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Cited by 357Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsGalectins and Cancer Biology

Galectin-3, a novel endogenous TREM2 ligand, detrimentally regulates inflammatory response in Alzheimer’s disease

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Boza-Serrano, Antonio, Ruiz, Rocío, Sanchez-Varo, Raquel, García-Revilla, Juan, Yang, Yiyi, Jimenez-Ferrer, Itzia, Paulus, Agnes, Wennström, Malin +19 more·2019·Acta Neuropathologica
DOI 10.1007/s00401-019-02013-zPMC PMC6660511
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Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease in which the formation of extracellular aggregates of amyloid beta (Aβ) peptide, fibrillary tangles of intraneuronal tau and microglial activation are major pathological hallmarks. One of the key molecules involved in microglial activation is galectin-3 (gal3), and we demonstrate here for the first time a key role of gal3 in AD pathology. Gal3 was highly upregulated in the brains of AD patients and 5xFAD (familial Alzheimer's disease) mice and found specifically expressed in microglia associated with Aβ plaques. Single-nucleotide polymorphisms in the LGALS3 gene, which encodes gal3, were associated with an increased risk of AD. Gal3 deletion in 5xFAD mice attenuated microglia-associated immune responses, particularly those associated with TLR and TREM2/DAP12 signaling. In vitro data revealed that gal3 was required to fully activate microglia in response to fibrillar Aβ. Gal3 deletion decreased the Aβ burden in 5xFAD mice and improved cognitive behavior. Interestingly, a single intrahippocampal injection of gal3 along with Aβ monomers in WT mice was sufficient to induce the formation of long-lasting (2 months) insoluble Aβ aggregates, which were absent when gal3 was lacking. High-resolution microscopy (stochastic optical reconstruction microscopy) demonstrated close colocalization of gal3 and TREM2 in microglial processes, and a direct interaction was shown by a fluorescence anisotropy assay involving the gal3 carbohydrate recognition domain. Furthermore, gal3 was shown to stimulate TREM2-DAP12 signaling in a reporter cell line. Overall, our data support the view that gal3 inhibition may be a potential pharmacological approach to counteract AD.

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  • LGALS3 was reported to promote Aβ oligomerization and toxicity.

    “Although LGALS3 was reported to promote Aβ oligomerization and toxicity, these studies were performed using either global Lgals3 -KO mice or Aβ monomers precultured with LGALS3 before injection into the brain 52,53 .”

    From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [52]

    The Results section reports that galectin-3 accompanied the formation of insoluble Aβ aggregates after Aβ monomers were injected into mouse hippocampi; Aβ alone produced no such deposits. The Discussion also links galectin-3 to harmful Aβ-associated inflammatory responses and reduced cognitive performance in 5xFAD mice. But the paper does not establish that galectin-3 promotes Aβ oligomerization specifically, or directly demonstrate increased toxicity of Aβ oligomers. (LLM, conf=0.87)

    Experimental — accuracy not yet measured

  • Gal3, a TREM2 ligand encoded by the Lgals3 gene specific to the XO4+-associated gene expression signature, is toxic in 5xFAD mice.

    “However, Gal3, a TREM2 ligand encoded by the Lgals3 gene specific to the XO4+-associated gene expression signature, is toxic in 5xFAD mice71.”

    From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [71]

    The Results section (‘Galectin-3 acts as a TREM2 ligand’; page unavailable) reports Gal3–TREM2 binding in 5xFAD brain sections. Another Results section (‘The lack of galectin-3 reduces AD pathology in 5xFAD mice’; page unavailable) reports reduced plaque burden and better cognitive performance after Gal3 deletion, supporting a detrimental role. The Introduction identifies Gal3 as Lgals3, but our copy does not establish that Lgals3 is specific to an XO4+-associated gene-expression signature. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Gal3 is found in close association with plaques in human AD microglia.

    “found in close association with plaques in human AD microglia”

    From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [71]

  • Gal3 is released in response to fAβ treatment in vitro.

    “Gal3 is released in response to fAβ treatment in vitro”

    From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [71]

  • Gal3 knockout in 5xFAD mice reduced plaques and improved memory function.

    “Gal3 knockout in 5xFAD mice reduced plaques and improved memory function71.”

    From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [71]

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Authors
Boza-Serrano, A., Ruiz, R., Sanchez-Varo, R., García-Revilla, J., Yang, Y., Jimenez-Ferrer, I., Paulus, A., Wennström, M., Vilalta, A., Allendorf, D., Davila, J. C., Stegmayr, J., Jiménez, S., Roca-Ceballos, M. A., Navarro-Garrido, V., Swanberg, M., Hsieh, C. L., Real, L. M., Englund, E., Linse, S., Leffler, H., Nilsson, U. J., Brown, G. C., Gutierrez, A., Vitorica, J., Venero, J. L., & Deierborg, T.
Affiliations
  • Instituto de Biomedicina de Sevilla (ES)
  • Biomedical Research Networking Center on Neurodegenerative Diseases (ES)
  • Lund University (SE)
  • University of Cambridge (GB)
  • San Francisco VA Medical Center (US)
Corresponding author
  • Venero, Jose Luis
  • Deierborg, Tomas
ORCID
Venue
Acta Neuropathologica
Publisher
Springer Science and Business Media LLC
Published
2019-04-20
Volume
138
Issue
2
Pages
251-273
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
DOI
10.1007/s00401-019-02013-z
PMC
PMC6660511
OpenAlex
W2938377166
Cited by
357
References
21
Citations by year
2026: 34 · 2025: 58 · 2024: 79 · 2023: 45 · 2022: 49 · 2021: 46 · 2020: 39 · 2019: 7
FWCI
15.63
Type
journal article
Language
en
Update notices
correction (2023-02-15)
Open access
Licence
Locations
  • Acta Neuropathologica (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RISalud Institutional Health Repository of Andalucía (submittedVersion, cc-by)
  • DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion, cc-by)
  • Deposito de Investigacion Universidad de Sevilla (University of Seville) (submittedVersion, cc-by-nc-nd)
  • Lund University Publications (Lund University) (submittedVersion)
  • Repositorio Institucional de la Universidad de Málaga (University of Málaga) (submittedVersion, cc-by)
  • Zenodo (CERN European Organization for Nuclear Research) (submittedVersion, cc-by)
Funders
  • Vetenskapsrådet
  • Multipark
  • Swedish Alzheimer’s Foundation
  • Swedish Brain Foundation
  • Anna och Edwin Bergers Stiftelse
  • Gyllenstiernska Krapperup Foundation
  • the Royal Physiographic Society
  • Olle Engkvist Byggmästare Foundation
  • Wiberg Foundation
  • G&J Kock Foundation
  • Stohnes Foundation
  • Swedish Dementia Association and the Medical Faculty at Lund University
  • MINECO/FEDER (SAF2015-64171R)
  • FIS (FIS PI12/O1431, FIS PI15/00796)
  • FEDER funds from European Union, through grants (PI12/01439, PI15/00957)
  • FEDER (PI12/01431, PI15/00796)
  • Proyecto Excelencia Junta Andalucia (CTS-2035)
  • Innovative Medicines Initiative 2 Joint Undertaking under grant agreement (No 115976 (PHAGO))
  • Knut and Alice Wallenberg Foundation ((KAW 2013.0022))
  • Swedish Research Council (621-2012-2978)
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 › Galectins and Cancer Biology
Keywords
galectin-3, TREM2, Alzheimer's disease, microglial activation, amyloid plaques, 5xFAD mice, Toll-like receptor signaling, carbohydrate recognition domain, galectin-3 inhibition, cognitive impairment, amyloid-beta aggregation
MeSH terms
Alzheimer Disease, Amyloid, Animals, Cells, Cultured, Disease Models, Animal, Female, Hippocampus, Humans, Inflammation, Male, Membrane Glycoproteins, Mice, Inbred C57BL, Mice, Transgenic, Receptors, Immunologic, Amyloid beta-Peptides, Microglia, Mice, Knockout, Maze Learning, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Galectin 3, Mice, Genome-Wide Association Study, Molecular Targeted Therapy, Protein Aggregation, Pathological

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