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Cited by 32Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsMicroRNA in disease regulation

Protective Signature of IFNγ-Stimulated Microglia Relies on miR-124-3p Regulation From the Secretome Released by Mutant APP Swedish Neuronal Cells

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Garcia, Gonçalo, Fernandes, Adelaide, Stein, Frank, Brites, Dora·2022·Frontiers in Pharmacology
DOI 10.3389/fphar.2022.833066PMC PMC9127204
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Abstract

Microglia-associated inflammation and miRNA dysregulation are key players in Alzheimer’s disease (AD) pathophysiology. Previously, we showed miR-124 upregulation in APP Swedish SH-SY5Y (SWE) and PSEN1 iPSC-derived neurons and its propagation by the secretome (soluble and exosomal fractions). After modulation with miR-124 mimic/inhibitor, we identified common responsive mechanisms between such models. We also reported miR-124 colocalization with microglia in AD patient hippocampi. Herein, we determined how miR-124 modulation in SWE cells influences microglia polarized subtypes in the context of inflammation. We used a coculture system without cell-to-cell contact formed by miR-124 modulated SWE cells and human CHME3 microglia stimulated with interferon-gamma (IFNγ-MG), in which we assessed their adopted gene/miRNA profile and proteomic signature. The increase of miR-124 in SWE cells/secretome (soluble and exosomal) was mimicked in IFNγ-MG. Treatment of SWE cells with the miR-124 inhibitor led to RAGE overexpression and loss of neuronal viability, while the mimic caused RAGE/HMGB1 downregulation and prevented mitochondria membrane potential loss. When accessing the paracrine effects on microglia, SWE miR-124 inhibitor favored their IFNγ-induced inflammatory signature (upregulated RAGE/HMGB1/iNOS/IL-1β; downregulated IL-10/ARG-1), while the mimic reduced microglia activation (downregulated TNF-α/iNOS) and deactivated extracellular MMP-2/MMP-9 levels. Microglia proteomics identified 113 responsive proteins to SWE miR-124 levels, including a subgroup of 17 proteins involved in immune function/inflammation and/or miR-124 targets. A total of 72 proteins were downregulated (e.g., MAP2K6) and 21 upregulated (e.g., PAWR) by the mimic, while the inhibitor also upregulated 21 proteins and downregulated 17 (e.g., TGFB1, PAWR, and EFEMP1). Other targets were associated with neurodevelopmental mechanisms, synaptic function, and vesicular trafficking. To examine the source of miR-124 variations in microglia, we silenced the RNase III endonuclease Dicer1 to block miRNA canonical biogenesis. Despite this suppression, the coculture with SWE cells/exosomes still raised microglial miR-124 levels, evidencing miR-124 transfer from neurons to microglia. This study is pioneer in elucidating that neuronal miR-124 reshapes microglia plasticity and in revealing the relevance of neuronal survival in mechanisms underlying inflammation in AD-associated neurodegeneration. These novel insights pave the way for the application of miRNA-based neuropharmacological strategies in AD whenever miRNA dysregulated levels are identified during patient stratification.

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  • miRNAs can be released by cells as free species directly into their secretome or selectively enriched in exosomes (diameter <150 nm) that, when internalized by target cells, affect their biological functions.

    “In general, miRNAs can be released by cells as free species directly into their secretome or selectively enriched in small extracellular vesicles (exosomes, diameter size <150 nm) that, when internalized by target cells, affect their biological functions [38,39,40,41].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [40]

    Results §3.1 reports miR-124 in both exosomes and exosome-free secretome, and Results §3.8 reports that miR-124-loaded exosomes are internalized by microglia and affect their function. However, Methods §2.4 defines the exosomes examined as 50–200 nm, not under 150 nm; the paper also describes exosome-free miRNAs as soluble without establishing that they are free, unbound species. Page numbers are unavailable in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • SWE cell transplantation caused increased hippocampal microglial activation compared with non-transplanted or SH engraftment.

    “Here, we observed the efficient transplantation of SWE cells, which caused increased hippocampal microglial activation when compared to non-transplanted or SH engraftment, further confirming our previous studies centered on the paracrine influence of SWE cells on microglial activation [39,40].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [40]

  • miR-21 is upregulated in SWE cells and in iPSC-derived neurons from patients with the PSEN1 mutation.

    “Our previously published data have shown the upregulation of miR-21 in SWE cells and in iPSC-derived neurons from patients with the PSEN1 mutation [25,39,40].”

    From Emerging Role of miR-21-5p in Neuron–Glia Dysregulation and Exosome Transfer Using Multiple Models of Alzheimer’s Disease (2022) · cites this paper as [40]

    The Results (section 3.1) report upregulation of miR-124 in SWE cells, not miR-21. The Discussion mentions miR-21 only as a predicted contributor of interest for future study, and the passages found do not report miR-21 levels in PSEN1-mutant iPSC-derived neurons (searched: miR-21, PSEN1 mutation, iPSC-derived neurons). (LLM, conf=0.76)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Garcia, G., Fernandes, A., Stein, F., & Brites, D.
Affiliations
  • University of Lisbon (PT)
  • European Molecular Biology Laboratory (DE)
Corresponding author
Brites, Dora
ORCID
Venue
Frontiers in Pharmacology
Publisher
Frontiers Media SA
Published
2022-05-10
Volume
13
Pages
833066-833066
ISSN
1663-9812 (ISSN-L)
DOI
10.3389/fphar.2022.833066
PMC
PMC9127204
OpenAlex
W4229455671
Cited by
32
References
13
Citations by year
2026: 10 · 2025: 5 · 2024: 7 · 2023: 5 · 2022: 5
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Pharmacology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • International Business Machines Corporation
  • Universidade de Lisboa (UIDB/04138/2020, UIDP/04138/2020)
  • Universidade do Porto
  • Fundação para a Ciência e a Tecnologia (01-0145, 04138, UIDB/04138, LISBOA‐01‐0145‐FEDER‐031395, UID/DTP/04138/2019, /2017, UIDB/04138/2020, JPCOFUND/0003/2015, SFRH/BD/128738/2017, UIDP/04138/2020, PTDC/MED-NEU/2382/2021, LISBOA-01-0145-FEDER)
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 › Cancer Research › MicroRNA in disease regulation
Keywords
miR-124-3p, Alzheimer's disease, microglia, interferon-gamma, exosomes, microglial polarization, neuroinflammation, RAGE, HMGB1, paracrine signaling, MAP2K6, PAWR, TGF-β1, EFEMP1

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