Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

Lee, Seung-Hye; Meilandt, William J.; Xie, Luke; Gandham, Vineela D.; Ngu, Hai; Barck, Kai H.; Rezzonico, Mitchell G.; Imperio, Jose; Lalehzadeh, Guita; Huntley, Melanie A.; Stark, Kimberly L.; Foreman, Oded; Carano, Richard A.D.; Friedman, Brad A.; Sheng, Morgan; Easton, Amy; Bohlen, Christopher J.; Hansen, David V.

doi:10.1016/j.neuron.2021.02.010

Cited by 303Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

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Lee, Seung-Hye, Meilandt, William J., Xie, Luke, Gandham, Vineela D., Ngu, Hai, Barck, Kai H., Rezzonico, Mitchell G., Imperio, Jose +10 more·2021·Neuron

DOI 10.1016/j.neuron.2021.02.010

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Abstract

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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TREM2 deletion exacerbates tau pathology and promotes brain atrophy in a mouse model overexpressing human tau with P301L and human APP.
“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]
Collectively, studies yielded disparate results regarding the effect of TREM2 on tau pathology and whether the effect is amyloid dependent or independent.
“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]
TREM2 deletion has no effect on tau pathology in a mouse model solely overexpressing mutant tau.
“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]
The dichotomy of immune effects on amyloid and tau has been demonstrated in multiple models of Trem2 and Tyrobp.
“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]
Manipulation of Trem2, Tyrobp, Cx3cl1/Cx3cr1, IL1β, and IFN-γ have opposing effects on amyloid and tau pathologies.
“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]

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Haimon, Z., Volaski, A., Orthgiess, J., Boura-Halfon, S., Varol, D., Shemer, A., Yona, S., Zuckerman, B., David, E., Chappell-Maor, L., et al. (2018) · Nature Immunology · doi:10.1038/s41590-018-0110-6 · Cited by 209 · see citing works
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Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement
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Impact of TREM2 risk variants on brain region-specific immune activation and plaque microenvironment in Alzheimer's disease patient brain samples
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Phosphorylation of Tau at S422 is enhanced by Aβ in TauPS2APP triple transgenic mice
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Heterogeneity of Satellite Cells Implicates DELTA1/NOTCH2 Signaling in Self-Renewal
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Assessment of the Genetic Architecture of Alzheimer’s Disease Risk in Rate of Memory Decline
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EGFR Inhibitor Erlotinib Delays Disease Progression but Does Not Extend Survival in the SOD1 Mouse Model of ALS
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TREM2 R47H exacerbates immune response in Alzheimer’s disease brainPreprint
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Price (1999) · doi:10.1002/1531-8249(199903)45:3

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Tipping points in neurodegeneration
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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: Lee, Seung-Hye
Meilandt, William J.
Xie, Luke
Gandham, Vineela D.
Ngu, Hai
Barck, Kai H.
Imperio, Jose
Huntley, Melanie A.
Foreman, Oded
Carano, Richard A.D.
Friedman, Brad A.
Sheng, Morgan
Easton, Amy
Bohlen, Christopher J.
Hansen, David V.
Venue: Neuron
Publisher: Elsevier BV
Published: 2021-04
Volume: 109
Issue: 8
Pages: 1283-1301.e6
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/j.neuron.2021.02.010
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: Health Sciences › Medicine › Physiology › 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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Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

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