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Cited by 147Retinal Diseases and TreatmentsNeuroinflammation and Neurodegeneration MechanismsPhagocytosis and Immune Regulation

microRNA-34a-Mediated Down-Regulation of the Microglial-Enriched Triggering Receptor and Phagocytosis-Sensor TREM2 in Age-Related Macular Degeneration

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Bhattacharjee, Surjyadipta, Zhao, Yuhai, Dua, Prerna, Rogaev, Evgeny I., Lukiw, Walter J.·2016·PLOS ONE
DOI 10.1371/journal.pone.0150211PMC PMC4780721
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Abstract

The aggregation of Aβ42-peptides and the formation of drusen in age-related macular degeneration (AMD) are due in part to the inability of homeostatic phagocytic mechanisms to clear self-aggregating Aβ42-peptides from the extracellular space. The triggering receptor expressed in myeloid/microglial cells-2 (TREM2), a trans-membrane-spanning, sensor-receptor of the immune-globulin/lectin-like gene superfamily is a critical component of Aβ42-peptide clearance. Here we report a significant deficit in TREM2 in AMD retina and in cytokine- or oxidatively-stressed microglial (MG) cells. RT-PCR, miRNA-array, LED-Northern and Western blot studies indicated up-regulation of a microglial-enriched NF-кB-sensitive miRNA-34a coupled to a down-regulation of TREM2 in the same samples. Bioinformatics/transfection-luciferase reporter assays indicated that miRNA-34a targets the 299 nucleotide TREM2-mRNA-3'UTR, resulting in TREM2 down-regulation. C8B4-microglial cells challenged with Aβ42 were able to phagocytose these peptides, while miRNA-34a down-regulated both TREM2 and the ability of microglial-cells to phagocytose. Treatment of TNFα-stressed MG cells with phenyl-butyl nitrone (PBN), caffeic-acid phenethyl ester (CAPE), the NF-kB - [corrected] inhibitor/resveratrol analog CAY10512 or curcumin abrogated these responses. Incubation of anti-miRNA-34a (AM-34a) normalized miRNA-34a abundance and restored TREM2 back to homeostatic levels. These data support five novel observations: (i) that a ROS- and NF-kB - [corrected] sensitive, miRNA-34a-mediated modulation of TREM2 may in part regulate the phagocytic response; (ii) that gene products encoded on two different chromosomes (miRNA-34a at chr1q36.22 and TREM2 at chr6p21.1) orchestrate a phagocytic-Aβ42-peptide clearance-system; (iii) that this NF-kB-mediated-miRNA-34a-TREM2 mechanism is inducible from outside of the cell; (iv) that when operating normally, this pathway can clear Aβ42 peptide monomers from the extracellular medium; and (v) that anti-NF-kB and/or anti-miRNA (AM)-based therapeutic strategies may be useful against deficits in TREM-2 receptor-based-sensing and -phagocytic signaling that promote pathogenic amyloidogenesis.

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  • Overexpression of miR-34a in C8B4 mouse microglia impairs phagocytosis of Aβ42 peptides, contributing to AMD progression.

    “Using C8B4 mice microglia cells, the authors demonstrated that overexpression of miR-34a impaired phagocytosis of Aβ42 peptides, derivatives of beta-amyloid precursor protein (βAPP), thus contributing to AMD progression [229].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [229]

    The Results section reports that a miRNA-34a mimic reduced TREM2 and Aβ42 internalization in microglial cells; the Fig. 6 description identifies the cells as murine C8B4 cells. The Discussion suggests this mechanism contributes to AMD-related amyloidogenesis, but the cell experiment did not demonstrate an effect on AMD progression. (LLM, conf=0.87)

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  • miR-34a targets TREM2, and in retina samples miR-34a expression is higher in AMD patients while TREM2 expression is lower.

    “A team led by Lukiw showed that miR-34a targets a triggering receptor expressed in myeloid/microglial cells-2 (TREM2). Using retina samples, they confirmed that expression of miR-34a was higher in those obtained from patients with age-related macular degeneration (AMD), whereas TREM2 expression was lower.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [229]

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Authors
Bhattacharjee, S., Zhao, Y., Dua, P., Rogaev, E. I., & Lukiw, W. J.
Affiliations
  • Louisiana State University (US)
  • Louisiana Tech University (US)
  • Russian Academy of Sciences (RU)
Corresponding author
Lukiw, Walter J.
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2016-03-07
Volume
11
Issue
3
Pages
e0150211
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0150211
PMC
PMC4780721
OpenAlex
W2296704298
Cited by
147
References
18
Citations by year
2026: 13 · 2025: 9 · 2024: 12 · 2023: 10 · 2022: 21 · 2021: 21 · 2020: 17 · 2019: 11 · 2018: 10 · 2017: 18 · 2016: 4 · 2015: 1
FWCI
15.23
Type
journal article
Language
en
Update notices
correction (2016-04-05)
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Research to Prevent Blindness (NIA AG038834, NEI EY006311, NIA AG18031 and NIA AG038834, NIA AG18031)
  • Louisiana Biomedical Research Network
  • Russian Science Foundation (14-15-01121, # 14‐50‐00029, 14-44-00077, 14-50-)
  • National Institutes of Health (AG18031, NEI EY006311, NIA AG18031 and NIA AG038834, NEI EY006311, NIA AG18031 and NIA AG038834, GM-103340, NIA AG18031)
  • National Institute on Aging (R01AG029360, AG038834, NIA AG18031, NIA AG18031 and NIA AG038834, AG18031, NIA AG038834, R01AG038834, R01AG018031)
  • National Eye Institute (NEI-EY-006311, R01EY006311, EY-006311)
  • National Institute of General Medical Sciences (GM-103340, P30GM103340)
Topics
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
Keywords
miR-34a, TREM2, age-related macular degeneration, microglia, amyloid-beta 42, phagocytosis, drusen, NF-κB signaling, oxidative stress, 3' UTR regulation, anti-miRNA, resveratrol, curcumin, caffeic acid phenethyl ester, TNF-α
MeSH terms
Aged, Animals, Base Sequence, Cell Line, Female, Humans, Hydrogen Peroxide, Macular Degeneration, Membrane Glycoproteins, Molecular Sequence Data, Phagocytosis, Receptors, Immunologic, Retina, Tumor Necrosis Factor-alpha, Down-Regulation, Case-Control Studies, Microglia, Oxidative Stress, Computational Biology, 3' Untranslated Regions, MicroRNAs, Mice, Interleukin-1beta

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