Abstract
Alzheimer's Disease (AD) is age-related neurodegenerative disorder recognized by a steadily gradual cognitive decline that has devastating personal and socioeconomic implications. Recently, some genetic factors for AD have been identified which attracted wide attention of researchers in different areas of AD biology and possible new therapeutic targets. Alternative forms of triggering receptor expressed on myeloid cells 2 (TREM2) genes are examples of such risk factors, which contribute higher risk for developing AD. Comprehending TREM2 function pledge to provide salient insight into how neuroinflammation contributes to AD pathology. The dearth of microglial TREM2 shepherd to augmented tau pathology is couple with frequent enhancement of activated neuronal stress kinases. The involvement of TREM2 in the regulation of tau-associated innate immune response of the CNS has clearly demonstrated through these findings. However, whether decrease level of TREM2 assists pathology of tau through changed clearance and pathological escalation of tau or through direct contact between microglia and neuron and any alternative possible mechanisms need to examine. This review briefly summarizes distinct functional roles of TREM2 in AD pathology and highlights the TREM2 gene regulation. We have also addressed the impact of TREM2 on β-amyloid plaques and tau pathology in Alzheimer’s disease.
Keywords: Alzheimer’s disease, TREM2, β-amyloid plaques, tau pathology, microglia, neuronal degeneration.
[1]
Wang WY, Tan MS, Yu JT, Tan L. Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann Transl Med 3(10): 136. (2015)
[2]
Zhao Y, Jaber V, Lukiw WJ. Over-expressed pathogenic miRNAs in Alzheimer’s disease (AD) and prion disease (PrD) drive deficits in TREM2-mediated Aβ42 peptide clearance. Front Aging Neurosci 8(14): 140. (2016)
[5]
Karch CM, Cruchaga C, Goate AM. Alzheimer’s disease genetics: from the bench to the clinic. Neuron 83(1): 11-26. (2014)
[6]
Bertram L, Tanzi RE. The genetics of Alzheimer’s disease. In Progress in molecular biology and translational science. Acad Press 107: 79-100. (2012)
[7]
Wingo TS, Lah JJ, Levey AI, Cutler DJ. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol 69(1): 59-64. (2012)
[8]
Bruni AC, Conidi ME, Bernardi L. Genetics in degenerative dementia: current status and applicability. Alzheimer Dis Assoc Disord 28(3): 199-205. (2014)
[9]
Di Marco LY, Marzo A, Muñoz-Ruiz M, Ikram MA, Kivipelto M, Ruefenacht D, et al. Modifiable lifestyle factors in dementia: a systematic review of longitudinal observational cohort studies. J Alzheimers Dis 42(1): 119-35. (2014)
[10]
Potter H, Wisniewski T. Apolipoprotein E: essential catalyst of the Alzheimer amyloid cascade. Intern J Alzheimer’s Dis 2012: (2012)
[11]
Boutajangout A, Wisniewski T. The innate immune system in Alzheimer’s disease. Int J Cell Biol 2013489428 (2013)
[12]
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al. TREM2 variants in Alzheimer’s disease. N Engl J Med 368(2): 117-27. (2013)
[13]
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368(2): 107-16. (2013)
[14]
Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, et al. Coding variants in TREM2 increase risk for Alzheimer’s disease. Hum Mol Genet 23(21): 5838-46. (2014)
[15]
Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, et al. Alzheimer’s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement 13(4): 381-7. (2017)
[16]
Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, O’Keeffe S, et al. An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34(36): 11929-47. (2014)
[17]
Srinivasan K, Friedman BA, Larson JL, Lauffer BE, Goldstein LD, Appling LL, et al. Untangling the brain’s neuroinflammatory and neurodegenerative transcriptional responses. Nat Commun 21(7): 11295. (2016)
[18]
Baruah S, Keck K, Vrenios M, Pope MR, Pearl M, Doerschug K, et al. Identification of a novel splice variant isoform of TREM-1 in human neutrophil granules. J Immunol 195: 5725-31. (2015)
[19]
Jay TR, Von Saucken VE, Landreth GE. TREM2 in neurodegenerative diseases. Mol Neurodegener 12(1): 56. (2017)
[20]
Yeh FL, Hansen DV, Sheng M. TREM2, microglia, and neurodegenerative diseases. Trends Mol Med 23(6): 512-33. (2017)
[21]
Ulrich JD, Ulland TK, Colonna M, Holtzman DM. Elucidating the role of TREM2 in Alzheimer’s disease. Neuron 94(2): 237-48. (2017)
[22]
Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, et al. TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160(6): 1061-71. (2015)
[23]
Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, et al. TREM2 sustains microglial expansion during aging and response to demyelination. J Clin Invest 125(5): 2161-70. (2015)
[24]
Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al. TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Sci Transl Med 6(243)243ra86 (2014)
[25]
Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, et al. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem 109(4): 1144-56. (2009)
[26]
Hall SC, Agrawal DK. Increased TREM-2 expression on the subsets of CD11c+ cells in the lungs and lymph nodes during allergic airway inflammation. Sci Rep 7(1): 11853. (2017)
[27]
Replogle JM, Chan G, White CC, Raj T, Winn PA, Evans DA, et al. A TREM 1 variant alters the accumulation of Alzheimer‐related amyloid pathology. Ann Neurol 77(3): 469-77. (2015)
[28]
Benitez BA, Jin SC, Guerreiro R, Graham R, Lord J, Harold D, et al. Missense variant in TREML2 protects against Alzheimer’s disease. Neurobiol Aging 35(6): 1510.e19-. (2014)
[29]
Liu G. No association of TREM1 rs6910730 and TREM2 rs7759295 with Alzheimer disease. Ann Neurol 78(4): 659. (2015)
[30]
Slattery CF, Beck JA, Harper L, Adamson G, Abdi Z, Uphill J, et al. R47H TREM2 variant increases risk of typical early-onset Alzheimer’s disease but not of prion or frontotemporal dementia. Alzheimers Dement 10(6): 602-8. (2014)
[32]
Luis EO, Ortega-Cubero S, Lamet I, Razquin C, Cruchaga C, Benitez BA, et al. Alzheimer’s Disease Neuroimaging Initiative (ADNI. Frontobasal gray matter loss is associated with the TREM2 p. R47H variant. Neurobiol Aging 35(12): 2681-90. (2014)
[33]
Korvatska O, Leverenz JB, Jayadev S, McMillan P, Kurtz I, Guo X, et al. R47H variant of TREM2 associated with Alzheimer disease in a large late-onset family: clinical, genetic, and neuropathological study. JAMA Neurol 72(8): 920-7. (2015)
[34]
N’Diaye EN, Branda CS, Branda SS, Nevarez L, Colonna M, Lowell C, et al. TREM-2 (triggering receptor expressed on myeloid cells 2) is a phagocytic receptor for bacteria. J Cell Biol 184(2): 215-23. (2009)
[35]
Mecca C, Giambanco I, Donato R, Arcuri C. Microglia and Aging: The role of the TREM2-DAP12 and CX3CL1-CX3CR1 Axes. Int J Mol Sci 19(1): 318. (2018)
[36]
Peng Q, Malhotra S, Torchia JA, Kerr WG, Coggeshall KM, Humphrey MB. TREM2-and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Sci Signal 3(122): ra38. (2010)
[37]
Gwack Y, Feske S, Srikanth S, Hogan PG, Rao A. Signalling to transcription: store-operated Ca2+ entry and NFAT activation in lymphocytes. Cell Calcium 42(2): 145-56. (2007)
[38]
Humphrey MB, Nakamura MC. A comprehensive review of immunoreceptor regulation of osteoclasts. Clin Rev Allergy Immunol 51(1): 48-58. (2016)
[39]
Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al. Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer’s disease. Nat Genet 43(5): 436. (2011)
[40]
Turnbull IR, Gilfillan S, Cella M, Aoshi T, Miller M, Piccio L, et al. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol 177(6): 3520-4. (2006)
[41]
Gonçalves LA, Rodrigues-Duarte L, Rodo J, de Moraes LV, Marques I, Penha-Gonçalves C. TREM2 governs Kupffer cell activation and explains belr1 genetic resistance to malaria liver stage infection. Proc Natl Acad Sci USA 110(48): 19531-6. (2013)
[42]
Gao X, Dong Y, Liu Z, Niu B. Silencing of triggering receptor expressed on myeloid cells-2 enhances the inflammatory responses of alveolar macrophages to lipopolysaccharide. Mol Med Rep 7(3): 921-6. (2013)
[43]
Sharif O, Gawish R, Warszawska JM, Martins R, Lakovits K, Hladik A, et al. The triggering receptor expressed on myeloid cells 2 inhibits complement component 1q effector mechanisms and exerts detrimental effects during pneumococcal pneumonia. PLoS Pathog 10(6)e1004167 (2014)
[44]
Zheng H, Liu CC, Atagi Y, Chen XF, Jia L, Yang 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: 132-41. (2016)
[45]
Chen LC, Laskin JD, Gordon MK, Laskin DL. Regulation of TREM expression in hepatic macrophages and endothelial cells during acute endotoxemia. Exp Mol Pathol 84(2): 145-55. (2008)
[46]
Gawish R, Martins R, Böhm B, Wimberger T, Sharif O, Lakovits K, et al. Triggering receptor expressed on myeloid cells-2 fine-tunes inflammatory responses in murine Gram-negative sepsis. FASEB J 29(4): 1247-57. (2014)
[47]
Zhao Y, Bhattacharjee S, Jones BM, Dua P, Alexandrov PN, Hill JM, et al. Regulation of TREM2 expression by an NF-κB-sensitive miRNA-34a. Neuroreport 24(6): 318. (2013)
[48]
Bhattacharjee S, Zhao Y, Dua P, Rogaev EI, Lukiw WJ. microRNA-34a-mediated down-regulation of the microglial-enriched triggering receptor and phagocytosis-sensor TREM2 in age-related macular degeneration. PLoS One 11(3)e0150211 (2016)
[49]
Ratnayaka JA, Serpell LC, Lotery AJ. Dementia of the eye: the role of amyloid beta in retinal degeneration. Eye 29(8): 1013. (2015)
[50]
Lynn SA, Keeling E, Munday R, Gabha G, Griffiths H, Lotery AJ, et al. The complexities underlying age-related macular degeneration: could amyloid beta play an important role? Neural Regen Res 12(4): 538. (2017)
[51]
Orre M, Kamphuis W, Osborn LM, Jansen AH, Kooijman L, Bossers K, et al. Isolation of glia from Alzheimer’s mice reveals inflammation and dysfunction. Neurobiol Aging 35(12): 2746-60. (2014)
[52]
Weehuizen TA, Hommes TJ, Lankelma JM, de Jong HK, Roelofs JJ, de Vos AF, et al. Triggering receptor expressed on myeloid cells (TREM)-2 impairs host defense in experimental melioidosis. PLoS Negl Trop Dis 10(6)e0004747 (2016)
[53]
Takahashi K, Prinz M, Stagi M, Chechneva O, Neumann H. TREM2-transduced myeloid precursors mediate nervous tissue debris clearance and facilitate recovery in an animal model of multiple sclerosis. PLoS Med 4(4)e124 (2007)
[54]
Cannon JP, O’Driscoll M, Litman GW. Specific lipid recognition is a general feature of CD300 and TREM molecules. Immunogenetics 64(1): 39-47. (2012)
[55]
Bailey CC, DeVaux LB, Farzan M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J Biol Chem 290(43): 26033-42. (2015)
[56]
Roe K, Gibot S, Verma S. Triggering receptor expressed on myeloid cells-1 (TREM-1): a new player in antiviral immunity? Front Microbiol 5: 627. (2014)
[57]
Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, et al. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife 5. pii: e20391(2016)
[58]
Yeh FL, Wang Y, Tom I, Gonzalez LC, Sheng M. TREM2 binds to apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-beta by microglia. Neuron 91(2): 328-40. (2016)
[59]
Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C. Zheng Het al. Apolipoprotein E is a ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem 290(43): 26043-50. (2015)
[60]
Holtzman DM, Herz J, Bu G. Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. Cold Spring Harb Perspect Med 2(3)a006312 (2012)
[61]
Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, Small G, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261(5123): 921-3. (1993)
[62]
Strittmatter WJ, Saunders AM, Schmechel D, Pericak-Vance M, Enghild J, Salvesen GS, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci USA 90(5): 1977-81. (1993)
[63]
Hanson AJ, Bayer-Carter JL, Green PS, Montine TJ, Wilkinson CW, Baker LD, et al. Effect of apolipoprotein E genotype and diet on apolipoprotein E lipidation and amyloid peptides: randomized clinical trial. JAMA Neurol 70(8): 972-80. (2013)
[64]
Youmans KL, Tai LM, Nwabuisi-Heath E, Jungbauer L, Kanekiyo T, Gan M, et al. APOE4-specific changes in Aβ accumulation in a new transgenic model of Alzheimer’s Disease. J Biol Chem 287(50): 41774-86. (2012)
[65]
Tai LM, Koster KP, Luo J, Lee SH, Wang YT, Collins NC, et al. Amyloid-β pathology and APOE genotype modulate retinoid X receptor agonist activity in vivo. J Biol Chem 289(44): 30538-55. (2014)
[66]
Daws MR, Sullam PM, Niemi EC, Chen TT, Tchao NK, Seaman WE. Pattern recognition by TREM-2: binding of anionic ligands. J Immunol 171(2): 594-9. (2003)
[67]
Hamerman JA, Jarjoura JR, Humphrey MB, Nakamura MC, Seaman WE, Lanier LL. 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): 2051-5. (2006)
[68]
Bouchon A, Hernández-Munain C, Cella M, Colonna MA. DAP12-mediated pathway regulates expression of CC chemokine receptor 7 and maturation of human dendritic cells. J Exp Med 194(8): 1111-22. (2001)
[69]
Calero M, Rostagno A, Matsubara E, Zlokovic B, Frangione B, Ghiso J. Apolipoprotein J (clusterin) and Alzheimer’s disease. Microsc Res Tech 50(4): 305-15. (2000)
[70]
Huynh TP, Davis AA, Ulrich JD, Holtzman DM. Apolipoprotein E and Alzheimer’s disease: the influence of apolipoprotein E on amyloid-ß and other amyloidogenic proteins. J Lipid Res 58(5): 824-36. (2017)
[72]
Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, et al. Axonopathy and transport deficits early in the pathogenesis of Alzheimer’s disease. Science 307(5713): 1282-8. (2005)
[73]
Mathew A, Fukuda T, Nagaoka Y, Hasumura T, Morimoto H, Yoshida Y, et al. Curcumin loaded-PLGA nanoparticles conjugated with Tet-1 peptide for potential use in Alzheimer’s disease. PLoS One 7(3)e32616 (2012)
[74]
Jack Jr CR, Knopman DS, Jagust WJ, Petersen RC, Weiner MW, Aisen PS, et al. Tracking pathophysiological processes in Alzheimer’s disease: an updated hypothetical model of dynamic biomarkers. Lancet Neurol 12(2): 207-16. (2013)
[75]
Sperling RA, Aisen PS, Beckett LA, Bennett DA, Craft S, Fagan AM, et al. Toward defining the preclinical stages of Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 280-92. (2011)
[76]
Hardy J. The amyloid hypothesis for Alzheimer’s disease: a critical reappraisal. J Neurochem 110(4): 1129-34. (2009)
[77]
Haass C. Take five-BACE and the γ‐secretase quartet conduct Alzheimer’s amyloid β‐peptide generation. EMBO J 23(3): 483-8. (2004)
[78]
Prokop S, Miller KR, Drost N, Handrick S, Mathur V, Luo J, et al. Impact of peripheral myeloid cells on amyloid-β pathology in Alzheimer’s disease-like mice. J Exp Med 212(11): 1811-8. (2015)
[79]
Spangenberg EE, Lee RJ, Najafi AR, Rice RA, Elmore MR, Blurton-Jones M, et al. Eliminating microglia in Alzheimer’s mice prevents neuronal loss without modulating amyloid-β pathology. Brain 139(4): 1265-81. (2016)
[80]
Varvel NH, Grathwohl SA, Degenhardt K, Resch C, Bosch A, Jucker M, et al. Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer’s disease. J Exp Med 212(11): 1803-9. (2015)
[81]
Guillot-Sestier MV, Doty KR, Gate D, Rodriguez J, Leung BP, Rezai-Zadeh K, et al. Il10 deficiency rebalances innate immunity to mitigate Alzheimer-like pathology. Neuron 85(3): 534-48. (2015)
[82]
Chakrabarty P, Li A, Ceballos-Diaz C, Eddy JA, Funk CC, Moore B, et al. IL-10 alters immunoproteostasis in APP mice, increasing plaque burden and worsening cognitive behavior. Neuron 85(3): 519-33. (2015)
[83]
Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, et al. CD33 Alzheimer’s disease locus: altered monocyte function and amyloid biology. Nat Neurosci 16(7): 848. (2013)
[84]
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al. Alzheimer’s disease risk gene CD33 inhibits microglial uptake of amyloid beta. Neuron 78(4): 631-43. (2013)
[85]
Savage JC, Jay T, Goduni E, Quigley C, Mariani MM, Malm T, et al. Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer’s disease. J Neurosci 35(16): 6532-43. (2015)
[86]
Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14(7): 463. (2014)
[87]
Ma L, Allen M, Sakae N, Ertekin-Taner N, Graff-Radford NR, Dickson DW, et al. Expression and processing analyses of wild type and p. R47H TREM2 variant in Alzheimer’s disease brains. Molecular Neurodegeneration 11(1): 72. (2016)
[88]
Jay TR, Hirsch AM, Broihier ML, Miller CM, Neilson LE, Ransohoff RM, et al. Disease progression-dependent effects of TREM2 deficiency in a mouse model of Alzheimer’s disease. J Neurosci 2110-6. (2016)
[89]
Yuan P, Condello C, Keene CD, Wang Y, Bird TD, Paul SM, et al. TREM2 haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron 90(4): 724-39. (2016)
[90]
Matarin M, Salih DA, Yasvoina M, Cummings DM, Guelfi S, Liu W, et al. A genome-wide gene-expression analysis and database in transgenic mice during development of amyloid or tau pathology. Cell Rep 10(4): 633-44. (2015)
[91]
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, et al. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease. Cell 153(3): 707-20. (2013)
[92]
Lefterov I, Schug J, Mounier A, Nam KN, Fitz NF, Koldamova R. RNA-sequencing reveals transcriptional up-regulation of TREM2 in response to bexarotene treatment. Neurobiol Dis 82: 132-40. (2015)
[93]
Jay TR, Miller CM, Cheng PJ, Graham LC, Bemiller S, Broihier ML, et al. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 2014: 2322. (2015)
[94]
Ulrich JD, Finn MB, Wang Y, Shen A, Mahan TE, Jiang H, et al. Altered microglial response to Aβ plaques in APPPS1-21 mice heterozygous for TREM2. Mol Neurodegener 9(1): 20. (2014)
[95]
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al. A unique microglia type associated with restricting development of Alzheimer’s disease. Cell 169(7): 1276-90. (2017)
[96]
Butovsky O, Jedrychowski MP, Cialic R, Krasemann S, Murugaiyan G, Fanek Z, et al. Targeting mi R‐155 restores abnormal microglia and attenuates disease in SOD 1 mice. Ann Neurol 77(1): 75-99. (2015)
[97]
Wang Y, Ulland TK, Ulrich JD, Song W, Tzaferis JA, Hole JT, et al. TREM2-mediated early microglial response limits diffusion and toxicity of amyloid plaques. J Exp Med 2015: 1948. (2016)
[98]
Naert G, Rivest S. A deficiency in CCR2+ monocytes: the hidden side of Alzheimer’s disease. J Mol Cell Biol 5(5): 284-93. (2013)
[99]
Öhrfelt A, Axelsson M, Malmeström C, Novakova L, Heslegrave A, Blennow K, et al. Soluble TREM-2 in cerebrospinal fluid from patients with multiple sclerosis treated with natalizumab or mitoxantrone. Mult Scler J22(12): 1587-95. (2016)
[100]
Elmore MR, Najafi AR, Koike MA, Dagher NN, Spangenberg EE, Rice RA, et al. Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain. Neuron 82(2): 380-97. (2014)
[101]
Wang Y, Szretter KJ, Vermi W, Gilfillan S, Rossini C, Cella M, et al. IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia. Nat Immunol 13(8): 753. (2012)
[102]
Dagher NN, Najafi AR, Kayala KM, Elmore MR, White TE, Medeiros R, et al. Colony-stimulating factor 1 receptor inhibition prevents microglial plaque association and improves cognition in 3xTg-AD mice. J Neuroinflammation 12(1): 139. (2015)
[103]
Rademakers R, Baker M, Nicholson AM, Rutherford NJ, Finch N, Soto-Ortolaza A, et al. Mutations in the colony stimulating factor 1 receptor (CSF1R) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat Genet 44(2): 200. (2012)
[104]
Condello C, Yuan P, Schain A, Grutzendler J. Microglia constitute a barrier that prevents neurotoxic protofibrillar Aβ42 hotspots around plaques. Nat Commun 6: 6176. (2015)
[105]
Jawhar S, Trawicka A, Jenneckens C, Bayer TA, Wirths O. Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal Aβ aggregation in the 5XFAD mouse model of Alzheimer’s disease. Neurobiol Aging 33(1): 196-e29. (2012)
[106]
Radde R, Bolmont T, Kaeser SA, Coomaraswamy J, Lindau D, Stoltze L, et al. Aβ42‐driven cerebral amyloidosis in transgenic mice reveals early and robust pathology. EMBO Rep 7(9): 940-6. (2006)
[107]
Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, et al. Single App knock-in mouse models of Alzheimer’s disease. Nat Neurosci 17(5): 661. (2014)
[108]
Barnes AP, Polleux F. Establishment of axon-dendrite polarity in developing neurons. Annu Rev Neurosci 32: 347-81. (2009)
[109]
Ballatore C, Lee VM, Trojanowski JQ. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nat Rev Neurosci 8(9): 663. (2007)
[110]
Clark CM, Xie S, Chittams J, Ewbank D, Peskind E, Galasko D, et al. Cerebrospinal fluid tau and β-amyloid: how well do these biomarkers reflect autopsy-confirmed dementia diagnoses? Arch Neurol 60(12): 1696-702. (2003)
[111]
Grossberg GT, Pejovic V, Miller ML. Current strategies for the treatment and prevention of Alzheimer’s disease. Prim Psychiatry 14(8): 39-54. (2007)
[112]
Jiang T, Zhang YD, Chen Q, Gao Q, Zhu XC, Zhou JS, et al. TREM2 modifies microglial phenotype and provides neuroprotection in P301S tau transgenic mice. Neuropharmacology 105: 196-206. (2016)
[113]
Lue LF, Schmitz CT, Serrano G, Sue LI, Beach TG, Walker DG. TREM 2 protein expression changes correlate with Alzheimer’s disease neurodegenerative pathologies in post‐mortem temporal cortices. Brain Pathol 25(4): 469-80. (2015)
[114]
Suárez‐Calvet M, Kleinberger G, Caballero MÁ, Brendel M, Rominger A, Alcolea 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 3e201506123 (2016)
[115]
Chan G, White CC, Winn PA, Cimpean M, Replogle JM, Glick LR, et al. CD33 modulates TREM2: convergence of Alzheimer loci. Nat Neurosci 18(11): 1556. (2015)
[116]
Rajagopalan P, Hibar DP, Thompson PM. TREM2 risk variant and loss of brain tissue. N Engl J Med 369(16): 1565. (2013)
[117]
Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, et al. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron 53(3): 337-51. (2007)
[118]
Maphis N, Xu G, Kokiko-Cochran ON, Jiang S, Cardona A, Ransohoff RM, et al. Reactive microglia drive tau pathology and contribute to the spreading of pathological tau in the brain. Brain 138(6): 1738-55. (2015)
[119]
Bemiller SM, McCray TJ, Allan K, Formica SV, Xu G, Wilson G, et al. TREM2 deficiency exacerbates tau pathology through dysregulated kinase signaling in a mouse model of tauopathy. Mol Neurodegener 12(1): 74. (2017)
[120]
Mazaheri F, Snaidero N, Kleinberger G, Madore C, Daria A, Werner G, et al. TREM2 deficiency impairs chemotaxis and microglial responses to neuronal injury. EMBO Rep 8e201743922 (2017)
[121]
Guerreiro RJ, Lohmann E, Brás JM, Gibbs JR, Rohrer JD, Gurunlian N, et al. Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia–like syndrome without bone involvement. JAMA Neurol 70(1): 78-84. (2013)
[122]
Giraldo M, Lopera F, Siniard AL, Corneveaux JJ, Schrauwen I, Carvajal J, et al. 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(8): 2077-e11. (2013)
[123]
Cuyvers E, Bettens K, Philtjens S, Van Langenhove T, Gijselinck I, van der Zee J, et al. Investigating the role of rare heterozygous TREM2 variants in Alzheimer’s disease and frontotemporal dementia. Neurobiol Aging 35(3): 726-e11. (2014)
[124]
Klünemann HH, Ridha BH, Magy L, Wherrett JR, Hemelsoet DM, Keen RW, et al. The genetic causes of basal ganglia calcification, dementia, and bone cysts DAP12 and TREM2. Neurology 64(9): 1502-7. (2005)
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