Different mechanisms of apolipoprotein E isoform‐dependent modulation of prostaglandin E 2 production and triggering receptor expressed on myeloid cells 2 ( TREM2 ) expression after innate immune activation of microglia

Li, Xianwu; Montine, Kathleen S.; Keene, C. Dirk; Montine, Thomas J.

doi:10.1096/fj.14-262683

Cited by 54Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsInflammasome and immune disorders

Different mechanisms of apolipoprotein E isoform‐dependent modulation of prostaglandin E 2 production and triggering receptor expressed on myeloid cells 2 ( TREM2 ) expression after innate immune activation of microglia

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Li, Xianwu, Montine, Kathleen S., Keene, C. Dirk, Montine, Thomas J.·2015·The FASEB Journal

DOI 10.1096/fj.14-262683PMC PMC4415020

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Abstract

Several lines of evidence support immune response in brain as a mechanism of injury in Alzheimer disease (AD). Moreover, immune activation is heightened in apolipoprotein E (APOE) ε4 carriers; inhibitors of prostaglandin (PG) synthesis show a partially protective effect on AD risk from APOE ε4; and genetic variants in triggering receptor expressed on myeloid cells 2 (TREM2) are a rare but potent risk for AD. We tested the hypothesis that APOE ε4 inheritance modulates both the PGE2 pathway and TREM2 expression using primary murine microglia from targeted replacement (TR) APOE3/3 and APOE4/4 mice. Microglial cyclooxygenase-2, microsomal PGE synthase, and PGE2 expression were increased 2- to 25-fold in both genotypes by TLR activators; however, this induction was significantly (P < 0.01) greater in TR APOE4/4 microglia with TLR3 and TLR4 activators. Microglial TREM2 expression was reduced approximately 85% by all TLR activators; this reduction was approximately one-third greater in microglia from TR APOE4/4 mice. Importantly, both receptor-associated protein and a nuclear factor κ-light-chain-enhancer inhibitor blocked TR APOE4/4-dependent effects on the PGE2 pathway but not on TREM2 expression. These data demonstrate complementary, but mechanistically distinct, regulation of pro- and anti-inflammatory mediators in TR APOE4/4 murine microglia that yields a more proinflammatory state than with TR APOE3/3.

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ApoE4 led to lower TREM2 expression compared with ApoE3 in primary microglia from apoE knock-in mice.
“ApoE4 led to a lower TREM2 expression as compared to ApoE3 [43]”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [43]
ApoE affects TREM2 expression in primary microglia cultured from apoE knock-in mice in response to various microglia activation reagents.
“ApoE is also found to affect TREM2 expression in primary microglia cultured from apoE knock-in mice in response to various microglia activation reagents.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [43]
ApoE4's lower TREM2 expression might impair TREM2-mediated amyloid β clearance.
“ApoE4 led to a lower TREM2 expression as compared to ApoE3 [43], which might impair the TREM2-mediated amyloid β clearance.”
From Apolipoprotein E metabolism and functions in brain and its role in Alzheimer's disease (2017) · cites this paper as [43]

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Apolipoprotein E-specific innate immune response in astrocytes from targeted replacement mice
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Authors: Li, X., Montine, K. S., Keene, C. D., & Montine, T. J.
Affiliations: University of Washington (US)
Corresponding author: Li, Xianwu
ORCID: Montine, Kathleen S.
Keene, C. Dirk
Montine, Thomas J.
Venue: The FASEB Journal
Publisher: Wiley
Published: 2015-01-15
Volume: 29
Issue: 5
Pages: 1754-1762
ISSN: 0892-6638 (ISSN-L)
1530-6860
DOI: 10.1096/fj.14-262683
PMC: PMC4415020
OpenAlex: W2121536490
Cited by: 54
References: 56
Citations by year: 2026: 2 · 2025: 4 · 2024: 3 · 2023: 2 · 2022: 2 · 2021: 3 · 2020: 1 · 2019: 4 · 2018: 9 · 2017: 9 · 2016: 11 · 2015: 4
FWCI: 5.88
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: The FASEB Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (R01‐ES016754, P50‐AG05136)
National Institute of Neurological Disorders and Stroke (P50‐NS062684)
Nancy and Buster Alvord Endowment
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords: apolipoprotein E, APOE ε4, TREM2, prostaglandin E2, microglia, innate immune activation, cyclooxygenase-2, TLR3, TLR4, Alzheimer's disease, neuroinflammation, NF-κB, receptor-associated protein
MeSH terms: Prostaglandin-E Synthases, Animals, Apolipoproteins E, Cells, Cultured, Enzyme-Linked Immunosorbent Assay, Flow Cytometry, Membrane Glycoproteins, Mice, Inbred C57BL, Receptors, Immunologic, RNA, Messenger, Blotting, Western, Dinoprostone, Microglia, Mice, Knockout, Intramolecular Oxidoreductases, Protein Isoforms, Reverse Transcriptase Polymerase Chain Reaction, Myeloid Cells, Toll-Like Receptors, Mice, Cyclooxygenase 2, Apolipoprotein E3, Apolipoprotein E4, Real-Time Polymerase Chain Reaction

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Different mechanisms of apolipoprotein E isoform‐dependent modulation of prostaglandin E 2 production and triggering receptor expressed on myeloid cells 2 ( TREM2 ) expression after innate immune activation of microglia

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