TREM2 function impedes tau seeding in neuritic plaques
Open accessAbstract
Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) have been associated with increased risk for sporadic, late-onset Alzheimer's disease. Here we show that germline knockout of Trem2 or the TREM2 R47H variant reduces microgliosis around amyloid-β plaques and facilitates the seeding and spreading of neuritic plaque tau aggregates. These findings demonstrate a key role for TREM2 and microglia in limiting the development of peri-plaque tau pathologies.
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Mice carrying R47H variation display impaired binding of TREM2 with anionic and zwitterionic lipids known to associate with fibrillar Aβ, leading to failure of microglia to cluster around Aβ plaques, apoptosis, augmented Aβ accumulation, and spread of neuritic plaque tau aggregates.
“Mice carrying R47H variation displayed impaired binding of TREM2 with anionic and zwitterionic lipids which are known to associate with fibrillar Aβ. As a result, microglia failed to cluster around Aβ plaques and became apoptotic, subsequently leading to augmented Aβ accumulation,198,199 and spread of neuritic plaque tau aggregates.200”
From Role of neuroinflammation in neurodegeneration development (2023) · cites this paper as [200]
Split into 2 atoms — 1 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredRecent in vivo studies suggest TREM2 may be protective or damaging depending on the pathological stage.
“recent in vivo studies suggest that TREM2 may be protective or damaging depending on the pathological stage [19,30,31,32].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [19]
The paper’s Abstract (page not provided) reports that reduced TREM2 function increases tau seeding around amyloid plaques, supporting a protective role for TREM2 in that setting. It does not show that TREM2 is damaging at another pathological stage or establish a stage-dependent switch between protective and damaging effects. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTREM2 deletion increased the abundance of hyperphosphorylated tau dystrophic neurites surrounding amyloid plaques in mice harboring beta-amyloid pathology injected with human AD tau aggregates.
“TREM2 deletion increased the abundance of hyperphosphorylated tau dystrophic neurites surrounding amyloid plaques [19].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [19]
Genetically decreasing TREM2 levels or altering its function in transgenic mice with amyloid plaque deposits injected with human AD brain-derived tau aggregates enhances tau propagation.
“Genetically decreasing TREM2 levels or altering its function in transgenic mice with amyloid plaque deposits injected with human AD brain-derived tau aggregates enhances tau propagation [19,30,31,32,39,40].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [19]
Extracellular tau can be taken up by neighboring cells, both neurons and glial cells, through various pathways including phagocytosis, macropinocytosis, receptor-mediated uptake, endocytosis, and/or membrane fusion of exosomes.
“Meanwhile, the extracellular tau can be taken up by neighboring cells, both neurons and glial cells, through various pathways, including phagocytosis [68], macropinocytosis [69], receptor-mediated uptake [67, 70], endocytosis [71], and/or membrane fusion of exosomes [72, 73].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [70]
TREM2 knockout or its R47H variant decreases microgliosis around Aβ plaques and enhances the propagation of tau aggregates.
“However, another study revealed that TREM2 knockout or its R47H variant decreases microgliosis around Aβ plaques and enhances the propagation of tau aggregates [70].”
From Tau and neuroinflammation in Alzheimer’s disease: interplay mechanisms and clinical translation (2023) · cites this paper as [70]
TREM2 knockout or TREM2 R47H variant dramatically enhances tau seeding and spreading around plaques in AD mice.
“TREM2 knockout (KO) or TREM2 R47H variant dramatically enhanced tau seeding and spreading around plaques in AD mice.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [176]
Impaired or absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage.
“Recent important studies have also shown that impaired/absent Trem2 function attenuates the microglial response to amyloid pathology by regulating microglial number around plaques, regulating microglial activity, and restricting neuritic damage (37,61,84–87,95–99).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [95]
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“However, another study revealed that TREM2 knockout or its R47H variant decreases microgliosis around Aβ plaques and enhances the propagation of tau aggregates [70].”
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Iguchi, A., Takatori, S., Kimura, S., Muneto, H., Wang, K., Etani, H., Ito, G., Sato, H., Hori, Y., Sasaki, J., et al. (2023) · iScience · doi:10.1016/j.isci.2023.106375 · Cited by 37 · see citing works
Microglial phagocytosis in Alzheimer disease
Brown, G. C., St George-Hyslop, P., Paolicelli, R. C., & Lemke, G. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-025-01162-y · Cited by 36 · see citing works
Etxeberria, A., Shen, Y.-A. A., Vito, S., Silverman, S. M., Imperio, J., Lalehzadeh, G., Soung, A. L., Du, C., Xie, L., Choy, M. K., et al. (2024) · The Journal of Neuroscience · doi:10.1523/jneurosci.2347-23.2024 · Cited by 34 · see citing works
Vautheny, A., Duwat, C., Aurégan, G., Joséphine, C., Hérard, A.-S., Jan, C., Mitja, J., Gipchtein, P., Gaillard, M.-C., Buée, L., et al. (2021) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105398 · Cited by 28 · see citing works
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TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo
Lee-Gosselin, A., Jury-Garfe, N., You, Y., Dabin, L., Soni, D., Dutta, S., Rochet, J.-C., Kim, J., Oblak, A. L., & Lasagna-Reeves, C. A. (2023) · Cells · doi:10.3390/cells12121597 · Cited by 19 · see citing works
“TREM2 deletion increased the abundance of hyperphosphorylated tau dystrophic neurites surrounding amyloid plaques [19].”
BackgroundSánchez‐Ruiz de Gordoa, J., Erro, M. E., Vicuña‐Urriza, J., Zelaya, M. V., Tellechea, P., Acha, B., Zueco, S., Urdánoz‐Casado, A., Roldán, M., Blanco‐Luquin, I., et al. (2020) · Movement Disorders · doi:10.1002/mds.27992 · Cited by 18 · see citing works
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- Authors
- Leyns, C. E. G., Gratuze, M., Narasimhan, S., Jain, N., Koscal, L. J., Jiang, H., Manis, M., Colonna, M., Lee, V. M. Y., Ulrich, J. D., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- University of Pennsylvania (US)
- Corresponding author
- Ulrich, Jason D.
- Holtzman, David M.
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2019-06-24
- Volume
- 22
- Issue
- 8
- Pages
- 1217-1222
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC6660358
- OpenAlex
- W2953373572
- Cited by
- 332
- References
- 25
- Citations by year
- 2026: 32 · 2025: 45 · 2024: 51 · 2023: 50 · 2022: 52 · 2021: 54 · 2020: 39 · 2019: 7
- FWCI
- 26.58
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health (1s10od021629-01a1)
- National Institute on Aging (R01AG013956, F31AG053976, P01AG017586, P50AG005681, R01 AG059082, R21AG059176, RF1AG051485, P01AG003991, RF1AG059082, P01AG026276)
- National Institute of Neurological Disorders and Stroke (RF1NS090934)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- TREM2, tau seeding, neuritic plaques, Alzheimer's disease, microglia, microglial activation, amyloid plaques, tau aggregation, prion-like spreading
- MeSH terms
- Animals, Cerebral Cortex, Membrane Glycoproteins, Receptors, Immunologic, tau Proteins, Microglia, Mice, Knockout, Tauopathies, Mice, Plaque, Amyloid
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