[en] Rare coding variants of the microglial triggering receptor expressed on myeloid cells 2 (TREM2) confer an increased risk for Alzheimer's disease (AD) characterized by the progressive accumulation of aggregated forms of amyloid β peptides (Aβ). Aβ peptides are generated by proteolytic processing of the amyloid precursor protein (APP). Heterogeneity in proteolytic cleavages and additional post-translational modifications result in the production of several distinct Aβ variants that could differ in their aggregation behavior and toxic properties. Here, we sought to assess whether post-translational modifications of Aβ affect the interaction with TREM2. Biophysical and biochemical methods revealed that TREM2 preferentially interacts with oligomeric Aβ, and that phosphorylation of Aβ increases this interaction. Phosphorylation of Aβ also affected the TREM2 dependent interaction and phagocytosis by primary microglia and in APP transgenic mouse models. Thus, TREM2 function is important for sensing phosphorylated Aβ variants in distinct aggregation states and reduces the accumulation and deposition of these toxic Aβ species in preclinical models of Alzheimer's disease.
Disciplines :
Neurology
Author, co-author :
Joshi, Pranav ; Department of Neurology, University of Bonn, Bonn, Germany
Riffel, Florian ; Department of Neurology, University of Bonn, Bonn, Germany
Satoh, Kanayo; Departments of Medical Biophysics and Medicine (Neurology), Tanz Centre for Research in Neurodegenerative Diseases and, Toronto, Ontario, Canada
Enomoto, Masahiro; Princess Margaret Cancer Centre Research Institute, University Health Network, Toronto, Ontario, Canada
Qamar, Seema; Cambridge Institute for Medical Research, Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Scheiblich, Hannah; Department of Neurodegenerative Diseases and Gerontopsychiatry, University Hospital Bonn, Bonn, Germany ; Neuroinflammation Unit, German Center for Neurodegenerative Diseases e. V. (DZNE), Bonn, Germany
Villacampa, Nàdia ; Department of Neurodegenerative Diseases and Gerontopsychiatry, University Hospital Bonn, Bonn, Germany ; Neuroinflammation Unit, German Center for Neurodegenerative Diseases e. V. (DZNE), Bonn, Germany
Kumar, Sathish ; Department of Neurology, University of Bonn, Bonn, Germany
Theil, Sandra; Department of Neurology, University of Bonn, Bonn, Germany
Parhizkar, Samira ; Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany
Haass, Christian; Chair of Metabolic Biochemistry, Biomedical Center (BMC), Faculty of Medicine, Ludwig-Maximilians-Universität München, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany ; Molecular Neurodegeneration Unit, German Center for Neurodegenerative Diseases e.V. (DZNE) Munich, Munich, Germany
HENEKA, Michael ; Department of Neurodegenerative Diseases and Gerontopsychiatry, University Hospital Bonn, Bonn, Germany ; Neuroinflammation Unit, German Center for Neurodegenerative Diseases e. V. (DZNE), Bonn, Germany
Fraser, Paul E; Departments of Medical Biophysics and Medicine (Neurology), Tanz Centre for Research in Neurodegenerative Diseases and, Toronto, Ontario, Canada
St George-Hyslop, Peter; Departments of Medical Biophysics and Medicine (Neurology), Tanz Centre for Research in Neurodegenerative Diseases and, Toronto, Ontario, Canada ; Cambridge Institute for Medical Research, Department of Clinical Neurosciences, School of Clinical Medicine, University of Cambridge, Cambridge, UK
Walter, Jochen ; Department of Neurology, University of Bonn, Bonn, Germany
Canadian Institutes of Health Research Deutsche Forschungsgemeinschaft Canadian Institutes of Health Research
Funding text :
Canadian Institutes of Health Research; Deutsche Forschungsgemeinschaft, Grant/Award Number: WA1477/6‐6; EU Innovative Medicines Initiative 2 Joint Undertaking, Grant/Award Number: 115976 (PHAGO); Alzheimer's Association (Zenith Award); Canadian Institutes of Health Research (CIHR) operating grant, Grant/Award Number: PJT17349; UK Alzheimer Society and ARUK; Wellcome Trust Collaborative Award in Science Funding informationThis work was supported by the Deutsche Forschungsgemeinschaft, Grant WA1477/6‐6 (to Jochen Walter), the EU Innovative Medicines Initiative 2 Joint Undertaking (IMI2 JU), Grant/Award Number: No 115976 (PHAGO), the Canadian Institutes of Health Research (CIHR) operating grant PJT17349 (to Paul E. Fraser) and the Canadian Institutes of Health Research (Foundation Award to Peter St George‐Hyslop), US Alzheimer Association (Zenith Award‐ to Peter St George‐Hyslop); UK Alzheimer Society and ARUK (to Peter St George‐Hyslop), Wellcome Trust Collaborative Award in Science (to Peter St George‐Hyslop). Pranav Joshi thanks the BIGS neuroscience and the University of Bonn for IPID4all‐DAAD travel grant. Authors thank the Microscopy Core Facility of the Medical Faculty at the University of Bonn for providing support and instrumentation funded by the Deutsche Forschungsgemeinschaft, Project number: 388169927. Open Access funding enabled and organized by Projekt DEAL.
Anderson, V. L., Ramlall, T. F., Rospigliosi, C. C., Webb, W. W., & Eliezer, D. (2010). Identification of a helical intermediate in trifluoroethanol-induced alpha-synuclein aggregation. Proceedings of the National Academy of Sciences of the United States of America, 107(44), 18850–18855. https://doi.org/10.1073/pnas.1012336107
Aricescu, A. R., Lu, W., & Jones, E. Y. (2006). A time- and cost-efficient system for high-level protein production in mammalian cells. Acta Crystallographica. Section D, Biological Crystallography, 62(Pt 10), 1243–1250. https://doi.org/10.1107/S0907444906029799
Backliwal, G., Hildinger, M., Hasija, V., & Wurm, F. M. (2008). High-density transfection with HEK-293 cells allows doubling of transient titers and removes need for a priori DNA complex formation with PEI. Biotechnology and Bioengineering, 99(3), 721–727. https://doi.org/10.1002/bit.21596
Bailey, C. C., DeVaux, L. B., & Farzan, M. (2015). The triggering receptor expressed on myeloid cells 2 binds Apolipoprotein E. The Journal of Biological Chemistry, 290(43), 26033–26042. https://doi.org/10.1074/jbc.M115.677286
Barykin, E. P., Mitkevich, V. A., Kozin, S. A., & Makarov, A. A. (2017). Amyloid beta modification: A key to the sporadic Alzheimer's disease? Frontiers in Genetics, 8, 58. https://doi.org/10.3389/fgene.2017.00058
Boon, B. D. C., Bulk, M., Jonker, A. J., Morrema, T. H. J., van den Berg, E., Popovic, M., Walter, J., Kumar, S., van der Lee, S. J., Holstege, H., Zhu, X., van Nostrand, W. E., Natté, R., van der Weerd, L., Bouwman, F. H., van de Berg, W. D. J., Rozemuller, A. J. M., & Hoozemans, J. J. M. (2020). The coarse-grained plaque: A divergent Abeta plaque-type in early-onset Alzheimer's disease. Acta Neuropathologica, 140(6), 811–830. https://doi.org/10.1007/s00401-020-02198-8
Burgess, R. R. (2009). Protein precipitation techniques. Methods in Enzymology, 463, 331–342. https://doi.org/10.1016/s0076-6879(09)63020-2
Condello, C., Yuan, P., Schain, A., & Grutzendler, J. (2015). Microglia constitute a barrier that prevents neurotoxic protofibrillar Abeta42 hotspots around plaques. Nature Communications, 6, 6176. https://doi.org/10.1038/ncomms7176
Dammers, C., Gremer, L., Reiß, K., Klein, A. N., Neudecker, P., Hartmann, R., Sun, N., Demuth, H. U., Schwarten, M., & Willbold, D. (2015). Structural analysis and aggregation propensity of Pyroglutamate Abeta(3-40) in aqueous Trifluoroethanol. PLoS One, 10(11), e0143647. https://doi.org/10.1371/journal.pone.0143647
d'Errico, P., & Meyer-Luehmann, M. (2020). Mechanisms of pathogenic tau and Abeta protein spreading in Alzheimer's disease. Frontiers in Aging Neuroscience, 12, 265. https://doi.org/10.3389/fnagi.2020.00265
Fang, X. T., Sehlin, D., Lannfelt, L., Syvanen, S., & Hultqvist, G. (2017). Efficient and inexpensive transient expression of multispecific multivalent antibodies in Expi293 cells. Biological Procedures Online, 19, 11. https://doi.org/10.1186/s12575-017-0060-7
Feuerbach, D., Schindler, P., Barske, C., Joller, S., Beng-Louka, E., Worringer, K. A., Kommineni, S., Kaykas, A., Ho, D. J., Ye, C., Welzenbach, K., Elain, G., Klein, L., Brzak, I., Mir, A. K., Farady, C. J., Aichholz, R., Popp, S., George, N., & Neumann, U. (2017). ADAM17 is the main sheddase for the generation of human triggering receptor expressed in myeloid cells (hTREM2) ectodomain and cleaves TREM2 after Histidine 157. Neuroscience Letters, 660, 109–114. https://doi.org/10.1016/j.neulet.2017.09.034
Gerth, J., Kumar, S., Rijal Upadhaya, A., Ghebremedhin, E., von Arnim, C. A. F., Thal, D. R., & Walter, J. (2018). Modified amyloid variants in pathological subgroups of beta-amyloidosis. Annals of Clinical Translational Neurology, 5(7), 815–831. https://doi.org/10.1002/acn3.577
Giulian, D., & Baker, T. J. (1986). Characterization of ameboid microglia isolated from developing mammalian brain. The Journal of Neuroscience, 6(8), 2163–2178. https://doi.org/10.1523/JNEUROSCI.06-08-02163.1986
Gouras, G. K., Tampellini, D., Takahashi, R. H., & Capetillo-Zarate, E. (2010). Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease. Acta Neuropathologica, 119(5), 523–541. https://doi.org/10.1007/s00401-010-0679-9
Gouras, G. K., Willen, K., & Tampellini, D. (2012). Critical role of intraneuronal Abeta in Alzheimer's disease: Technical challenges in studying intracellular Abeta. Life Sciences, 91(23–24), 1153–1158. https://doi.org/10.1016/j.lfs.2012.06.004
Guerreiro, R., Bilgic, B., Guven, G., Brás, J., Rohrer, J., Lohmann, E., Hanagasi, H., Gurvit, H., & Emre, M. (2013). Novel compound heterozygous mutation in TREM2 found in a Turkish frontotemporal dementia-like family. Neurobiology of Aging, 34(12), 2890.e1–2890.e5. https://doi.org/10.1016/j.neurobiolaging.2013.06.005
Guerreiro, R., Wojtas, A., Bras, J., Carrasquillo, M., Rogaeva, E., Majounie, E., Cruchaga, C., Sassi, C., Kauwe, J. S., Younkin, S., Hazrati, L., Collinge, J., Pocock, J., Lashley, T., Williams, J., Lambert, J. C., Amouyel, P., Goate, A., Rademakers, R., … Alzheimer Genetic Analysis Group. (2013). TREM2 variants in Alzheimer's disease. The New England Journal of Medicine, 368(2), 117–127. https://doi.org/10.1056/NEJMoa1211851
Guerreiro, R. J., Lohmann, E., Brás, J. M., Gibbs, J. R., Rohrer, J. D., Gurunlian, N., Dursun, B., Bilgic, B., Hanagasi, H., Gurvit, H., Emre, M., Singleton, A., & Hardy, J. (2013). Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementia-like syndrome without bone involvement. JAMA Neurology, 70(1), 78–84. https://doi.org/10.1001/jamaneurol.2013.579
Haass, C., & Selkoe, D. J. (2007). Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer's amyloid beta-peptide. Nature Reviews. Molecular Cell Biology, 8(2), 101–112. https://doi.org/10.1038/nrm2101
Hu, Z. W., Ma, M. R., Chen, Y. X., Zhao, Y. F., Qiang, W., & Li, Y. M. (2017). Phosphorylation at Ser(8) as an intrinsic regulatory switch to regulate the morphologies and structures of Alzheimer's 40-residue beta-amyloid (Abeta40) fibrils. The Journal of Biological Chemistry, 292(7), 2611–2623. https://doi.org/10.1074/jbc.M116.757179
Huang, Y., Happonen, K. E., Burrola, P. G., O'Connor, C., Hah, N., Huang, L., et al. (2021). Microglia use TAM receptors to detect and engulf amyloid beta plaques. Nature Immunology, 22(5), 586–594. https://doi.org/10.1038/s41590-021-00913-5
Hyman, B. T., Phelps, C. H., Beach, T. G., Bigio, E. H., Cairns, N. J., Carrillo, M. C., Dickson, D. W., Duyckaerts, C., Frosch, M. P., Masliah, E., Mirra, S. S., Nelson, P. T., Schneider, J. A., Thal, D. R., Thies, B., Trojanowski, J. Q., Vinters, H. V., & Montine, T. J. (2012). National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease. Alzheimers Dement, 8(1), 1–13. https://doi.org/10.1016/j.jalz.2011.10.007
Ibach, M., Mathews, M., Linnartz-Gerlach, B., Theil, S., Kumar, S., Feederle, R., Brüstle, O., Neumann, H., & Walter, J. (2021). A reporter cell system for the triggering receptor expressed on myeloid cells 2 reveals differential effects of disease-associated variants on receptor signaling and activation by antibodies against the stalk region. Glia, 69(5), 1126–1139. https://doi.org/10.1002/glia.23953
Jonsson, T., Stefansson, H., Steinberg, S., Jonsdottir, I., Jonsson, P. V., Snaedal, J., Bjornsson, S., Huttenlocher, J., Levey, A. I., Lah, J. J., Rujescu, D., Hampel, H., Giegling, I., Andreassen, O. A., Engedal, K., Ulstein, I., Djurovic, S., Ibrahim-Verbaas, C., Hofman, A., … Stefansson, K. (2013). Variant of TREM2 associated with the risk of Alzheimer's disease. The New England Journal of Medicine, 368(2), 107–116. https://doi.org/10.1056/NEJMoa1211103
Kim, S. M., Mun, B. R., Lee, S. J., Joh, Y., Lee, H. Y., Ji, K. Y., Choi, H. R., Lee, E. H., Kim, E. M., Jang, J. H., Song, H. W., Mook-Jung, I., Choi, W. S., & Kang, H. S. (2017). TREM2 promotes Abeta phagocytosis by upregulating C/EBPalpha-dependent CD36 expression in microglia. Scientific Reports, 7(1), 11118. https://doi.org/10.1038/s41598-017-11634-x
Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T., & Shatz, C. J. (2013). Human LilrB2 is a beta-amyloid receptor and its murine homolog PirB regulates synaptic plasticity in an Alzheimer's model. Science, 341(6152), 1399–1404. https://doi.org/10.1126/science.1242077
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, J. L., Sanchez-Valle, R., Antonell, A., … Haass, C. (2014). TREM2 mutations implicated in neurodegeneration impair cell surface transport and phagocytosis. Science Translational Medicine, 6(243), 243ra86. https://doi.org/10.1126/scitranslmed.3009093
Kober, D. L., & Brett, T. J. (2017). TREM2-ligand interactions in health and disease. Journal of Molecular Biology, 429(11), 1607–1629. https://doi.org/10.1016/j.jmb.2017.04.004
Kober, D. L., Stuchell-Brereton, M. D., Kluender, C. E., Dean, H. B., Strickland, M. R., Steinberg, D. F., Nelson, S. S., Baban, B., Holtzman, D. M., Frieden, C., Alexander-Brett, J., Roberson, E. D., Song, Y., & Brett, T. J. (2020). Functional insights from biophysical study of TREM2 interactions with apoE and Abeta1-42. Alzheimer's & Dementia, 17, 475–488. https://doi.org/10.1002/alz.12194
Kumar, S., Kapadia, A., Theil, S., Joshi, P., Riffel, F., Heneka, M. T., & Walter, J. (2021). Novel phosphorylation-state specific antibodies reveal differential deposition of ser26 phosphorylated Aβ species in a mouse model of Alzheimer's disease. Frontiers in Molecular Neuroscience, 13, 257. https://doi.org/10.3389/fnmol.2020.619639
Kumar, S., Rezaei-Ghaleh, N., Terwel, D., Thal, D. R., Richard, M., Hoch, M., Mc Donald, J. M., Wüllner, U., Glebov, K., Heneka, M. T., Walsh, D. M., Zweckstetter, M., & Walter, J. (2011). Extracellular phosphorylation of the amyloid beta-peptide promotes formation of toxic aggregates during the pathogenesis of Alzheimer's disease. The EMBO Journal, 30(11), 2255–2265. https://doi.org/10.1038/emboj.2011.138
Kumar, S., Singh, S., Hinze, D., Josten, M., Sahl, H. G., Siepmann, M., & Walter, J. (2012). Phosphorylation of amyloid-beta peptide at serine 8 attenuates its clearance via insulin-degrading and angiotensin-converting enzymes. The Journal of Biological Chemistry, 287(11), 8641–8651. https://doi.org/10.1074/jbc.M111.279133
Kumar, S., Wirths, O., Stüber, K., Wunderlich, P., Koch, P., Theil, S., Rezaei-Ghaleh, N., Zweckstetter, M., Bayer, T. A., Brüstle, O., Thal, D. R., & Walter, J. (2016). Phosphorylation of the amyloid beta-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity. Acta Neuropathologica, 131(4), 525–537. https://doi.org/10.1007/s00401-016-1546-0
Kumar, S., Wirths, O., Theil, S., Gerth, J., Bayer, T. A., & Walter, J. (2013). Early intraneuronal accumulation and increased aggregation of phosphorylated Abeta in a mouse model of Alzheimer's disease. Acta Neuropathologica, 125(5), 699–709. https://doi.org/10.1007/s00401-013-1107-8
Kummer, M. P., & Heneka, M. T. (2014). Truncated and modified amyloid-beta species. Alzheimer's Research & Therapy, 6(3), 28. https://doi.org/10.1186/alzrt258
Kummer, M. P., Hermes, M., Delekarte, A., Hammerschmidt, T., Kumar, S., Terwel, D., Walter, J., Pape, H. C., König, S., Roeber, S., Jessen, F., Klockgether, T., Korte, M., & Heneka, M. T. (2011). Nitration of tyrosine 10 critically enhances amyloid beta aggregation and plaque formation. Neuron, 71(5), 833–844. https://doi.org/10.1016/j.neuron.2011.07.001
le Ber, I., de Septenville, A., Guerreiro, R., Bras, J., Camuzat, A., Caroppo, P., Lattante, S., Couarch, P., Kabashi, E., Bouya-Ahmed, K., Dubois, B., & Brice, A. (2014). Homozygous TREM2 mutation in a family with atypical frontotemporal dementia. Neurobiology of Aging, 35(10), 2419.e23–2419.e25. https://doi.org/10.1016/j.neurobiolaging.2014.04.010
Lessard, C. B., Malnik, S. L., Zhou, Y., Ladd, T. B., Cruz, P. E., Ran, Y., Mahan, T. E., Chakrabaty, P., Holtzman, D. M., Ulrich, J. D., Colonna, M., & Golde, T. E. (2018). High-affinity interactions and signal transduction between Abeta oligomers and TREM2. EMBO Molecular Medicine, 10(11), e9027. https://doi.org/10.15252/emmm.201809027
Mandrekar, S., Jiang, Q., Lee, C. Y., Koenigsknecht-Talboo, J., Holtzman, D. M., & Landreth, G. E. (2009). Microglia mediate the clearance of soluble Abeta through fluid phase macropinocytosis. The Journal of Neuroscience, 29(13), 4252–4262. https://doi.org/10.1523/JNEUROSCI.5572-08.2009
Mintun, M. A., Lo, A. C., Duggan Evans, C., Wessels, A. M., Ardayfio, P. A., Andersen, S. W., Shcherbinin, S., Sparks, J. D., Sims, J. R., Brys, M., Apostolova, L. G., Salloway, S. P., & Skovronsky, D. M. (2021). Donanemab in early Alzheimer's disease. The New England Journal of Medicine, 384(18), 1691–1704. https://doi.org/10.1056/NEJMoa2100708
Nussbaum, J. M., Schilling, S., Cynis, H., Silva, A., Swanson, E., Wangsanut, T., Tayler, K., Wiltgen, B., Hatami, A., Rönicke, R., Reymann, K., Hutter-Paier, B., Alexandru, A., Jagla, W., Graubner, S., Glabe, C. G., Demuth, H. U., & Bloom, G. S. (2012). Prion-like behaviour and tau-dependent cytotoxicity of pyroglutamylated amyloid-beta. Nature, 485(7400), 651–655. https://doi.org/10.1038/nature11060
Paloneva BM, 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(11), 1552–1558. https://doi.org/10.1212/wnl.56.11.1552
Parhizkar, S., Arzberger, T., Brendel, M., Kleinberger, G., Deussing, M., Focke, C., Nuscher, B., Xiong, M., Ghasemigharagoz, A., Katzmarski, N., Krasemann, S., Lichtenthaler, S. F., Müller, S. A., Colombo, A., Monasor, L. S., Tahirovic, S., Herms, J., Willem, M., Pettkus, N., … Haass, C. (2019). Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE. Nature Neuroscience, 22(2), 191–204. https://doi.org/10.1038/s41593-018-0296-9
Rezaei-Ghaleh, N., Amininasab, M., Giller, K., Kumar, S., Stündl, A., Schneider, A., Becker, S., Walter, J., & Zweckstetter, M. (2014). Turn plasticity distinguishes different modes of amyloid-beta aggregation. Journal of the American Chemical Society, 136(13), 4913–4919. https://doi.org/10.1021/ja411707y
Rezaei-Ghaleh, N., Amininasab, M., Kumar, S., Walter, J., & Zweckstetter, M. (2016). Phosphorylation modifies the molecular stability of beta-amyloid deposits. Nature Communications, 7, 11359. https://doi.org/10.1038/ncomms11359
Rijal Upadhaya, A., Kosterin, I., Kumar, S., von Arnim, C. A., Yamaguchi, H., Fändrich, M., Walter, J., & Thal, D. R. (2014). Biochemical stages of amyloid-beta peptide aggregation and accumulation in the human brain and their association with symptomatic and pathologically preclinical Alzheimer's disease. Brain, 137(Pt 3), 887–903. https://doi.org/10.1093/brain/awt362
Saido, T. C., Iwatsubo, T., Mann, D. M., Shimada, H., Ihara, Y., & Kawashima, S. (1995). Dominant and differential deposition of distinct beta-amyloid peptide species, a beta N3(pE), in senile plaques. Neuron, 14(2), 457–466. https://doi.org/10.1016/0896-6273(95)90301-1
Schilling, S., Zeitschel, U., Hoffmann, T., Heiser, U., Francke, M., Kehlen, A., Holzer, M., Hutter-Paier, B., Prokesch, M., Windisch, M., Jagla, W., Schlenzig, D., Lindner, C., Rudolph, T., Reuter, G., Cynis, H., Montag, D., Demuth, H. U., & Rossner, S. (2008). Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer's disease-like pathology. Nature Medicine, 14(10), 1106–1111. https://doi.org/10.1038/nm.1872
Schlepckow, K., Kleinberger, G., Fukumori, A., Feederle, R., Lichtenthaler, S. F., Steiner, H., & Haass, C. (2017). An Alzheimer-associated TREM2 variant occurs at the ADAM cleavage site and affects shedding and phagocytic function. EMBO Molecular Medicine, 9(10), 1356–1365. https://doi.org/10.15252/emmm.201707672
Selkoe, D. J., & Hardy, J. (2016). The amyloid hypothesis of Alzheimer's disease at 25 years. EMBO Molecular Medicine, 8(6), 595–608. https://doi.org/10.15252/emmm.201606210
Spangenberg, E., Severson, P. L., Hohsfield, L. A., Crapser, J., Zhang, J., Burton, E. A., Zhang, Y., Spevak, W., Lin, J., Phan, N. Y., Habets, G., Rymar, A., Tsang, G., Walters, J., Nespi, M., Singh, P., Broome, S., Ibrahim, P., Zhang, C., … Green, K. N. (2019). Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease model. Nature Communications, 10(1), 3758. https://doi.org/10.1038/s41467-019-11674-z
Styren, S. D., Hamilton, R. L., Styren, G. C., & Klunk, W. E. (2000). X-34, a fluorescent derivative of Congo red: A novel histochemical stain for Alzheimer's disease pathology. The Journal of Histochemistry and Cytochemistry, 48(9), 1223–1232. https://doi.org/10.1177/002215540004800906
Tamboli, I. Y., Prager, K., Thal, D. R., Thelen, K. M., Dewachter, I., Pietrzik, C. U., St. George-Hyslop, P., Sisodia, S. S., de Strooper, B., Heneka, M. T., Filippov, M. A., Muller, U., van Leuven, F., Lutjohann, D., & Walter, J. (2008). Loss of gamma-secretase function impairs endocytosis of lipoprotein particles and membrane cholesterol homeostasis. The Journal of Neuroscience, 28(46), 12097–12106. https://doi.org/10.1523/JNEUROSCI.2635-08.2008
Thal, D. R., Capetillo-Zarate, E., Larionov, S., Staufenbiel, M., Zurbruegg, S., & Beckmann, N. (2009). Capillary cerebral amyloid angiopathy is associated with vessel occlusion and cerebral blood flow disturbances. Neurobiology of Aging, 30(12), 1936–1948. https://doi.org/10.1016/j.neurobiolaging.2008.01.017
Thal, D. R., Griffin, W. S., & Braak, H. (2008). Parenchymal and vascular Abeta-deposition and its effects on the degeneration of neurons and cognition in Alzheimer's disease. Journal of Cellular and Molecular Medicine, 12(5B), 1848–1862. https://doi.org/10.1111/j.1582-4934.2008.00411.x
Thal, D. R., Ronisz, A., Tousseyn, T., Rijal Upadhaya, A., Balakrishnan, K., Vandenberghe, R., Vandenbulcke, M., von Arnim, C. A. F., Otto, M., Beach, T. G., Lilja, J., Heurling, K., Chakrabarty, A., Ismail, A., Buckley, C., Smith, A. P. L., Kumar, S., Farrar, G., & Walter, J. (2019). Different aspects of Alzheimer's disease-related amyloid beta-peptide pathology and their relationship to amyloid positron emission tomography imaging and dementia. Acta Neuropathologica Communications, 7(1), 178. https://doi.org/10.1186/s40478-019-0837-9
Thornton, P., Sevalle, J., Deery, M. J., Fraser, G., Zhou, Y., Ståhl, S., Franssen, E. H., Dodd, R. B., Qamar, S., Gomez Perez-Nievas, B., Nicol, L. S. C., Eketjäll, S., Revell, J., Jones, C., Billinton, A., St George-Hyslop, P. H., Chessell, I., & Crowther, D. C. (2017). TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant. EMBO Molecular Medicine, 9(10), 1366–1378. https://doi.org/10.15252/emmm.201707673
Turnbull, I. R., Gilfillan, S., Cella, M., Aoshi, T., Miller, M., Piccio, L., Hernandez, M., & Colonna, M. (2006). Cutting edge: TREM-2 attenuates macrophage activation. Journal of Immunology, 177(6), 3520–3524. https://doi.org/10.4049/jimmunol.177.6.3520
Ulrich, J. D., Ulland, T. K., Colonna, M., & Holtzman, D. M. (2017). Elucidating the role of TREM2 in Alzheimer's disease. Neuron, 94(2), 237–248. https://doi.org/10.1016/j.neuron.2017.02.042
Verdier, Y., Zarandi, M., & Penke, B. (2004). Amyloid beta-peptide interactions with neuronal and glial cell plasma membrane: Binding sites and implications for Alzheimer's disease. Journal of Peptide Science, 10(5), 229–248. https://doi.org/10.1002/psc.573
Vilalta, A., Zhou, Y., Sevalle, J., Griffin, J. K., Satoh, K., Allendorf, D. H., De, S., Puigdellívol, M., Bruzas, A., Burguillos, M. A., Dodd, R. B., Chen, F., Zhang, Y., Flagmeier, P., Needham, L.-M., Enomoto, M., Qamar, S., Henderson, J., Walter, J., … Brown, G. C. (2021). Wild-type sTREM2 blocks Aβ aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aβ aggregation. Journal of Biological Chemistry, 296, 100631. https://doi.org/10.1016/j.jbc.2021.100631
Walter, J. (2016). The triggering receptor expressed on myeloid cells 2: A molecular link of Neuroinflammation and neurodegenerative diseases. The Journal of Biological Chemistry, 291(9), 4334–4341. https://doi.org/10.1074/jbc.R115.704981
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., Holtzman, D. M., Cirrito, J. R., & Colonna, M. (2015). TREM2 lipid sensing sustains the microglial response in an Alzheimer's disease model. Cell, 160(6), 1061–1071. https://doi.org/10.1016/j.cell.2015.01.049
Wesen, E., Jeffries, G. D. M., Matson Dzebo, M., & Esbjorner, E. K. (2017). Endocytic uptake of monomeric amyloid-beta peptides is clathrin- and dynamin-independent and results in selective accumulation of Abeta(1-42) compared to Abeta(1-40). Scientific Reports, 7(1), 2021. https://doi.org/10.1038/s41598-017-02227-9
Wingfield, P. (2001). Protein precipitation using ammonium sulfate. Current Protocols in Protein Science, Appendix 3, Appendix 3F. https://doi.org/10.1002/0471140864.psa03fs13
Wirths, O., Breyhan, H., Cynis, H., Schilling, S., Demuth, H. U., & Bayer, T. A. (2009). Intraneuronal pyroglutamate-Abeta 3-42 triggers neurodegeneration and lethal neurological deficits in a transgenic mouse model. Acta Neuropathologica, 118(4), 487–496. https://doi.org/10.1007/s00401-009-0557-5
Wunderlich, P., Glebov, K., Kemmerling, N., Tien, N. T., 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. The Journal of Biological Chemistry, 288(46), 33027–33036. https://doi.org/10.1074/jbc.M113.517540
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 Molecular Medicine, 8(9), 992–1004. https://doi.org/10.15252/emmm.201606370
Yeh, F. L., Wang, Y., Tom, I., Gonzalez, L. C., & Sheng, M. (2016). TREM2 binds to Apolipoproteins, including APOE and CLU/APOJ, and thereby facilitates uptake of amyloid-Beta by microglia. Neuron, 91(2), 328–340. https://doi.org/10.1016/j.neuron.2016.06.015
Yu, Y., & Ye, R. D. (2015). Microglial Abeta receptors in Alzheimer's disease. Cellular and Molecular Neurobiology, 35(1), 71–83. https://doi.org/10.1007/s10571-014-0101-6
Yuan, P., Condello, C., Keene, C. D., Wang, Y., Bird, T. D., Paul, S. M., Luo, W., Colonna, M., Baddeley, D., & Grutzendler, J. (2016). TREM2 Haplodeficiency in mice and humans impairs the microglia barrier function leading to decreased amyloid compaction and severe axonal dystrophy. Neuron, 90(4), 724–739. https://doi.org/10.1016/j.neuron.2016.05.003
Zhao, Y., Wu, X., Li, X., Jiang, L.-L., Gui, X., Liu, Y., Sun, Y., Zhu, B., Piña-Crespo, J. C., Zhang, M., Zhang, N., Chen, X., Bu, G., An, Z., Huang, T. Y., & Xu, H. (2018). TREM2 is a receptor for β-amyloid that mediates microglial function. Neuron, 97(5), 1023–1031.e7. https://doi.org/10.1016/j.neuron.2018.01.031
Zhong, L., Wang, Z., Wang, D., Wang, Z., Martens, Y. A., Wu, L., Xu, Y., Wang, K., Li, J., Huang, R., Can, D., Xu, H., Bu, G., & Chen, X. F. (2018). Amyloid-beta modulates microglial responses by binding to the triggering receptor expressed on myeloid cells 2 (TREM2). Molecular Neurodegeneration, 13(1), 15. https://doi.org/10.1186/s13024-018-0247-7
