Activated microglia mitigate Aβ-associated tau seeding and spreading
Open accessAbstract
In Alzheimer’s disease (AD) models, AD risk variants in the microglial-expressed TREM2 gene decrease Aβ plaque–associated microgliosis and increase neuritic dystrophy as well as plaque-associated seeding and spreading of tau aggregates. Whether this Aβ-enhanced tau seeding/spreading is due to loss of microglial function or a toxic gain of function in TREM2-deficient microglia is unclear. Depletion of microglia in mice with established brain amyloid has no effect on amyloid but results in less spine and neuronal loss. Microglial repopulation in aged mice improved cognitive and neuronal deficits. In the context of AD pathology, we asked whether microglial removal and repopulation decreased Aβ-driven tau seeding and spreading. We show that both TREM2KO and microglial ablation dramatically enhance tau seeding and spreading around plaques. Interestingly, although repopulated microglia clustered around plaques, they had a reduction in disease-associated microglia (DAM) gene expression and elevated tau seeding/spreading. Together, these data suggest that TREM2-dependent activation of the DAM phenotype is essential in delaying Aβ-induced pathological tau propagation.
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Tau-PHF degradation was delayed in Trem2 KO BMDMs compared with Trem2 WT BMDMs.
“tau-PHF degradation was delayed in Trem2 KO BMDMs compared with that in Trem2 WT BMDMs [39].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [39]
The Results and discussion section, under “TREM2 regulates AD-tau clearance” (page not available), reports that the tau-associated signal decayed more rapidly in WT than in TREM2-KO BMDMs, supporting slower clearance in the KO cells. The assay used AD-tau isolated from human AD brain; the paper does not identify the tested material specifically as tau-PHF. (LLM, conf=0.86)
Experimental — accuracy not yet measuredTotal removal of microglia enhanced amyloid-associated tau seeding.
“the total removal of microglia enhanced amyloid-associated tau seeding [39]”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [39]
The Results and discussion report increased Aβ-associated NP-tau seeding and spreading after microglial depletion. But the same section says PLX treatment removed most microglia, with approximately 20% remaining, so the experiment does not support “total removal.” (LLM, conf=0.90)
Experimental — accuracy not yet measuredEfficient microglial clustering around Aβ plaques mitigates amyloid-driven tau seeding.
“Moreover, efficient microglial clustering around Aβ plaques mitigates amyloid-driven tau seeding [32].”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [32]
The Results and discussion section (page unavailable) supports a protective role for resident, TREM2-expressing microglia in slowing plaque-associated tau seeding. But it also reports that repopulated microglia clustered around plaques at a density similar to controls while tau pathology was markedly elevated. Clustering alone therefore does not establish the mitigation claimed. (LLM, conf=0.87)
Experimental — accuracy not yet measuredIn a transgenic mouse model of AD, efficient microglial clustering around Aβ plaques mitigates amyloid-driven tau seeding.
“Considering a previous study in a transgenic mouse model of AD demonstrating that efficient microglial clustering around Aβ plaques mitigates amyloid-driven tau seeding [32]”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [32]
The Conclusion reports that microglial depletion or TREM2 deficiency increased Aβ-associated tau pathology, supporting a protective role for microglia. But the Introduction and Abstract state that repopulated microglia clustered around plaques yet showed elevated tau seeding and spreading. The paper therefore supports protection by appropriately activated microglia, not clustering alone. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAsymAD individuals might be characterized by the presence of microglia with enhanced migration and extension toward newly formed amyloid plaques.
“AsymAD individuals might be characterized by the presence of microglia with enhanced migration and extension toward newly formed amyloid plaques.”
From Enhanced microglial dynamics and a paucity of tau seeding in the amyloid plaque microenvironment contribute to cognitive resilience in Alzheimer’s disease (2024) · cites this paper as [32]
The Introduction and Results and discussion (page unavailable) report that microglia cluster around amyloid plaques, including in 5XFAD mice. They do not establish enhanced migration or extension toward newly formed plaques, or characterize microglia in asymptomatic AD individuals; the study’s experiments used mice. (LLM, conf=0.86)
Experimental — accuracy not yet measured
Microglia or macrophage uptake of tau does not depend on TREM2 expression.
“in vitro experiments suggest that microglia or macrophage uptake of tau does not depend on TREM2 expression [39,43].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [39]
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 [39]
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 [175]
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References 39 · Cited by 215
Research works printed but not linked: 1
- Zhan, L., P.D. Sohn, Y. Zhou, Y. Li, and L. Gan. 2019. A Mac2-positive progenitor-like microglial population survives independent of CSF1R signaling in adult mouse brain. bioRxiv. 10.1101/722090 (Preprint posted August 1, 2019) · DOI
- Authors
- Gratuze, M., Chen, Y., Parhizkar, S., Jain, N., Strickland, M. R., Serrano, J. R., Colonna, M., Ulrich, J. D., & Holtzman, D. M.
- Affiliations
- Washington University in St. Louis (US)
- Corresponding author
- Holtzman, David M.
- ORCID
- Venue
- Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2021-06-08
- Volume
- 218
- Issue
- 8
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC8190588
- OpenAlex
- W3170190396
- Cited by
- 215
- References
- 39
- Citations by year
- 2026: 28 · 2025: 40 · 2024: 46 · 2023: 41 · 2022: 50 · 2021: 9
- FWCI
- 23.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The Journal of Experimental Medicine (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Digital Commons@Becker (Washington University School of Medicine) (submittedVersion, cc-by-nc-sa)
- HAL (submittedVersion)
- Funders
- BrightFocus Foundation (A2020257F)
- National Institutes of Health (AG047644, UL1 TR000448)
- JPB Foundation
- Charles and Helen Schwab Foundation
- Edward N. and Della L. Thome Memorial Foundation
- NIH Office of the Director (OD021629)
- Washington University School of Medicine
- Children’s Discovery Institute of Washington University
- St. Louis Children’s Hospital (CDI-CORE-2015-505, CDI-CORE-2019-813)
- Foundation for Barnes-Jewish Hospital (3770, 4642)
- National Cancer Institute (P30 CA91842)
- National Center for Research Resources
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- Alzheimer's disease, microglia, TREM2, amyloid-beta, tau seeding, tau propagation, disease-associated microglia, microglial ablation, microglial repopulation, microglial activation, amyloid plaques
- MeSH terms
- Animals, Apolipoproteins E, Homeostasis, Macrophages, Membrane Glycoproteins, Phenotype, Receptors, Immunologic, Amyloid beta-Peptides, Neurites, tau Proteins, Microglia, Mice, Knockout, Mice, Plaque, Amyloid
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