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

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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, 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.·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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“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…”
Background
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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: 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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Trem2 restrains the enhancement of tau accumulation and neurodegeneration by β-amyloid pathology

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