Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer’s disease
Open accessAbstract
Amyloid-β (Aβ) oligomers largely initiate the cascade underlying the pathology of Alzheimer’s disease (AD). Galectin-3 (Gal-3), which is a member of the galectin protein family, promotes inflammatory responses and enhances the homotypic aggregation of cancer cells. Here, we examined the role and action mechanism of Gal-3 in Aβ oligomerization and Aβ toxicities. Wild-type (WT) and Gal-3-knockout (KO) mice, APP/PS1;WT mice, APP/PS1;Gal-3 +/− mice and brain tissues from normal subjects and AD patients were used. We found that Aβ oligomerization is reduced in Gal-3 KO mice injected with Aβ, whereas overexpression of Gal-3 enhances Aβ oligomerization in the hippocampi of Aβ-injected mice. Gal-3 expression shows an age-dependent increase that parallels endogenous Aβ oligomerization in APP/PS1 mice. Moreover, Aβ oligomerization, Iba1 expression, GFAP expression and amyloid plaque accumulation are reduced in APP/PS1;Gal-3 +/− mice compared with APP/PS1;WT mice. APP/PS1;Gal-3 +/− mice also show better acquisition and retention performance compared to APP/PS1;WT mice. In studying the mechanism underlying Gal-3-promoted Aβ oligomerization, we found that Gal-3 primarily co-localizes with Iba1, and that microglia-secreted Gal-3 directly interacts with Aβ. Gal-3 also interacts with triggering receptor expressed on myeloid cells-2, which then mediates the ability of Gal-3 to activate microglia for further Gal-3 expression. Immunohistochemical analyses show that the distribution of Gal-3 overlaps with that of endogenous Aβ in APP/PS1 mice and partially overlaps with that of amyloid plaque. Moreover, the expression of the Aβ-degrading enzyme, neprilysin, is increased in Gal-3 KO mice and this is associated with enhanced integrin-mediated signaling. Consistently, Gal-3 expression is also increased in the frontal lobe of AD patients, in parallel with Aβ oligomerization. Because Gal-3 expression is dramatically increased as early as 3 months of age in APP/PS1 mice and anti-Aβ oligomerization is believed to protect against Aβ toxicity, Gal-3 could be considered a novel therapeutic target in efforts to combat 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 [53]
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- Authors
- Tao, C.-C., Cheng, K.-M., Ma, Y.-L., Hsu, W.-L., Chen, Y.-C., Fuh, J.-L., Lee, W.-J., Chao, C.-C., & Lee, E. H. Y.
- Affiliations
- Institute of Biomedical Sciences, Academia Sinica (TW)
- Taipei Veterans General Hospital (TW)
- Taichung Veterans General Hospital (TW)
- National Chengchi University (TW)
- Corresponding author
- Lee, Eminy H. Y.
- ORCID
- Venue
- Cell Death & Differentiation
- Published
- 2019-05-24
- Volume
- 27
- Issue
- 1
- Pages
- 192-209
- ISSN
- 1350-9047 (ISSN-L)
- 1476-5403
- PMC
- PMC7206130
- OpenAlex
- W2944988109
- Cited by
- 138
- References
- 51
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 32 · 2023: 13 · 2022: 30 · 2021: 20 · 2020: 9 · 2019: 1
- FWCI
- 10.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell Death and Differentiation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ministry of Science and Technology, Taiwan (MOST 106-2320-B-001-005-MY3)
- Institute of Biomedical Sciences, Academia Sinica, Taiwan
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Galectins and Cancer Biology
- Keywords
- amyloid-beta oligomers, Alzheimer's disease, amyloid-beta toxicity, microglia, TREM2, neprilysin, APP/PS1 mice, amyloid plaques, hippocampus, integrin signaling, galectin-3 knockout mice, cognitive impairment, therapeutic target
- MeSH terms
- Age Factors, Alzheimer Disease, Animals, Blood Proteins, Calcium-Binding Proteins, Disease Models, Animal, Female, Glial Fibrillary Acidic Protein, Hippocampus, Male, Memory, Mice, Transgenic, Microfilament Proteins, Peptide Fragments, Neprilysin, Signal Transduction, Integrins, Amyloid beta-Peptides, Rats, Sprague-Dawley, Mice, Knockout, Galectins, Galectin 3, Mice, Plaque, Amyloid, Amyloidogenic Proteins
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