Paper
- Alzforum Recommends
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. TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell. 2015 Mar 12;160(6):1061-71. Epub 2015 Feb 26 PubMed.
Please login to recommend the paper.
Comments
Klinik und Poliklinik für Neurologie
Neuroinflammatory mechanisms have emerged as an important feature and pathogenic event in Alzheimer’s disease. Recently, mutations in TREM2 have been identified as risk factors for the development of the sporadic type of this neurodegenerative disease. In this study, the Colonna group publishes the first profound analysis of microglial TREM2 function in murine AD models. One of the most intriguing findings of this study is that TREM2-deficient microglia seem to show an impaired reaction to Aβ deposition. Since TREM2-deficient 5xFAD mice showed an increase in the overall Aβ load in the hippocampus, this suggest that, at the investigated time point, TREM2 mediated mechanisms that restrict the deposition of Aβ. In keeping with this, TREM2 deficiency impaired microglial recruitment to the site of Aβ deposition. Importantly, the authors excluded, at least by in vitro experiments, that TREM2 deficiency affects microglia Aβ phagocytosis or degradation directly.
Instead TREM2 seems to be involved in microglial survival mechanisms and TREM2 deficiency increased microglial apoptosis, possibly linked to restricted colony-stimulating factor 1 levels. Alternatively, TREM2-deficient cells may harm themselves by an increased release of TNFα, although several types of microglial cell death need to be considered (Kim and Li , 2013; Jung et al. 2005). Thus, TREM2-deficient microglia seem to not survive the Aβ challenge and therefore fail to mount an appropriate clearance response, in line with previous findings showing that improving microglial phagocytosis in vivo can restrict Aβ deposition (Heneka et al., 2013).
Another important finding of this study is that TREM2 is not activated by Aβ itself, as previously suggested, but by certain anionic membrane phospholipids, a a response that was severely limited by the human R47H mutation, which has been linked to sporadic AD. Therefore, TREM2 expression at Aβ plaque sites (Frank et al., 2008; Lue et al., 2014) can be interpreted as an attempt to survive the local inflammatory and toxic milieu, a prerequisite to restrict Aβ accumulation by phagocytosis or release of degrading proteases.
Overall this study further highlights the role of microglia in neurodegeneration and in particular in Alzheimer’s disease. Similar to previous studies, (e.g., Bradshaw et al., 2013) it points to microglial uptake and degradation of Aβ as an important method for restricting the peptide's accumulation. Given the plethora of GWAS-identified mutations that are potentially linked to immune function (Lambert et al., 2013), it can be expected that further disease-relevant microglial functions will be discovered.
Naturally, these findings fuel the hope of developing therapeutics that modify microglia functions. For this to be successful, we need to consider not only the different innate immune mechanisms, but the precise disease stage when they manifest.
References:
Kim SJ, Li J. Caspase blockade induces RIP3-mediated programmed necrosis in Toll-like receptor-activated microglia. Cell Death Dis. 2013 Jul 11;4:e716. PubMed.
Jung DY, Lee H, Suk K. Pro-apoptotic activity of N-myc in activation-induced cell death of microglia. J Neurochem. 2005 Jul;94(1):249-56. PubMed.
Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, Gelpi E, Halle A, Korte M, Latz E, Golenbock DT. NLRP3 is activated in Alzheimer's disease and contributes to pathology in APP/PS1 mice. Nature. 2013 Jan 31;493(7434):674-8. Epub 2012 Dec 19 PubMed.
Frank S, Burbach GJ, Bonin M, Walter M, Streit W, Bechmann I, Deller T. TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia. 2008 Oct;56(13):1438-47. PubMed.
Lue LF, Schmitz CT, Serrano G, Sue LI, Beach TG, Walker DG. TREM2 Protein Expression Changes Correlate with Alzheimer's Disease Neurodegenerative Pathologies in Post-Mortem Temporal Cortices. Brain Pathol. 2014 Sep 3; PubMed.
Bradshaw EM, Chibnik LB, Keenan BT, Ottoboni L, Raj T, Tang A, Rosenkrantz LL, Imboywa S, Lee M, Von Korff A, , Morris MC, Evans DA, Johnson K, Sperling RA, Schneider JA, Bennett DA, De Jager PL. CD33 Alzheimer's disease locus: altered monocyte function and amyloid biology. Nat Neurosci. 2013 Jul;16(7):848-50. PubMed.
Lambert JC, Ibrahim-Verbaas CA, Harold D, Naj AC, Sims R, Bellenguez C, DeStafano AL, Bis JC, Beecham GW, Grenier-Boley B, Russo G, Thorton-Wells TA, Jones N, Smith AV, Chouraki V, Thomas C, Ikram MA, Zelenika D, Vardarajan BN, Kamatani Y, Lin CF, Gerrish A, Schmidt H, Kunkle B, Dunstan ML, Ruiz A, Bihoreau MT, Choi SH, Reitz C, Pasquier F, Cruchaga C, Craig D, Amin N, Berr C, Lopez OL, De Jager PL, Deramecourt V, Johnston JA, Evans D, Lovestone S, Letenneur L, Morón FJ, Rubinsztein DC, Eiriksdottir G, Sleegers K, Goate AM, Fiévet N, Huentelman MW, Gill M, Brown K, Kamboh MI, Keller L, Barberger-Gateau P, McGuiness B, Larson EB, Green R, Myers AJ, Dufouil C, Todd S, Wallon D, Love S, Rogaeva E, Gallacher J, St George-Hyslop P, Clarimon J, Lleo A, Bayer A, Tsuang DW, Yu L, Tsolaki M, Bossù P, Spalletta G, Proitsi P, Collinge J, Sorbi S, Sanchez-Garcia F, Fox NC, Hardy J, Deniz Naranjo MC, Bosco P, Clarke R, Brayne C, Galimberti D, Mancuso M, Matthews F, European Alzheimer's Disease Initiative (EADI), Genetic and Environmental Risk in Alzheimer's Disease, Alzheimer's Disease Genetic Consortium, Cohorts for Heart and Aging Research in Genomic Epidemiology, Moebus S, Mecocci P, Del Zompo M, Maier W, Hampel H, Pilotto A, Bullido M, Panza F, Caffarra P, Nacmias B, Gilbert JR, Mayhaus M, Lannefelt L, Hakonarson H, Pichler S, Carrasquillo MM, Ingelsson M, Beekly D, Alvarez V, Zou F, Valladares O, Younkin SG, Coto E, Hamilton-Nelson KL, Gu W, Razquin C, Pastor P, Mateo I, Owen MJ, Faber KM, Jonsson PV, Combarros O, O'Donovan MC, Cantwell LB, Soininen H, Blacker D, Mead S, Mosley TH Jr, Bennett DA, Harris TB, Fratiglioni L, Holmes C, de Bruijn RF, Passmore P, Montine TJ, Bettens K, Rotter JI, Brice A, Morgan K, Foroud TM, Kukull WA, Hannequin D, Powell JF, Nalls MA, Ritchie K, Lunetta KL, Kauwe JS, Boerwinkle E, Riemenschneider M, Boada M, Hiltuenen M, Martin ER, Schmidt R, Rujescu D, Wang LS, Dartigues JF, Mayeux R, Tzourio C, Hofman A, Nöthen MM, Graff C, Psaty BM, Jones L, Haines JL, Holmans PA, Lathrop M, Pericak-Vance MA, Launer LJ, Farrer LA, van Duijn CM, Van Broeckhoven C, Moskvina V, Seshadri S, Williams J, Schellenberg GD, Amouyel P, Wang J, Uitterlinden AG, Rivadeneira F, Koudstgaal PJ, Longstreth WT Jr, Becker JT, Kuller LH, Lumley T, Rice K, Garcia M, Aspelund T, Marksteiner JJ, Dal-Bianco P, Töglhofer AM, Freudenberger P, Ransmayr G, Benke T, Toeglhofer AM, Bressler J, Breteler MM, Fornage M, Hernández I, Rosende Roca M, Ana Mauleón M, Alegrat M, Ramírez-Lorca R, González-Perez A, Chapman J, Stretton A, Morgan A, Kehoe PG, Medway C, Lord J, Turton J, Hooper NM, Vardy E, Warren JD, Schott JM, Uphill J, Ryan N, Rossor M, Ben-Shlomo Y, Makrina D, Gkatzima O, Lupton M, Koutroumani M, Avramidou D, Germanou A, Jessen F, Riedel-Heller S, Dichgans M, Heun R, Kölsch H, Schürmann B, Herold C, Lacour A, Drichel D, Hoffman P, Kornhuber J, Gu W, Feulner T, van den Bussche H, Lawlor B, Lynch A, Mann D, Smith AD, Warden D, Wilcock G, Heuser I, Wiltgang J, Frölich L, Hüll M, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Jöckel KH, Klopp N, Wichmann HE, Dickson DW, Graff-Radford NR, Ma L, Bisceglio G, Fisher E, Warner N, Pickering-Brown S. Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet. 2013 Dec;45(12):1452-8. Epub 2013 Oct 27 PubMed.
Icahn School of Medicine at Mount Sinai
The results of these two papers are consistent with a model of AD etiology that can be derived from the network analysis of AD (Rosenthal and Kamboh, 2014; Zhang et al., 2013) and TREM2 (Forabosco et al., 2013). This model strongly implicates dysregulation of efferocytosis (i.e., apoptotic cell clearance or, more generally, defective clearance of cellular "debris") in the etiology of AD.
For example, the three major "pathways" previously shown to be enriched in GWA studies for LOAD (lipid/sterol efflux, innate immune cell function, and endocytosis) (Jones et al., 2010) are key components of efferocytosis (Ravichandran and Lorenz, 2007; Poon et al., 2014; A-González and Castrillo, 2010). Moreover, network analysis of human genetic variants associated with LOAD (Rosenthal and Kamboh, 2014) or of human brain gene co-expression data associated with TREM2 (Forabosco et al., 2013) also points to efferocytosis. This scavenging function of microglia and macrophages is critical to inflammation resolution and tissue repair after infection and injury. However, it is also known to play an important role in the maintenance of tissue homeostasis (Davies et al., 2013).
A better understanding of 1) the role of efferocytosis/clearance of cellular “debris” in the maintenance of brain tissue (including myelin and synapses) and 2) the gene network that supports this biological process (which is likely to include APOE, TREM2, TREML2, ABCA7 [an orthologue of the C. elegans efferocytosis gene ced-7], ABCA1, MEGF10, ABCG1, ELMO1, SORL1/retromer, C1Q, LXR, RXR, TRIP4, and several other candidate AD loci/genes) (Hsieh et al., 2009; Takahashi et al., 2005; de Freitas et al., 2012; Jehle et al., 2006; Hamon et al., 2006; Yvan-Charvet et al., 2010; Cash et al., 2012; Kiss et al., 2006; A-Gonzalez et al., 2009; Ruiz et al., 2014) could shed some light on the mystery of AD etiology beyond the amyloid hypothesis (Seong and Matzinger, 2004; Medzhitov 2008; Kotas and Medzhitov, 2015) and inspire the development of novel therapeutic approaches for this devastating disease (Schadt et al., 2009).
References:
Rosenthal SL, Kamboh MI. Late-Onset Alzheimer's Disease Genes and the Potentially Implicated Pathways. Curr Genet Med Rep. 2014;2:85-101. Epub 2014 Mar 22 PubMed.
Zhang B, Gaiteri C, Bodea LG, Wang Z, McElwee J, Podtelezhnikov AA, Zhang C, Xie T, Tran L, Dobrin R, Fluder E, Clurman B, Melquist S, Narayanan M, Suver C, Shah H, Mahajan M, Gillis T, Mysore J, MacDonald ME, Lamb JR, Bennett DA, Molony C, Stone DJ, Gudnason V, Myers AJ, Schadt EE, Neumann H, Zhu J, Emilsson V. Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease. Cell. 2013 Apr 25;153(3):707-20. PubMed.
Forabosco P, Ramasamy A, Trabzuni D, Walker R, Smith C, Bras J, Levine AP, Hardy J, Pocock JM, Guerreiro R, Weale ME, Ryten M. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging. 2013 Dec;34(12):2699-714. PubMed.
Jones L, Holmans PA, Hamshere ML, Harold D, Moskvina V, Ivanov D, Pocklington A, Abraham R, Hollingworth P, Sims R, Gerrish A, Pahwa JS, Jones N, Stretton A, Morgan AR, Lovestone S, Powell J, Proitsi P, Lupton MK, Brayne C, Rubinsztein DC, Gill M, Lawlor B, Lynch A, Morgan K, Brown KS, Passmore PA, Craig D, McGuinness B, Todd S, Holmes C, Mann D, Smith AD, Love S, Kehoe PG, Mead S, Fox N, Rossor M, Collinge J, Maier W, Jessen F, Schürmann B, Heun R, Kölsch H, van den Bussche H, Heuser I, Peters O, Kornhuber J, Wiltfang J, Dichgans M, Frölich L, Hampel H, Hüll M, Rujescu D, Goate AM, Kauwe JS, Cruchaga C, Nowotny P, Morris JC, Mayo K, Livingston G, Bass NJ, Gurling H, McQuillin A, Gwilliam R, Deloukas P, Al-Chalabi A, Shaw CE, Singleton AB, Guerreiro R, Mühleisen TW, Nöthen MM, Moebus S, Jöckel KH, Klopp N, Wichmann HE, Rüther E, Carrasquillo MM, Pankratz VS, Younkin SG, Hardy J, O'Donovan MC, Owen MJ, Williams J. Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease. PLoS One. 2010;5(11):e13950. PubMed.
Ravichandran KS, Lorenz U. Engulfment of apoptotic cells: signals for a good meal. Nat Rev Immunol. 2007 Dec;7(12):964-74. PubMed.
Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014 Mar;14(3):166-80. Epub 2014 Jan 31 PubMed.
A-González N, Castrillo A. Liver X receptors as regulators of macrophage inflammatory and metabolic pathways. Biochim Biophys Acta. 2011 Aug;1812(8):982-94. Epub 2010 Dec 28 PubMed.
Rosenthal SL, Kamboh MI. Late-Onset Alzheimer's Disease Genes and the Potentially Implicated Pathways. Curr Genet Med Rep. 2014;2:85-101. Epub 2014 Mar 22 PubMed.
Forabosco P, Ramasamy A, Trabzuni D, Walker R, Smith C, Bras J, Levine AP, Hardy J, Pocock JM, Guerreiro R, Weale ME, Ryten M. Insights into TREM2 biology by network analysis of human brain gene expression data. Neurobiol Aging. 2013 Dec;34(12):2699-714. PubMed.
Davies LC, Jenkins SJ, Allen JE, Taylor PR. Tissue-resident macrophages. Nat Immunol. 2013 Oct;14(10):986-95. Epub 2013 Sep 18 PubMed.
Hsieh CL, Koike M, Spusta SC, Niemi EC, Yenari M, Nakamura MC, Seaman WE. A role for TREM2 ligands in the phagocytosis of apoptotic neuronal cells by microglia. J Neurochem. 2009 May;109(4):1144-56. Epub 2009 Mar 19 PubMed.
Takahashi K, Rochford CD, Neumann H. Clearance of apoptotic neurons without inflammation by microglial triggering receptor expressed on myeloid cells-2. J Exp Med. 2005 Feb 21;201(4):647-57. PubMed.
de Freitas A, Banerjee S, Xie N, Cui H, Davis KI, Friggeri A, Fu M, Abraham E, Liu G. Identification of TLT2 as an engulfment receptor for apoptotic cells. J Immunol. 2012 Jun 15;188(12):6381-8. Epub 2012 May 9 PubMed.
Jehle AW, Gardai SJ, Li S, Linsel-Nitschke P, Morimoto K, Janssen WJ, Vandivier RW, Wang N, Greenberg S, Dale BM, Qin C, Henson PM, Tall AR. ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages. J Cell Biol. 2006 Aug 14;174(4):547-56. PubMed.
Hamon Y, Trompier D, Ma Z, Venegas V, Pophillat M, Mignotte V, Zhou Z, Chimini G. Cooperation between engulfment receptors: the case of ABCA1 and MEGF10. PLoS One. 2006 Dec 27;1:e120. PubMed.
Yvan-Charvet L, Pagler TA, Seimon TA, Thorp E, Welch CL, Witztum JL, Tabas I, Tall AR. ABCA1 and ABCG1 protect against oxidative stress-induced macrophage apoptosis during efferocytosis. Circ Res. 2010 Jun 25;106(12):1861-9. Epub 2010 Apr 29 PubMed.
Cash JG, Kuhel DG, Basford JE, Jaeschke A, Chatterjee TK, Weintraub NL, Hui DY. Apolipoprotein e4 impairs macrophage efferocytosis and potentiates apoptosis by accelerating endoplasmic reticulum stress. J Biol Chem. 2012 Aug 10;287(33):27876-84. PubMed.
Kiss RS, Elliott MR, Ma Z, Marcel YL, Ravichandran KS. Apoptotic cells induce a phosphatidylserine-dependent homeostatic response from phagocytes. Curr Biol. 2006 Nov 21;16(22):2252-8. PubMed.
A-Gonzalez N, Bensinger SJ, Hong C, Beceiro S, Bradley MN, Zelcer N, Deniz J, Ramirez C, Díaz M, Gallardo G, de Galarreta CR, Salazar J, Lopez F, Edwards P, Parks J, Andujar M, Tontonoz P, Castrillo A. Apoptotic cells promote their own clearance and immune tolerance through activation of the nuclear receptor LXR. Immunity. 2009 Aug 21;31(2):245-58. Epub 2009 Jul 30 PubMed.
Ruiz A, Heilmann S, Becker T, Hernández I, Wagner H, Thelen M, Mauleón A, Rosende-Roca M, Bellenguez C, Bis JC, Harold D, Gerrish A, Sims R, Sotolongo-Grau O, Espinosa A, Alegret M, Arrieta JL, Lacour A, Leber M, Becker J, Lafuente A, Ruiz S, Vargas L, Rodríguez O, Ortega G, Dominguez MA, IGAP, Mayeux R, Haines JL, Pericak-Vance MA, Farrer LA, Schellenberg GD, Chouraki V, Launer LJ, van Duijn C, Seshadri S, Antúnez C, Breteler MM, Serrano-Ríos M, Jessen F, Tárraga L, Nöthen MM, Maier W, Boada M, Ramírez A. Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene. Transl Psychiatry. 2014 Feb 4;4:e358. PubMed.
Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004 Jun;4(6):469-78. PubMed.
Medzhitov R. Origin and physiological roles of inflammation. Nature. 2008 Jul 24;454(7203):428-35. PubMed.
Kotas ME, Medzhitov R. Homeostasis, Inflammation, and Disease Susceptibility. Cell. 2015 Feb 26;160(5):816-827. PubMed.
Schadt EE, Friend SH, Shaywitz DA. A network view of disease and compound screening. Nat Rev Drug Discov. 2009 Apr;8(4):286-95. PubMed.
View all comments by Edoardo MarcoraCase Western Reserve University
The intriguing finding of the Wang et al. study is that lipids “activate” wild-type TREM2 and turn on NFAT signaling pathways whereas the R47H variant of TREM2, which is a risk allele for AD, PD, FTD, and ALS, is almost completely inactive in the NFAT reporter assay.
NFAT singling regulates expression of pro-inflammatory cytokines TNF-α, IL-2, IFNg, etc. Thus, the charged lipids—presumably released from apoptotic neurons and coating the amyloid plaques—should activate WT microglia and stimulate the release of inflammatory cytokines, whereas those expressing R47H-TREM2 should not. By implication, WT-TREM2 should be proinflammatory and R47H-TREM2 should not promote inflammation in response to apoptotic cells. This seems to run counterintuitive to the common finding that increased inflammation is observed in the brains of patients with all four neurodegenerative diseases indicated above, and there is increasing evidence that chronic neuroinflammation is toxic to the brain function and initiates neurodegeneration.
One thing to keep in mind is that the NFAT reporter assay was performed by overexpressing WT-TREM2 or R47H-TREM2 in 2B4 reporter T-cells. TREM2 has an extremely short cytoplasmic tail and is known to signal by binding another membrane protein ,DAP12/TYRO-BP, which possesses a longer cytoplasmic tail with an immunoreceptor tyrosine-based activation (ITAM) motif. From the information in the manuscript, it seems that Wang et al. transfected TREM2 alone and not TREM2+DAP12. Also unclear is whether 2B4 T-cells express endogenous DAP12 and if so, what the stoichiometry of overexpressed TREM2 to endogenous DAP12 is. Thus, at present it remains an open question whether the effects of R47H mutation on NFAT signaling reported here shed any light on the role of TREM2 in AD pathogenesis or are due to overexpression of the protein in a non-microglial cell line. Future studies will need to resolve the conundrum of how R47H-TREM2, which does not seem to promote inflammation, increases the risk for neurodegeneration.
Make a Comment
To make a comment you must login or register.