Alzheimer's disease‐associated TREM2 variants exhibit either decreased or increased ligand‐dependent activation
Open accessAbstract
Introduction: TREM2 is a lipid‐sensing activating receptor on microglia known to be important for Alzheimer's disease (AD), but whether it plays a beneficial or detrimental role in disease pathogenesis is controversial. Methods: We analyzed AD risk of TREM2 variants in the NIMH AD Genetics Initiative Study and AD Sequencing Project. We compared each variant's risk and functional impact by a reporter assay. Finally, we analyzed expression of TREM2 on human monocytes. Results: We provide more evidence for increased AD risk associated with several TREM2 variants, and show that these variants decreased or markedly increased binding to TREM2 ligands. We identify HDL and LDL as novel TREM2 ligands. We also show that TREM2 expression in human monocytes is minimal compared to monocyte‐derived dendritic cells. Discussion: Our results suggest that TREM2 signaling helps protect against AD but can cause harm in excess, supporting the idea that proper TREM2 function is important to counteract disease progression.
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The most characterised variant of TREM2 (p.R47H) shows defects in ligand binding, which impacts the ability of TREM2 to recognise damage, and induce microglial changes, resulting in a dampened response to pathological insults such as Aβ deposition.
“The most characterised variant of TREM2 (p.R47H) shows defects in ligand binding [6, 37, 38, 97], which impacts the ability of TREM2 to recognise damage, and induce microglial changes, resulting in a dampened response to pathological insults such as Aβ deposition.”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [97]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredp.R47H and p.R62H reduce ligand binding.
“such as reduced ligand binding (p.R47H [96], p.R62H [97])”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [97]
About 75% of mutations in PLCG2 previously implicated in various inflammatory diseases map to the autoinhibitory interface on the PLCγ2 model structure and can be considered pathogenic.
“A number of mutations in PLCG2 (about 75%), that have been previously implicated in various inflammatory diseases [92–102], actually map to the autoinhibitory interface on the PLCγ2 model structure and can be considered as pathogenic (Fig. 2c)”
From TREM2/PLCγ2 signalling in immune cells: function, structural insight, and potential therapeutic modulation (2021) · cites this paper as [97]
The Introduction (§1.1) and Results (§2.2) discuss TREM2 variants, not PLCG2 mutations. Searches for PLCG2, the PLCγ2 autoinhibitory interface, and the 75% figure found no passage in our copy addressing the claim. (LLM, conf=0.77)
Experimental — accuracy not yet measuredTREM2 binds polyanions, phospholipids, sulfatides, apoptotic-cell phospholipids, HDL and LDL particles, and ApoE.
“TREM2 binds polyanions, particularly phospholipids and sulfatides that may be exposed in the brain during Aβ accumulation due to neuronal cell apoptosis and myelin damage (114).”
From Microglia Function in the Central Nervous System During Health and Neurodegeneration (2017) · cites this paper as [115]
In the initial week following injury, the microglia population adopts a balanced distribution between pro- and anti-inflammatory states to promote neurogenesis and enhance the immune response to injury.
“In the initial week following injury, the microglia population adopts a balanced distribution between pro- and anti-inflammatory states to promote neurogenesis and enhance the immune response to injury [89,110,111].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [89]
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Distinct Signaling Pathways Regulate TREM2 Phagocytic and NFκB Antagonistic Activities
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Microglia in Alzheimer’s disease: A target for immunotherapy
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Self-citationSingle-nucleus RNA-sequencing of autosomal dominant Alzheimer disease and risk variant carriers
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Cellular Receptors of Amyloid β Oligomers (AβOs) in Alzheimer’s Disease
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Spatially restricted and ontogenically distinct hepatic macrophages are required for tissue repair
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TREM2 in Alzheimer’s Disease: Microglial Survival and Energy Metabolism
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Metabolic Dysfunction in Alzheimer’s Disease: From Basic Neurobiology to Clinical Approaches
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TREM2-Dependent Effects on Microglia in Alzheimer’s Disease
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Functional insights from biophysical study of TREM2 interactions with apoE and Aβ 1‐42
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TREM2 regulates innate immunity in Alzheimer’s disease
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Neuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease
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Current views on meningeal lymphatics and immunity in aging and Alzheimer’s disease
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Role of TREM2 in Alzheimer’s Disease: A Long Road Ahead
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- Authors
- Song, W., Hooli, B., Mullin, K., Jin, S. C., Cella, M., Ulland, T. K., Wang, Y., Tanzi, R. E., & Colonna, M.
- Affiliations
- Washington University in St. Louis (US)
- Harvard University (US)
- Yale University (US)
- Corresponding author
- Tanzi, Rudolph E.
- Colonna, Marco
- ORCID
- Venue
- Alzheimer's & Dementia
- Publisher
- Wiley
- Published
- 2016-08-09
- Volume
- 13
- Issue
- 4
- Pages
- 381-387
- ISSN
- 1552-5260 (ISSN-L)
- 1552-5279
- PMC
- PMC5299056
- OpenAlex
- W2500839489
- Cited by
- 297
- References
- 22
- Citations by year
- 2026: 15 · 2025: 36 · 2024: 22 · 2023: 65 · 2022: 45 · 2021: 31 · 2020: 22 · 2019: 20 · 2018: 26 · 2017: 13 · 2016: 2
- FWCI
- 11.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alzheimer s & Dementia (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eli Lilly and Company
- National Institute of Mental Health (5R01MH060009‐14)
- JPB Foundation (RG4687A1/1)
- National Multiple Sclerosis Society
- Cure Alzheimer's Fund
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- TREM2, Alzheimer's disease
- MeSH terms
- Alzheimer Disease, Cells, Cultured, Family, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Membrane Glycoproteins, Monocytes, Protein Binding, Receptors, Immunologic, Genetic Variation, Cohort Studies, Logistic Models, Genetic Predisposition to Disease, Genetic Association Studies
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