{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T22:15:20Z","timestamp":1794003320497,"version":"4.8.0"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T00:00:00Z","timestamp":1736380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["AARG-16-441560"],"award-info":[{"award-number":["AARG-16-441560"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer\u2019s Association","doi-asserted-by":"publisher","award":["ZEN-25-1269507"],"award-info":[{"award-number":["ZEN-25-1269507"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006312","name":"BrightFocus Foundation","doi-asserted-by":"publisher","award":["A2022032S"],"award-info":[{"award-number":["A2022032S"]}],"id":[{"id":"10.13039\/100006312","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000861","name":"Burroughs Wellcome Fund","doi-asserted-by":"publisher","award":["CAMS 1014685"],"award-info":[{"award-number":["CAMS 1014685"]}],"id":[{"id":"10.13039\/100000861","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL152245"],"award-info":[{"award-number":["R01HL152245"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01HL170198"],"award-info":[{"award-number":["R01HL170198"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI159678"],"award-info":[{"award-number":["R01AI159678"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI169850"],"award-info":[{"award-number":["R01AI169850"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Mol Neurodegeneration"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>TREM2 is a signaling receptor expressed on microglia that has emerged as an important drug target for Alzheimer\u2019s disease and other neurodegenerative diseases. While a number of TREM2 ligands have been identified, little is known regarding the structural details of how they engage. To better understand this, we created a protein library of 28 different TREM2 variants that could be used to map interactions with various ligands using biolayer interferometry. The variants are located in previously identified putative binding surfaces on TREM2 called the hydrophobic site, basic site, and site 2. We found that mutations to the hydrophobic site ablated binding to apoE4 and TDP-43. Competition binding experiments indicated that apoE4 and oA\u03b242 share overlapping binding sites on TREM2. In contrast, binding to C1q was disrupted most strongly by mutations to the basic site, including R46, with some mutations to the hydrophobic site also attenuating binding, thus suggesting a broader mediation of binding across the two sites. Supporting this, competition experiments indicated that C1q binding could be blocked by both apoE and oA\u03b242. TREM2 binding to IL-34 was mediated by the basic site at a surface centering on R76. Competition binding experiments validated the unique site for IL-34, showing little to no competition with either oA\u03b242 or apoE4. However, competition experiments between C1q and IL34 suggest that the ligands compete for binding at the basic site. Altogether, our results suggest that TREM2 utilizes the hydrophobic site (consisting of CDR1, CDR2, and CDR3) as a common site to engage multiple ligands, and uses distinct basic sites to engage others. Our findings imply that pharmaceutical strategies targeting these surfaces might be effective to modulate TREM2 functions.<\/jats:p>","DOI":"10.1186\/s13024-024-00795-9","type":"journal-article","created":{"date-parts":[[2025,1,9]],"date-time":"2025-01-09T11:50:33Z","timestamp":1736423433000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Biophysical mapping of TREM2-ligand interactions reveals shared surfaces for engagement of multiple Alzheimer\u2019s disease ligands"],"prefix":"10.1186","volume":"20","author":[{"given":"Jessica A.","family":"Greven","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua R.","family":"Wydra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rory A.","family":"Greer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia","family":"Zhi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David A.","family":"Price","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordyn D.","family":"Svoboda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher L. M.","family":"Camitta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mya","family":"Washington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisy W.","family":"Leung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhua","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jen","family":"Alexander-Brett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6871-6676","authenticated-orcid":false,"given":"Tom J.","family":"Brett","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,1,9]]},"reference":[{"key":"795_CR1","doi-asserted-by":"publisher","first-page":"1207","DOI":"10.1016\/j.cell.2020.05.003","volume":"181","author":"A Deczkowska","year":"2020","unstructured":"Deczkowska A, Weiner A, Amit I. The Physiology, Pathology, and potential therapeutic applications of the TREM2 signaling pathway. Cell. 2020;181:1207\u201317.","journal-title":"Cell"},{"key":"795_CR2","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa1211851","volume":"368","author":"R Guerreiro","year":"2013","unstructured":"Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, Cruchaga C, Sassi C, Kauwe JS, Younkin S, et al. TREM2 variants in Alzheimer\u2019s disease. N Engl J Med. 2013;368:117\u201327.","journal-title":"N Engl J Med"},{"key":"795_CR3","doi-asserted-by":"publisher","first-page":"5838","DOI":"10.1093\/hmg\/ddu277","volume":"23","author":"SC Jin","year":"2014","unstructured":"Jin SC, Benitez BA, Karch CM, Cooper B, Skorupa T, Carrell D, Norton JB, Hsu S, Harari O, Cai Y, et al. Coding variants in TREM2 increase risk for Alzheimer\u2019s disease. Hum Mol Genet. 2014;23:5838\u201346.","journal-title":"Hum Mol Genet"},{"key":"795_CR4","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1056\/NEJMoa1211103","volume":"368","author":"T Jonsson","year":"2013","unstructured":"Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Snaedal J, Bjornsson S, Huttenlocher J, Levey AI, Lah JJ, et al. Variant of TREM2 associated with the risk of Alzheimer\u2019s disease. N Engl J Med. 2013;368:107\u201316.","journal-title":"N Engl J Med"},{"key":"795_CR5","doi-asserted-by":"crossref","unstructured":"Shi Q, Gutierrez RA, Bhat MA. Microglia, Trem2, and Neurodegeneration. Neuroscientist 2024:10738584241254118.","DOI":"10.1177\/10738584241254118"},{"key":"795_CR6","doi-asserted-by":"publisher","first-page":"1365","DOI":"10.1038\/s41467-019-09118-9","volume":"10","author":"L Zhong","year":"2019","unstructured":"Zhong L, Xu Y, Zhuo R, Wang T, Wang K, Huang R, Wang D, Gao Y, Zhu Y, Sheng X, et al. Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer\u2019s disease model. Nat Commun. 2019;10:1365.","journal-title":"Nat Commun"},{"key":"795_CR7","doi-asserted-by":"crossref","unstructured":"Ewers M, Franzmeier N, Suarez-Calvet M, Morenas-Rodriguez E, Caballero MAA, Kleinberger G, Piccio L, Cruchaga C, Deming Y, Dichgans M et al. Increased soluble TREM2 in cerebrospinal fluid is associated with reduced cognitive and clinical decline in Alzheimer\u2019s disease. Sci Transl Med 2019, 11.","DOI":"10.1126\/scitranslmed.aav6221"},{"key":"795_CR8","doi-asserted-by":"crossref","unstructured":"Belsare KD, Wu H, Mondal D, Bond A, Castillo E, Jin J, Jo H, Roush AE, Pilla KB, Sali A et al. Soluble TREM2 inhibits secondary nucleation of Abeta fibrillization and enhances cellular uptake of fibrillar abeta. Proc Natl Acad Sci U S A 2022, 119.","DOI":"10.1073\/pnas.2114486119"},{"key":"795_CR9","doi-asserted-by":"crossref","unstructured":"Kober DL, Stuchell-Brereton MD, Kluender CE, Dean HB, Strickland MR, Steinberg DF, Nelson SS, Baban B, Holtzman DM, Frieden C et al. Functional insights from biophysical study of TREM2 interactions with apoE and Abeta(1\u201342). Alzheimers Dement 2020.","DOI":"10.1101\/2020.02.24.963264"},{"key":"795_CR10","doi-asserted-by":"publisher","first-page":"100631","DOI":"10.1016\/j.jbc.2021.100631","volume":"296","author":"A Vilalta","year":"2021","unstructured":"Vilalta A, Zhou Y, Sevalle J, Griffin JK, Satoh K, Allendorf DH, De S, Puigdellivol M, Bruzas A, Burguillos MA, et al. Wild-type sTREM2 blocks abeta aggregation and neurotoxicity, but the Alzheimer\u2019s R47H mutant increases abeta aggregation. J Biol Chem. 2021;296:100631.","journal-title":"J Biol Chem"},{"key":"795_CR11","doi-asserted-by":"publisher","first-page":"26043","DOI":"10.1074\/jbc.M115.679043","volume":"290","author":"Y Atagi","year":"2015","unstructured":"Atagi Y, Liu CC, Painter MM, Chen XF, Verbeeck C, Zheng H, Li X, Rademakers R, Kang SS, Xu H, et al. Apolipoprotein E is a Ligand for triggering receptor expressed on myeloid cells 2 (TREM2). J Biol Chem. 2015;290:26043\u201350.","journal-title":"J Biol Chem"},{"key":"795_CR12","doi-asserted-by":"publisher","first-page":"26033","DOI":"10.1074\/jbc.M115.677286","volume":"290","author":"CC Bailey","year":"2015","unstructured":"Bailey CC, DeVaux LB, Farzan M. The triggering receptor expressed on myeloid cells 2 binds apolipoprotein E. J Biol Chem. 2015;290:26033\u201342.","journal-title":"J Biol Chem"},{"key":"795_CR13","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1186\/s12974-017-0835-4","volume":"14","author":"C Jendresen","year":"2017","unstructured":"Jendresen C, Arskog V, Daws MR, Nilsson LN. The Alzheimer\u2019s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway. J Neuroinflammation. 2017;14:59.","journal-title":"J Neuroinflammation"},{"key":"795_CR14","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1016\/j.neuron.2016.06.015","volume":"91","author":"FL Yeh","year":"2016","unstructured":"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. 2016;91:328\u201340.","journal-title":"Neuron"},{"key":"795_CR15","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1038\/s41593-021-00975-6","volume":"25","author":"M Xie","year":"2022","unstructured":"Xie M, Liu YU, Zhao S, Zhang L, Bosco DB, Pang YP, Zhong J, Sheth U, Martens YA, Zhao N, et al. TREM2 interacts with TDP-43 and mediates microglial neuroprotection against TDP-43-related neurodegeneration. Nat Neurosci. 2022;25:26\u201338.","journal-title":"Nat Neurosci"},{"key":"795_CR16","doi-asserted-by":"publisher","first-page":"130","DOI":"10.1126\/science.1134108","volume":"314","author":"M Neumann","year":"2006","unstructured":"Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006;314:130\u20133.","journal-title":"Science"},{"key":"795_CR17","doi-asserted-by":"crossref","unstructured":"Cairns NJ, Neumann M, Bigio EH, Holm IE, Troost D, Hatanpaa KJ, Foong C, White CL 3rd, Schneider JA, Kretzschmar HA, et al. TDP-43 in familial and sporadic frontotemporal lobar degeneration with ubiquitin inclusions. Am J Pathol. 2007;171:227\u201340.","DOI":"10.2353\/ajpath.2007.070182"},{"key":"795_CR18","first-page":"3184","volume":"141","author":"X Xie","year":"2023","unstructured":"Xie X, Zhang W, Xiao M, Wei T, Qiu Y, Qiu J, Wang H, Qiu Z, Zhang S, Pan Y, et al. TREM2 acts as a receptor for IL-34 to suppress acute myeloid leukemia in mice. Blood. 2023;141:3184\u201398.","journal-title":"Blood"},{"key":"795_CR19","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1080\/00207454.2021.1963962","volume":"133","author":"G Chhetri","year":"2023","unstructured":"Chhetri G. Emerging roles of IL-34 in neurodegenerative and neurological infectious disease. Int J Neurosci. 2023;133:660\u201371.","journal-title":"Int J Neurosci"},{"key":"795_CR20","doi-asserted-by":"publisher","first-page":"1794","DOI":"10.1016\/j.immuni.2023.06.016","volume":"56","author":"L Zhong","year":"2023","unstructured":"Zhong L, Sheng X, Wang W, Li Y, Zhuo R, Wang K, Zhang L, Hu DD, Hong Y, Chen L, et al. TREM2 receptor protects against complement-mediated synaptic loss by binding to complement C1q during neurodegeneration. Immunity. 2023;56:1794\u2013e18081798.","journal-title":"Immunity"},{"key":"795_CR21","doi-asserted-by":"crossref","unstructured":"Kober DL, Alexander-Brett JM, Karch CM, Cruchaga C, Colonna M, Holtzman MJ, Brett TJ. Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms. Elife 2016, 5.","DOI":"10.7554\/eLife.20391"},{"key":"795_CR22","doi-asserted-by":"publisher","first-page":"12634","DOI":"10.1074\/jbc.RA118.002352","volume":"293","author":"A Sudom","year":"2018","unstructured":"Sudom A, Talreja S, Danao J, Bragg E, Kegel R, Min X, Richardson J, Zhang Z, Sharkov N, Marcora E, et al. Molecular basis for the loss-of-function effects of the Alzheimer\u2019s disease-associated R47H variant of the immune receptor TREM2. J Biol Chem. 2018;293:12634\u201346.","journal-title":"J Biol Chem"},{"key":"795_CR23","doi-asserted-by":"crossref","unstructured":"Stine WB Jr., Dahlgren KN, Krafft GA, LaDu MJ. In vitro characterization of conditions for amyloid-beta peptide oligomerization and fibrillogenesis. J Biol Chem. 2003;278:11612\u201322.","DOI":"10.1074\/jbc.M210207200"},{"key":"795_CR24","doi-asserted-by":"publisher","first-page":"1243","DOI":"10.1107\/S0907444906029799","volume":"62","author":"AR Aricescu","year":"2006","unstructured":"Aricescu AR, Lu W, Jones EY. A time- and cost-efficient system for high-level protein production in mammalian cells. Acta Crystallogr D Biol Crystallogr. 2006;62:1243\u201350.","journal-title":"Acta Crystallogr D Biol Crystallogr"},{"key":"795_CR25","doi-asserted-by":"publisher","first-page":"W535","DOI":"10.1093\/nar\/gkab354","volume":"49","author":"M Bernhofer","year":"2021","unstructured":"Bernhofer M, Dallago C, Karl T, Satagopam V, Heinzinger M, Littmann M, Olenyi T, Qiu J, Schutze K, Yachdav G, et al. PredictProtein - Predicting protein structure and function for 29 years. Nucleic Acids Res. 2021;49:W535\u201340.","journal-title":"Nucleic Acids Res"},{"key":"795_CR26","doi-asserted-by":"publisher","first-page":"2428","DOI":"10.1016\/j.jmb.2020.02.026","volume":"432","author":"J Qiu","year":"2020","unstructured":"Qiu J, Bernhofer M, Heinzinger M, Kemper S, Norambuena T, Melo F, Rost B. ProNA2020 predicts protein-DNA, protein-RNA, and protein-protein binding proteins and residues from sequence. J Mol Biol. 2020;432:2428\u201343.","journal-title":"J Mol Biol"},{"key":"795_CR27","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1016\/0022-2836(82)90515-0","volume":"157","author":"J Kyte","year":"1982","unstructured":"Kyte J, Doolittle RF. A simple method for displaying the hydropathic character of a protein. J Mol Biol. 1982;157:105\u201332.","journal-title":"J Mol Biol"},{"key":"795_CR28","doi-asserted-by":"publisher","first-page":"4243","DOI":"10.1128\/JB.185.14.4243-4247.2003","volume":"185","author":"SG Jacchieri","year":"2003","unstructured":"Jacchieri SG, Torquato R, Brentani RR. Structural study of binding of flagellin by toll-like receptor 5. J Bacteriol. 2003;185:4243\u20137.","journal-title":"J Bacteriol"},{"key":"795_CR29","doi-asserted-by":"publisher","first-page":"1731","DOI":"10.1021\/ja026939x","volume":"125","author":"C Dominguez","year":"2003","unstructured":"Dominguez C, Boelens R, Bonvin AM. HADDOCK: a protein-protein docking approach based on biochemical or biophysical information. J Am Chem Soc. 2003;125:1731\u20137.","journal-title":"J Am Chem Soc"},{"key":"795_CR30","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.str.2012.02.010","volume":"20","author":"X Ma","year":"2012","unstructured":"Ma X, Lin WY, Chen Y, Stawicki S, Mukhyala K, Wu Y, Martin F, Bazan JF, Starovasnik MA. Structural basis for the dual recognition of helical cytokines IL-34 and CSF-1 by CSF-1R. Structure. 2012;20:676\u201387.","journal-title":"Structure"},{"key":"795_CR31","doi-asserted-by":"publisher","first-page":"e512","DOI":"10.1002\/cpz1.512","volume":"2","author":"JA Greven","year":"2022","unstructured":"Greven JA, Brett TJ. Production of eukaryotic glycoproteins for structural and functional studies using Expi293F cells. Curr Protoc. 2022;2:e512.","journal-title":"Curr Protoc"},{"key":"795_CR32","doi-asserted-by":"crossref","unstructured":"Lessard CB, Malnik SL, Zhou Y, Ladd TB, Cruz PE, Ran Y, Mahan TE, Chakrabaty P, Holtzman DM, Ulrich JD et al. High-affinity interactions and signal transduction between Abeta oligomers and TREM2. EMBO Mol Med 2018, 10.","DOI":"10.15252\/emmm.201809027"},{"key":"795_CR33","doi-asserted-by":"publisher","first-page":"6323","DOI":"10.1021\/bi5008172","volume":"53","author":"K Garai","year":"2014","unstructured":"Garai K, Verghese PB, Baban B, Holtzman DM, Frieden C. The binding of apolipoprotein E to oligomers and fibrils of amyloid-beta alters the kinetics of amyloid aggregation. Biochemistry. 2014;53:6323\u201331.","journal-title":"Biochemistry"},{"key":"795_CR34","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1016\/j.jmb.2017.04.004","volume":"429","author":"DL Kober","year":"2017","unstructured":"Kober DL, Brett TJ. TREM2-Ligand interactions in Health and Disease. J Mol Biol. 2017;429:1607\u201329.","journal-title":"J Mol Biol"},{"key":"795_CR35","doi-asserted-by":"publisher","first-page":"3775","DOI":"10.4049\/jimmunol.1700373","volume":"198","author":"MR PrabhuDas","year":"2017","unstructured":"PrabhuDas MR, Baldwin CL, Bollyky PL, Bowdish DME, Drickamer K, Febbraio M, Herz J, Kobzik L, Krieger M, Loike J, et al. A Consensus definitive classification of scavenger receptors and their roles in Health and Disease. J Immunol. 2017;198:3775\u201389.","journal-title":"J Immunol"},{"key":"795_CR36","doi-asserted-by":"publisher","first-page":"1252","DOI":"10.3389\/fneur.2019.01252","volume":"10","author":"HB Dean","year":"2019","unstructured":"Dean HB, Roberson ED, Song Y. Neurodegenerative Disease-Associated variants in TREM2 destabilize the apical ligand-binding region of the Immunoglobulin Domain. Front Neurol. 2019;10:1252.","journal-title":"Front Neurol"},{"key":"795_CR37","doi-asserted-by":"publisher","first-page":"381","DOI":"10.1016\/j.jalz.2016.07.004","volume":"13","author":"W Song","year":"2017","unstructured":"Song W, Hooli B, Mullin K, Jin SC, Cella M, Ulland TK, Wang Y, Tanzi RE, Colonna M. Alzheimer\u2019s disease-associated TREM2 variants exhibit either decreased or increased ligand-dependent activation. Alzheimers Dement. 2017;13:381\u20137.","journal-title":"Alzheimers Dement"},{"key":"795_CR38","doi-asserted-by":"publisher","first-page":"6332","DOI":"10.1002\/alz.14124","volume":"20","author":"HB Dean","year":"2024","unstructured":"Dean HB, Greer RA, Yang SZ, Elston DS, Brett TJ, Roberson ED, Song Y. Multimerization of TREM2 is impaired by Alzheimer\u2019s disease-associated variants. Alzheimers Dement. 2024;20:6332\u201350.","journal-title":"Alzheimers Dement"},{"key":"795_CR39","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.neulet.2017.09.034","volume":"660","author":"D Feuerbach","year":"2017","unstructured":"Feuerbach D, Schindler P, Barske C, Joller S, Beng-Louka E, Worringer KA, Kommineni S, Kaykas A, Ho DJ, Ye C, et al. ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after histidine 157. Neurosci Lett. 2017;660:109\u201314.","journal-title":"Neurosci Lett"},{"key":"795_CR40","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.15252\/emmm.201707672","volume":"9","author":"K Schlepckow","year":"2017","unstructured":"Schlepckow K, Kleinberger G, Fukumori A, Feederle R, Lichtenthaler SF, Steiner H, Haass C. An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Mol Med. 2017;9:1356\u201365.","journal-title":"EMBO Mol Med"},{"key":"795_CR41","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1186\/s13024-019-0319-3","volume":"14","author":"JL Del-Aguila","year":"2019","unstructured":"Del-Aguila JL, Benitez BA, Li Z, Dube U, Mihindukulasuriya KA, Budde JP, Farias FHG, Fernandez MV, Ibanez L, Jiang S, et al. TREM2 brain transcript-specific studies in AD and TREM2 mutation carriers. Mol Neurodegener. 2019;14:18.","journal-title":"Mol Neurodegener"},{"key":"795_CR42","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1186\/s13073-023-01160-z","volume":"15","author":"M Moutinho","year":"2023","unstructured":"Moutinho M, Coronel I, Tsai AP, Di Prisco GV, Pennington T, Atwood BK, Puntambekar SS, Smith DC, Martinez P, Han S, et al. TREM2 splice isoforms generate soluble TREM2 species that disrupt long-term potentiation. Genome Med. 2023;15:11.","journal-title":"Genome Med"}],"container-title":["Molecular Neurodegeneration"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-024-00795-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13024-024-00795-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13024-024-00795-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T09:51:48Z","timestamp":1745747508000},"score":1,"resource":{"primary":{"URL":"https:\/\/molecularneurodegeneration.biomedcentral.com\/articles\/10.1186\/s13024-024-00795-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,9]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["795"],"URL":"https:\/\/doi.org\/10.1186\/s13024-024-00795-9","relation":{"has-preprint":[{"id-type":"doi","id":"10.21203\/rs.3.rs-4850141\/v1","asserted-by":"object"}]},"ISSN":["1750-1326"],"issn-type":[{"value":"1750-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,9]]},"assertion":[{"value":"2 August 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 December 2024","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 January 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"N\/A.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors report no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"3"}}