The FTD-like syndrome causing TREM2 T66M mutation impairs microglia function, brain perfusion, and glucose metabolism

EMBO Journal

Volumn 36, Issue 13, 2017, Pages 1837-1853

  Kleinberger, Gernot ^a,b   Brendel, Matthias ^a   Mracsko, Eva ^c   Wefers, Benedikt ^d,e   Groeneweg, Linda ^c   Xiang, Xianyuan ^a   Focke, Carola ^a   Deußing, Maximilian ^a   Suárez Calvet, Marc ^a,d   Mazaheri, Fargol ^d   Parhizkar, Samira ^a   Pettkus, Nadine ^a   Wurst, Wolfgang ^b,d,e,f   Feederle, Regina ^b,d,e   Bartenstein, Peter ^a,b   Mueggler, Thomas ^c   Arzberger, Thomas ^a,d   Knuesel, Irene ^c   Rominger, Axel ^a,b   Haass, Christian ^a,b,d  

^a UNIVERSITY OF MUNICH   (Germany)

^b Germany 3 Munich Cluster for Systems Neurology   (Germany)

^c F HOFFMANN LA ROCHE LTD   (Switzerland)

^d GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^e INSTITUTE OF EPIDEMIOLOGY   (Germany)

^f TECHNICAL UNIVERSITY OF MUNICH   (Germany)

Author keywords

frontotemporal dementia; neurodegeneration; neuroinflammation; regulated intramembrane proteolysis; TREM2

Indexed keywords

CASPASE 3; CASPASE 7; CYCLIN D1; GAMMA SECRETASE; GLUCOSE; INTERLEUKIN 6; LIPOPOLYSACCHARIDE; MESSENGER RNA; MONOCYTE CHEMOTACTIC PROTEIN 1; TRIGGERING RECEPTOR EXPRESSED ON MYELOID CELLS 2; TUMOR NECROSIS FACTOR; IMMUNOGLOBULIN RECEPTOR; MEMBRANE PROTEIN; MUTANT PROTEIN; TREM2 PROTEIN, MOUSE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BONE MARROW DERIVED MACROPHAGE; BRAIN BLOOD FLOW; BRAIN METABOLISM; BRAIN PERFUSION; CARBOXY TERMINAL SEQUENCE; CELL FUNCTION; CONTROLLED STUDY; CRISPR CAS SYSTEM; EMBRYO; ENZYME ACTIVATION; FRONTOTEMPORAL DEMENTIA; GENE EDITING; GLUCOSE BLOOD LEVEL; GLUCOSE METABOLISM; HETEROZYGOSITY; HOMOZYGOSITY; IMMUNOHISTOCHEMISTRY; IN VIVO STUDY; LOSS OF FUNCTION MUTATION; METABOLIC REGULATION; MICROGLIA; MOUSE; NONHUMAN; PERFUSION WEIGHTED IMAGING; PHAGOCYTOSIS; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; PROTEIN DEGRADATION; ANIMAL; BRAIN; DISEASE MODEL; GENE TARGETING; GENETICS; HUMAN; METABOLISM; MISSENSE MUTATION; NUCLEAR MAGNETIC RESONANCE IMAGING; PATHOLOGY; PERFUSION; PHYSIOLOGY;

ANIMALS; BRAIN; DISEASE MODELS, ANIMAL; FRONTOTEMPORAL DEMENTIA; GENE KNOCK-IN TECHNIQUES; GLUCOSE; HUMANS; IMMUNOHISTOCHEMISTRY; MAGNETIC RESONANCE IMAGING; MEMBRANE GLYCOPROTEINS; MICE; MICROGLIA; MUTANT PROTEINS; MUTATION, MISSENSE; PERFUSION; POSITRON-EMISSION TOMOGRAPHY; RECEPTORS, IMMUNOLOGIC;

EID: 85019682722     PISSN: 02614189     EISSN: 14602075     Source Type: Journal    
DOI: 10.15252/embj.201796516     Document Type: Article

References (78)

1. Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, Li X, Rademakers R, Kang SS, Xu H, Younkin S, Das P, Fryer JD, Bu G (2015) Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 290: 26043–26050
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
3. Borroni B, Ferrari F, Galimberti D, Nacmias B, Barone C, Bagnoli S, Fenoglio C, Piaceri I, Archetti S, Bonvicini C, Gennarelli M, Turla M, Scarpini E, Sorbi S, Padovani A (2014) Heterozygous TREM2 mutations in frontotemporal dementia. Neurobiol Aging 35: 934 e937–910
4. Brandl C, Ortiz O, Rottig B, Wefers B, Wurst W, Kuhn R (2015) Creation of targeted genomic deletions using TALEN or CRISPR/Cas nuclease pairs in one-cell mouse embryos. FEBS Open Bio 5: 26–35
5. Brendel M, Jaworska A, Herms J, Trambauer J, Rotzer C, Gildehaus FJ, Carlsen J, Cumming P, Bylund J, Luebbers T, Bartenstein P, Steiner H, Haass C, Baumann K, Rominger A (2015) Amyloid-PET predicts inhibition of de novo plaque formation upon chronic gamma-secretase modulator treatment. Mol Psychiatry 20: 1179–1187
6. Brendel M, Probst F, Jaworska A, Overhoff F, Korzhova V, Albert NL, Beck R, Lindner S, Gildehaus FJ, Baumann K, Bartenstein P, Kleinberger G, Haass C, Herms J, Rominger A (2016) Glial activation and glucose metabolism in a transgenic amyloid mouse model: a triple-tracer PET study. J Nucl Med 57: 954–960
7. Brendel M, Kleinberger G, Probst F, Jaworska A, Overhoff F, Blume T, Albert NL, Carlsen J, Lindner S, Gildehaus FJ, Ozmen L, Suarez-Calvet M, Bartenstein P, Baumann K, Ewers M, Herms J, Haass C, Rominger A (2017) Increase of TREM2 during aging of an Alzheimer's disease mouse model is paralleled by microglial activation and amyloidosis. Front Aging Neurosci 9: 8
8. Bruns A, Kunnecke B, Risterucci C, Moreau JL, von Kienlin M (2009) Validation of cerebral blood perfusion imaging as a modality for quantitative pharmacological MRI in rats. Magn Reson Med 61: 1451–1458
9. Cantoni C, Bollman B, Licastro D, Xie M, Mikesell R, Schmidt R, Yuede CM, Galimberti D, Olivecrona G, Klein RS, Cross AH, Otero K, Piccio L (2015) TREM2 regulates microglial cell activation in response to demyelination in vivo. Acta Neuropathol 129: 429–447
10. Chu VT, Weber T, Wefers B, Wurst W, Sander S, Rajewsky K, Kuhn R (2015) Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells. Nat Biotechnol 33: 543–548
11. Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, Engelborghs S, Vandenbulcke M, Van Dongen J, Geerts N, Maes G, Mattheijssens M, Peeters K, Cras P, Vandenberghe R, De Deyn PP, Van Broeckhoven C, Cruts M, Sleegers K, Consortium B (2014) Investigating the role of rare heterozygous TREM2 variants in Alzheimer's disease and frontotemporal dementia. Neurobiol Aging 35: 726.e11–726.e19
12. Cuyvers E, Sleegers K (2016) Genetic variations underlying Alzheimer's disease: evidence from genome-wide association studies and beyond. Lancet Neurol 15: 857–868
13. Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE (2003) Pattern recognition by TREM-2: binding of anionic ligands. J Immunol 171: 594–599
14. Dickens AM, Vainio S, Marjamaki P, Johansson J, Lehtiniemi P, Rokka J, Rinne J, Solin O, Haaparanta-Solin M, Jones PA, Trigg W, Anthony DC, Airas L (2014) Detection of microglial activation in an acute model of neuroinflammation using PET and radiotracers 11C-(R)-PK11195 and 18F-GE-180. J Nucl Med 55: 466–472
15. Dorr A, Sled JG, Kabani N (2007) Three-dimensional cerebral vasculature of the CBA mouse brain: a magnetic resonance imaging and micro computed tomography study. NeuroImage 35: 1409–1423
16. Glebov K, Wunderlich P, Karaca I, Walter J (2016) Functional involvement of gamma-secretase in signaling of the triggering receptor expressed on myeloid cells-2 (TREM2). J Neuroinflammation 13: 17
17. Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, Hazrati L, Collinge J, Pocock J, Lashley T, Williams J, Lambert JC, Amouyel P, Goate A, Rademakers R, Morgan K et al (2013a) TREM2 variants in Alzheimer's disease. N Engl J Med 368: 117–127
18. Guerreiro RJ, Lohmann E, Bras JM, Gibbs JR, Rohrer JD, Gurunlian N, Dursun B, Bilgic B, Hanagasi H, Gurvit H, Emre M, Singleton A, Hardy J (2013b) Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurol 70: 78–84
19. Haase A, Frahm J, Matthaei D, Hanicke W, Bomsdorf H, Kunz D, Tischler R (1986) MR imaging using stimulated echoes (STEAM). Radiology 160: 787–790
20. 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: 2051–2055
21. Henjum K, Almdahl IS, Arskog V, Minthon L, Hansson O, Fladby T, Nilsson LN (2016) Cerebrospinal fluid soluble TREM2 in aging and Alzheimer's disease. Alzheimer's Res Ther 8: 17
22. Herholz K (2011) Perfusion SPECT and FDG-PET. Int Psychogeriatr 23(Suppl. 2): S25–S31
23. Heslegrave A, Heywood W, Paterson R, Magdalinou N, Svensson J, Johansson P, Ohrfelt A, Blennow K, Hardy J, Schott J, Mills K, Zetterberg H (2016) Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease. Mol Neurodegener 11: 3
24. Hickman SE, Kingery ND, Ohsumi TK, Borowsky ML, Wang LC, Means TK, El Khoury J (2013) The microglial sensome revealed by direct RNA sequencing. Nat Neurosci 16: 1896–1905
25. Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, Seaman WE (2009) A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109: 1144–1156
26. 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: 176–185
27. Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, Rujescu D, Hampel H, Giegling I, Andreassen OA, Engedal K, Ulstein I, Djurovic S, Ibrahim-Verbaas C, Hofman A, Ikram MA et al (2013) Variant of TREM2 associated with the risk of Alzheimer's disease. N Engl J Med 368: 107–116
28. Kleinberger G, Yamanishi Y, Suarez-Calvet M, Czirr E, Lohmann E, Cuyvers E, Struyfs H, Pettkus N, Wenninger-Weinzierl A, Mazaheri F, Tahirovic S, Lleo A, Alcolea D, Fortea J, Willem M, Lammich S, Molinuevo JL, Sanchez-Valle R, Antonell A, Ramirez A et al (2014) TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6: 243ra286
29. Klunemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, De Bleecker JL, Rossor MN, Marienhagen J, Klein HE, Peltonen L, Paloneva J (2005) The genetic causes of basal ganglia calcification, dementia, and bone cysts: DAP12 and TREM2. Neurology 64: 1502–1507
30. Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ (2016) Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. eLife 5: e20391
31. Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48: 405–415
32. Liu GJ, Middleton RJ, Hatty CR, Kam WW, Chan R, Pham T, Harrison-Brown M, Dodson E, Veale K, Banati RB (2014) The 18 kDa translocator protein, microglia and neuroinflammation. Brain Pathol 24: 631–653
33. Liu B, Le KX, Park MA, Wang S, Belanger AP, Dubey S, Frost JL, Holton P, Reiser V, Jones PA, Trigg W, Di Carli MF, Lemere CA (2015) In vivo detection of age- and disease-related increases in neuroinflammation by 18F-GE180 TSPO microPET imaging in wild-type and Alzheimer's transgenic mice. J Neurosci 35: 15716–15730
34. Lourbopoulos A, Erturk A, Hellal F (2015) Microglia in action: how aging and injury can change the brain's guardians. Front Cell Neurosci 9: 54
35. Mazaheri F, Snaidero N, Kleinberger G, Madore C, Daria A, Werner G, Krasemann S, Capell A, Trümbach D, Wurst W, Brunner B, Bultmann S, Tahirovic S, Kerschensteiner M, Misgeld T, Butovsky O, Haass C (2017) TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep 18: 1186–1198
36. Mergenthaler P, Lindauer U, Dienel GA, Meisel A (2013) Sugar for the brain: the role of glucose in physiological and pathological brain function. Trends Neurosci 36: 587–597
37. 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
38. N'Diaye EN, Branda CS, Branda SS, Nevarez L, Colonna M, Lowell C, Hamerman JA, Seaman WE (2009) TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol 184: 215–223
39. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308: 1314–1318
40. Otero K, Shinohara M, Zhao H, Cella M, Gilfillan S, Colucci A, Faccio R, Ross FP, Teitelbaum SL, Takayanagi H, Colonna M (2012) TREM2 and beta-catenin regulate bone homeostasis by controlling the rate of osteoclastogenesis. J Immunol 188: 2612–2621
41. Overhoff F, Brendel M, Jaworska A, Korzhova V, Delker A, Probst F, Focke C, Gildehaus FJ, Carlsen J, Baumann K, Haass C, Bartenstein P, Herms J, Rominger A (2016) Automated spatial brain normalization and hindbrain white matter reference tissue give improved [(18)F]-Florbetaben PET quantitation in Alzheimer's model mice. Front Neurosci 10: 45
42. Paloneva J, Autti T, Raininko R, Partanen J, Salonen O, Puranen M, Hakola P, Haltia M (2001) CNS manifestations of Nasu-Hakola disease: a frontal dementia with bone cysts. Neurology 56: 1552–1558
43. Park JS, Ji IJ, An HJ, Kang MJ, Kang SW, Kim DH, Yoon SY (2015) Disease-associated mutations of TREM2 alter the processing of N-linked oligosaccharides in the golgi apparatus. Traffic 16: 510–518
44. th edn. San Diego, CA: Academic Press
45. Paxinos G, Franklin K (2001) The mouse brain in stereotaxic coordinates. New York: Academic Press
46. Piccio L, Buonsanti C, Cella M, Tassi I, Schmidt RE, Fenoglio C, Rinker J II, Naismith RT, Panina-Bordignon P, Passini N, Galimberti D, Scarpini E, Colonna M, Cross AH (2008) Identification of soluble TREM-2 in the cerebrospinal fluid and its association with multiple sclerosis and CNS inflammation. Brain 131: 3081–3091
47. Piccio L, Deming Y, Del-Aguila JL, Ghezzi L, Holtzman DM, Fagan AM, Fenoglio C, Galimberti D, Borroni B, Cruchaga C (2016) Cerebrospinal fluid soluble TREM2 is higher in Alzheimer disease and associated with mutation status. Acta Neuropathol 131: 925–933
48. Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M (2015) TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 125: 2161–2170
49. Raichle ME (1998) Behind the scenes of functional brain imaging: a historical and physiological perspective. Proc Natl Acad Sci USA 95: 765–772
50. Rayaprolu S, Mullen B, Baker M, Lynch T, Finger E, Seeley WW, Hatanpaa KJ, Lomen-Hoerth C, Kertesz A, Bigio EH, Lippa C, Josephs KA, Knopman DS, White CL III, Caselli R, Mackenzie IR, Miller BL, Boczarska-Jedynak M, Opala G, Krygowska-Wajs A et al (2013) TREM2 in neurodegeneration: evidence for association of the p. R47H variant with frontotemporal dementia and Parkinson's disease. Mol Neurodegener 8: 19
51. Salter MW, Beggs S (2014) Sublime microglia: expanding roles for the guardians of the CNS. Cell 158: 15–24
52. Schelle J, Hasler L, Gopfert JC, Joos TO, Vanderstichele H, Stoops E, Mandelkow EM, Neumann U, Shimshek DR, Staufenbiel M, Jucker M, Kaeser SA (2016) Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimer's Dement 13: 701–709
53. Singh S, Metz I, Amor S, van der Valk P, Stadelmann C, Bruck W (2013) Microglial nodules in early multiple sclerosis white matter are associated with degenerating axons. Acta Neuropathol 125: 595–608
54. Sokoloff L (1977) Relation between physiological function and energy metabolism in the central nervous system. J Neurochem 29: 13–26
55. Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28: 897–916
56. Sokoloff L (1999) Energetics of functional activation in neural tissues. Neurochem Res 24: 321–329
57. Suarez-Calvet M, Caballero M, Kleinberger G, Bateman R, Fagan AM, Morris J, Levin J, Danek A, Ewers M, Haass C, Network ftDIA (2016a) Early changes of CSF sTREM2 in dominantly inherited Alzheimer's disease follow markers of amyloid deposition and neuronal injury. Sci Transl Med 8: 369ra178
58. Suarez-Calvet M, Kleinberger G, Araque Caballero MA, Brendel M, Rominger A, Alcolea D, Fortea J, Lleo A, Blesa R, Gispert JD, Sanchez-Valle R, Antonell A, Rami L, Molinuevo JL, Brosseron F, Traschutz A, Heneka MT, Struyfs H, Engelborghs S, Sleegers K et al (2016b) 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: 466–476
59. 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: 647–657
60. Takeshita T, Kaminaga T, Tatsumi T, Hatanaka Y, Furui S (2005) Regional cerebral blood flow in a patient with Nasu-Hakola disease. Ann Nucl Med 19: 309–312
61. Tosun D, Schuff N, Rabinovici GD, Ayakta N, Miller BL, Jagust W, Kramer J, Weiner MM, Rosen HJ (2016) Diagnostic utility of ASL-MRI and FDG-PET in the behavioral variant of FTD and AD. Ann Clin Transl Neurol 3: 740–751
62. Tremblay ME, Majewska AK (2011) A role for microglia in synaptic plasticity? Commun Integr Biol 4: 220–222
63. Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, Hernandez M, Colonna M (2006) Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177: 3520–3524
64. Ueki Y, Kohara N, Oga T, Fukuyama H, Akiguchi I, Kimura J, Shibasaki H (2000) Membranous lipodystrophy presenting with palilalia: a PET study of cerebral glucose metabolism. Acta Neurol Scand 102: 60–64
65. Varrone A, Asenbaum S, Vander Borght T, Booij J, Nobili F, Nagren K, Darcourt J, Kapucu OL, Tatsch K, Bartenstein P, Van Laere K, European Association of Nuclear Medicine Neuroimaging C (2009) EANM procedure guidelines for PET brain imaging using [18F]FDG, version 2. Eur J Nucl Med Mol Imaging 36: 2103–2110
66. Verfaillie SC, Adriaanse SM, Binnewijzend MA, Benedictus MR, Ossenkoppele R, Wattjes MP, Pijnenburg YA, van der Flier WM, Lammertsma AA, Kuijer JP, Boellaard R, Scheltens P, van Berckel BN, Barkhof F (2015) Cerebral perfusion and glucose metabolism in Alzheimer's disease and frontotemporal dementia: two sides of the same coin? Eur Radiol 25: 3050–3059
67. Villegas-Llerena C, Phillips A, Garcia-Reitboeck P, Hardy J, Pocock JM (2016) Microglial genes regulating neuroinflammation in the progression of Alzheimer's disease. Curr Opin Neurobiol 36: 74–81
68. Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH, Holtzman DM, Cirrito JR, Colonna M (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell 160: 1061–1071
69. Wefers B, Panda SK, Ortiz O, Brandl C, Hensler S, Hansen J, Wurst W, Kuhn R (2013) Generation of targeted mouse mutants by embryo microinjection of TALEN mRNA. Nat Protoc 8: 2355–2379
70. Wickstrom T, Clarke A, Gausemel I, Horn E, Jorgensen K, Khan I, Mantzilas D, Rajanayagam T, in‘t Veld DJ, Trigg W (2014) The development of an automated and GMP compliant FASTlab Synthesis of [(18) F]GE-180; a radiotracer for imaging translocator protein (TSPO). J Labelled Compd Radiopharm 57: 42–48
71. Williams DS, Detre JA, Leigh JS, Koretsky AP (1992) Magnetic resonance imaging of perfusion using spin inversion of arterial water. Proc Natl Acad Sci USA 89: 212–216
72. Wu K, Byers DE, Jin X, Agapov E, Alexander-Brett J, Patel AC, Cella M, Gilfilan S, Colonna M, Kober DL, Brett TJ, Holtzman MJ (2015) TREM-2 promotes macrophage survival and lung disease after respiratory viral infection. J Exp Med 212: 681–697
73. Wunderlich P, Glebov K, Kemmerling N, Tien NT, Neumann H, Walter J (2013) Sequential proteolytic processing of the triggering receptor expressed on myeloid cells-2 (TREM2) protein by ectodomain shedding and gamma-secretase-dependent intramembranous cleavage. J Biol Chem 288: 33027–33036
74. Xiang X, Werner G, Bohrmann B, Liesz A, Mazaheri F, Capell A, Feederle R, Knuesel I, Kleinberger G, Haass C (2016) TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance. EMBO Mol Med 8: 992–1004
75. Yang W, Tu Z, Sun Q, Li XJ (2016) CRISPR/Cas9: implications for modeling and therapy of neurodegenerative diseases. Front Mol Neurosci 9: 30
76. Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M (2016) TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91: 328–340
77. Zhong L, Chen XF, Zhang ZL, Wang Z, Shi XZ, Xu K, Zhang YW, Xu H, Bu G (2015) DAP12 stabilizes the C-terminal fragment of the triggering receptor expressed on myeloid cells-2 (TREM2) and protects against LPS-induced pro-inflammatory response. J Biol Chem 290: 15866–15877
78. Zhong L, Chen XF, Wang T, Wang Z, Liao C, Wang Z, Huang R, Wang D, Li X, Wu L, Jia L, Zheng H, Painter M, Atagi Y, Liu CC, Zhang YW, Fryer JD, Xu H, Bu G (2017) Soluble TREM2 induces inflammatory responses and enhances microglial survival. J Exp Med 214: 597–607