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.
“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]
The Results (page unavailable in our copy) report that the TREM2-stimulating antibody 4D9 reduced cortical plaque burden and soluble Aβ in mice, increased Aβ uptake by cultured mouse microglia, and improved survival of cultured mouse macrophages. The Discussion says the fate of engulfed Aβ is unknown, so the proposed explanation that more efficient clearance caused the reduction in amyloidogenesis is not established by this paper. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAdministration of 4D9 in AD mouse model increased the level of TREM2 in microglia and reduced amyloidogenesis, though no changes to cognitive ability were reported.
“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]
The opposite phenotypes observed in PLCG2 KO iMGs and Plcγ2-P522R KI mice support the notion to therapeutically stimulate TREM2 functions.
“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]
TREM2 p.H157Y increases shedding from microglia, leading to phagocytosis deficits.
“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]
Other similar strategies, based on monoclonal antibodies (4D9), act via a dual mechanism: as direct agonists of TREM2 signalling, and by stabilizing TREM2 on the cell surface and reducing its shedding.
“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]
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.
“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]
Increased expression of TREM2 in Alzheimer's disease has a protective function slowing disease progression.
“Our findings are thus compatible with increased expression of TREM2 in Alzheimer’s disease having a protective function slowing disease progression”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [106]
Loss of function due to the presence of the Trem2 R47H mutation increases the chance of AD reaching the stage of diagnosis.
“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 <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [106]
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- 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
- Health Sciences › Medicine › Physiology › 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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