T.C., Maeda, J., Suhara, T., Trojanowski, J.Q., Lee, V.M., Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53 (2007), 337–351.
81. Yuan, P., Condello, C., Keene, C.D., Wang, Y., Bird, T.D., Paul, S.M., Luo, W., Colonna, M., Baddeley, D., Grutzendler, J., TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90 (2016), 724–739.
82. Zhang, B., Gaiteri, C., Bodea, L.G., Wang, Z., McElwee, J., Podtelezhnikov, A.A., Zhang, C., Xie, T., Tran, L., Dobrin, R., et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell 153 (2013), 707–720.
83. Zheng, H., Liu, C.-C., Atagi, Y., Chen, X.-F., Jia, L., Yang, L., He, W., Zhang, X., Kang, S.S., Rosenberry, T.L., et al. Opposing roles of the triggering receptor expressed on myeloid cells 2 and triggering receptor expressed on myeloid cells-like transcript 2 in microglia activation. Neurobiol. Aging 42 (2016), 132–141.
84. Zhu, C., Herrmann, U.S., Li, B., Abakumova, I., Moos, R., Schwarz, P., Rushing, E.J., Colonna, M., Aguzzi, A., Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains. Neurobiol. Aging 36 (2015), 1994–2003.