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Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology
Open accessAbstract
Loss-of-function TREM2 mutations strongly increase Alzheimer's disease (AD) risk. Trem2 deletion has revealed protective Trem2 functions in preclinical models of β-amyloidosis, a prominent feature of pre-diagnosis AD stages. How TREM2 influences later AD stages characterized by tau-mediated neurodegeneration is unclear. To understand Trem2 function in the context of both β-amyloid and tau pathologies, we examined Trem2 deficiency in the pR5-183 mouse model expressing mutant tau alone or in TauPS2APP mice, in which β-amyloid pathology exacerbates tau pathology and neurodegeneration. Single-cell RNA sequencing in these models revealed robust disease-associated microglia (DAM) activation in TauPS2APP mice that was amyloid-dependent and Trem2-dependent. In the presence of β-amyloid pathology, Trem2 deletion further exacerbated tau accumulation and spreading and promoted brain atrophy. Without β-amyloid pathology, Trem2 deletion did not affect these processes. Therefore, TREM2 may slow AD progression and reduce tau-driven neurodegeneration by restricting the degree to which β-amyloid facilitates the spreading of pathogenic tau.
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“In a recently published study, TREM2 deletion was found to exacerbate tau pathology and promote brain atrophy in a mouse model that overexpressed human tau with the P301L mutation and human amyloid precursor protein (APP) but had no effect in a model that solely overexpressed mutant tau, suggesting that TREM2 function is neither protective nor detrimental in a pure tauopathy setting [14].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [14]
In the citing paper
“Collectively, these studies yielded disparate results regarding the effect of TREM2 on tau pathology and whether the effect is amyloid dependent or independent.”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [14]
In the citing paper
“In a recently published study, TREM2 deletion was found to exacerbate tau pathology and promote brain atrophy in a mouse model that overexpressed human tau with the P301L mutation and human amyloid precursor protein (APP) but had no effect in a model that solely overexpressed mutant tau, suggesting that TREM2 function is neither protective nor detrimental in a pure tauopathy setting [14].”
From TREM2-Deficient Microglia Attenuate Tau Spreading In Vivo (2023) · cites this paper as [14]
In the citing paper
“More recently, this dichotomy has been elegantly demonstrated in multiple models of Trem2 and Tyrobp [49–51, 55–59].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [51]
In the citing paper
“Indeed, manipulation of expression of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have all been shown to have opposing effects on amyloid and tau pathologies [49–51, 55–65].”
From Deletion of Abi3/Gngt2 influences age-progressive amyloid β and tau pathologies in distinctive ways (2022) · cites this paper as [51]
In the citing paper
“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 [177]
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Metadata
- Authors
- Lee, S.-H., Meilandt, W. J., Xie, L., Gandham, V. D., Ngu, H., Barck, K. H., Rezzonico, M. G., Imperio, J., Lalehzadeh, G., Huntley, M. A., Stark, K. L., Foreman, O., Carano, R. A. D., Friedman, B. A., Sheng, M., Easton, A., Bohlen, C. J., & Hansen, D. V.
- Affiliations
- Genentech (US)
- Corresponding author
- Meilandt, William J.
- Hansen, David V.
- ORCID
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2021-04
- Volume
- 109
- Issue
- 8
- Pages
- 1283-1301.e6
- ISSN
- 0896-6273 (ISSN-L)
- OpenAlex
- W3135733909
- Cited by
- 300
- References
- 80
- Citations by year
- 2026: 32 · 2025: 51 · 2024: 56 · 2023: 45 · 2022: 82 · 2021: 33
- FWCI
- 34.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 385 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Genentech Inc
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease, amyloid-beta, tau pathology, neurodegeneration, disease-associated microglia, microglial activation, tau propagation, brain atrophy, TREM2 deficiency, disease progression
- MeSH terms
- Alzheimer Disease, Amyloid, Animals, Atrophy, Brain, Disease Models, Animal, Membrane Glycoproteins, Mice, Transgenic, Receptors, Immunologic, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Mice
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