The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region
Open accessAbstract
Triggering receptor expressed on myeloid cells 2 (TREM2) is essential for the transition of homeostatic microglia to a disease-associated microglial state. To enhance TREM2 activity, we sought to selectively increase the full-length protein on the cell surface via reducing its proteolytic shedding by A Disintegrin And Metalloproteinase (i.e., α-secretase) 10/17. We screened a panel of monoclonal antibodies against TREM2, with the aim to selectively compete for α-secretase-mediated shedding. Monoclonal antibody 4D9, which has a stalk region epitope close to the cleavage site, demonstrated dual mechanisms of action by stabilizing TREM2 on the cell surface and reducing its shedding, and concomitantly activating phospho-SYK signaling. 4D9 stimulated survival of macrophages and increased microglial uptake of myelin debris and amyloid β-peptide in vitro. In vivo target engagement was demonstrated in cerebrospinal fluid, where nearly all soluble TREM2 was 4D9-bound. Moreover, in a mouse model for Alzheimer's disease-related pathology, 4D9 reduced amyloidogenesis, enhanced microglial TREM2 expression, and reduced a homeostatic marker, suggesting a protective function by driving microglia toward a disease-associated state.
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“recent in vivo and in vitro models seem to support the idea that activation of Trem2 leads to reduced amyloidogenesis by a more efficient clearance, and promotes cell phagocytosis and survival, at least in mouse models ([46], see more below)”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [46]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Administration of 4D9 in AD mouse model increased the level of TREM2 in microglia and reduced amyloidogenesis,539 though no changes to cognitive ability were reported.”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [539]
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In the citing paper
“The opposite phenotypes observed in PLCG2 KO iMGs and Plcγ2-P522R KI mice also support the notion to therapeutically stimulate TREM2 functions [6, 16, 17, 43].”
From The Alzheimer’s disease-associated protective Plcγ2-P522R variant promotes immune functions (2020) · cites this paper as [16]
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In the citing paper
“Increased shedding from microglia [45], leading to phagocytosis deficits [46]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [46]
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In the citing paper
“Other similar strategies, based on monoclonal antibodies (4D9), act via a dual mechanism: as direct agonists of the TREM2 signalling, and by stabilizing TREM2 on the cell surface and reducing its shedding [46]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [46]
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In the citing paper
“This strategy demonstrated increased microglial uptake of myelin debris and amyloid β-peptide in vitro, and reduced amyloid plaque burden in the cortex of APPNLGF mice [46]”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [46]
In the citing paper
“Our findings are thus compatible with increased expression of TREM2 in Alzheimer’s disease having a protective function slowing disease progression”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [106]
In the citing paper
“loss of function due to the presence of the Trem2 R47H mutation increasing the chance of AD reaching the stage of diagnosis (44,104–107)”
From Trem2 promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [106]
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Citations
Cites
Continuous cultures of fused cells secreting antibody of predefined specificity
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Self-citationVariant of TREM2 Associated with the Risk of Alzheimer's Disease
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“In addition to the selective deposition of amyloidogenic proteins, neuroinflammation associated with microgliosis is a common feature of many neurodegenerative disorders (Ransohoff, 2016).”
BackgroundTREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model
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., et al. (2015) · Cell · doi:10.1016/j.cell.2015.01.049 · Cited by 1,736
Marschallinger, J., Iram, T., Zardeneta, M., Lee, S. E., Lehallier, B., Haney, M. S., Pluvinage, J. V., Mathur, V., Hahn, O., Morgens, D. W., et al. (2020) · Nature Neuroscience · doi:10.1038/s41593-019-0566-1 · Cited by 1,384 · cited 1×
“Notably, lipid metabolism, storage, and processing has emerged as a potentially important contributor to proper microglial function in the CNS (Chan et al, 2012; Wang et al, 2015; Keren-Shaul et al, 2017; Griciuc et al, 2019; Marschallinger et al, 2020; Nugent et al, 2019).”
BackgroundLipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner
Jaitin, D. A., Adlung, L., Thaiss, C. A., Weiner, A., Li, B., Descamps, H., Lundgren, P., Bleriot, C., Liu, Z., Deczkowska, A., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.054 · Cited by 1,377
Flagged first, then by citations
Research works printed but not linked: 2
- Bradbury A (2010) Antibody engineering, Vol. 1. Berlin Heidelberg: Springer‐Verlag
- Jonsson T, Stefansson K (2013) TREM2 and neurodegenerative disease. N Engl J Med 369: 1568–1569
Cited by
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Soluble TREM2 reduces DAP12 surface expression by dissociating the TREM2–DAP12 complexPreprint
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The microglial lineage: from molecular states to context-dependent functions
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Dejanovic, B., Figley, M. D., Weisman, E. F., Kiragasi, B., Gergits, F. W., Larson, K., Renoux, A. J., Rajagovindan, R., Pandya, B. A., Houze, J. B., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.aec5740 · Cited by 1
TREM2 Signaling and Alzheimer’s Disease: Experimental Modulators, Progress, and Challenges
Sayegh, M., Azarfar, K., Reyna, E. M., Kennedy, J. M., Sabbagh, M. N., & Decourt, B. (2026) · Drug Design Development and Therapy · doi:10.2147/dddt.s611558
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Metadata
- Authors
- Schlepckow, K., Monroe, K. M., Kleinberger, G., Cantuti‐Castelvetri, L., Parhizkar, S., Xia, D., Willem, M., Werner, G., Pettkus, N., Brunner, B., Sülzen, A., Nuscher, B., Hampel, H., Xiang, X., Feederle, R., Tahirovic, S., Park, J. I., Prorok, R., Mahon, C., Liang, C., Shi, J., Kim, D. J., Sabelström, H., Huang, F., Di Paolo, G., Simons, M., Lewcock, J. W., & Haass, C.
- Affiliations
- German Center for Neurodegenerative Diseases (DE)
- Denali Therapeutics (United States) (US)
- Ludwig-Maximilians-Universität München (DE)
- Corresponding author
- Lewcock, Joseph W
- Haass, Christian
- ORCID
- Schlepckow, Kai
- Monroe, Kathryn M
- Kleinberger, Gernot
- Cantuti‐Castelvetri, Ludovico
- Parhizkar, Samira
- Willem, Michael
- Werner, Georg
- Nuscher, Brigitte
- Xiang, Xianyuan
- Feederle, Regina
- Tahirovic, Sabina
- Prorok, Rachel
- Mahon, Cathal
- Shi, Ju
- Kim, Do Jin
- Sabelström, Hanna
- Huang, Fen
- Simons, Mikael
- Lewcock, Joseph W
- Haass, Christian
- Venue
- EMBO Molecular Medicine
- Published
- 2020-03-10
- Volume
- 12
- Issue
- 4
- Pages
- e11227-e11227
- ISSN
- 1757-4676 (ISSN-L)
- 1757-4684
- PMC
- PMC7136959
- OpenAlex
- W3012091890
- Cited by
- 324
- References
- 63
- Citations by year
- 2026: 42 · 2025: 55 · 2024: 52 · 2023: 58 · 2022: 50 · 2021: 39 · 2020: 28
- FWCI
- 16.91
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- EMBO Molecular Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Open access LMU (Ludwid Maxmilian's Universitat Munchen) (submittedVersion, cc-by)
- mediaTUM (Technical University of Munich) (submittedVersion)
- DZNE Pub (submittedVersion, other-oa)
- Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
- Funders
- Deutsche Forschungsgemeinschaft (EXC 2145; ID 390857198 SyNergy, HA1737/16‐1)
- Helmholtz Association (ZT‐0027)
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Innovative Medicines Initiative (115976)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, microglia, antibody therapy, Syk signaling, disease-associated microglia, macrophage survival, amyloid-beta, Alzheimer's disease, soluble TREM2, cerebrospinal fluid
- MeSH terms
- Animals, Antibodies, Monoclonal, Female, Macrophages, Membrane Glycoproteins, Multiple Myeloma, Receptors, Immunologic, Amyloid beta-Peptides, Rats, Wistar, Microglia, Cell Line, Tumor, Mice, Rats
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