The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

Jendresen, Charlotte; Årskog, Vibeke; Daws, Michael R.; Nilsson, Lars N. G.

doi:10.1186/s12974-017-0835-4

Cited by 94Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammation biomarkers and pathways

The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

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Jendresen, Charlotte, Årskog, Vibeke, Daws, Michael R., Nilsson, Lars N. G.·2017·Journal of Neuroinflammation

DOI 10.1186/s12974-017-0835-4PMC PMC5360024

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Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) and apolipoprotein E (APOE) are genetically linked to Alzheimer’s disease. Here, we investigated whether human ApoE mediates signal transduction through human and murine TREM2 and sought to identify a TREM2-binding domain in human ApoE. To investigate cell signaling through TREM2, a cell line was used which expressed an NFAT-inducible β-galactosidase reporter and human or murine TREM2, fused to CD8 transmembrane and CD3ζ intracellular signaling domains. ELISA-based binding assays were used to determine binding affinities of human ApoE isoforms to human TREM2 and to identify a TREM2-binding domain in ApoE. ApoE was found to be an agonist to human TREM2 with EC50 in the low nM range, and to murine TREM2 with reduced potency. In the reporter cells, TREM2 expression was lower than in nontransgenic mouse brain. Human ApoE isoforms ε2, ε3, and ε4 bound to human TREM2 with K d in the low nM range. The binding was displaced by an ApoE-mimetic peptide (amino acids 130–149). An ApoE-mediated dose-dependent signal transduction through TREM2 in reporter cells was demonstrated, and a TREM2-binding region in ApoE was identified. The relevance of an ApoE-TREM2 receptor signaling pathway to Alzheimer’s disease is discussed.

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APOE-TREM2 interactions facilitate phagocytosis of apoptotic neurons and increased uptake of Aβ.
“APOE-TREM2 interactions have been found to facilitate phagocytosis of apoptotic neurons and increased uptake of Aβ [80–83].”
From APOE Christchurch enhances a disease-associated microglial response to plaque but suppresses response to tau pathology (2025) · cites this paper as [82]
The Results report ApoE–TREM2 binding and signaling in reporter cells. The Discussion proposes that this interaction might participate in clearance and could activate phagocytosis, but does not establish phagocytosis of apoptotic neurons or increased Aβ uptake. The latter finding appears in a cited study’s title in the References, not as a result demonstrated by this paper. (LLM, conf=0.88)
Experimental — accuracy not yet measured
ApoE is a ligand of TREM2 and can trigger TREM2 signaling, thereby regulating microglia function and neuroinflammation.
“apoE is a ligand of TREM2 and can trigger TREM2 signaling, thereby regulating microglia function and neuroinflammation”
From ApoE4 reduction: An emerging and promising therapeutic strategy for Alzheimer's disease (2022) · cites this paper as Jendresen et al 2017
The Results (page unavailable) show that ApoE acts as a TREM2 agonist and triggers dose-dependent signaling in reporter cells. The Discussion (page unavailable) says ApoE could potentially regulate microglial responses to neuroinflammatory stimuli, but does not establish that it regulates microglial function or neuroinflammation as the claim states. (LLM, conf=0.88)
Experimental — accuracy not yet measured
TREM2 is an ApoE receptor.
“as TREM2 has been demonstrated to be an ApoE receptor116–119.”
From Interplay between innate immunity and Alzheimer disease: APOE and TREM2 in the spotlight (2018) · cites this paper as [117]

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Authors: Jendresen, C., Årskog, V., Daws, M. R., & Nilsson, L. N. G.
Affiliations: Oslo University Hospital (NO)
University of Oslo (NO)
Corresponding author: Nilsson, Lars N. G.
ORCID: Daws, Michael R.
Nilsson, Lars N. G.
Venue: Journal of Neuroinflammation
Publisher: Springer Science and Business Media LLC
Published: 2017-03-21
Volume: 14
Issue: 1
Pages: 59-59
ISSN: 1742-2094 (ISSN-L)
DOI: 10.1186/s12974-017-0835-4
PMC: PMC5360024
OpenAlex: W2601545624
Cited by: 94
References: 96
Citations by year: 2026: 5 · 2025: 17 · 2024: 10 · 2023: 8 · 2022: 7 · 2021: 8 · 2020: 8 · 2019: 16 · 2018: 10 · 2017: 5
FWCI: 5.29
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
Locations: Journal of Neuroinflammation (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders: Helse Sør-Øst RHF (2013016)
Norges Forskningsråd (237250, 240316)
Universitetet i Oslo
Anders Jahres Fond til Vitenskapens Fremme
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
Keywords: Alzheimer's disease, apolipoprotein E, TREM2, receptor signaling, APOE isoforms, signal transduction, genetic risk factors, myeloid cells
MeSH terms: Protein Domains, Age Factors, Alzheimer Disease, Animals, Apolipoproteins E, Brain, Cell Line, Transformed, Humans, Membrane Glycoproteins, Mice, Transgenic, Models, Biological, Models, Molecular, Protein Binding, Receptors, Immunologic, Risk Factors, T-Lymphocytes, Signal Transduction, Amyloid beta-Protein Precursor, Protein Isoforms, Protein Array Analysis, Mice

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The Alzheimer’s disease risk factors apolipoprotein E and TREM2 are linked in a receptor signaling pathway

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