Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer's disease

Cell Death Differ. 2020 Jan;27(1):192-209. doi: 10.1038/s41418-019-0348-z. Epub 2019 May 24.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age Factors
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / psychology
  • Amyloid beta-Peptides
  • Amyloidogenic Proteins / metabolism*
  • Animals
  • Blood Proteins / metabolism
  • Calcium-Binding Proteins
  • Disease Models, Animal
  • Female
  • Galectin 3 / genetics
  • Galectin 3 / metabolism
  • Galectin 3 / physiology*
  • Galectins / metabolism
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / metabolism
  • Integrins / metabolism
  • Male
  • Memory
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Microfilament Proteins
  • Neprilysin / metabolism
  • Peptide Fragments
  • Plaque, Amyloid
  • Rats, Sprague-Dawley
  • Signal Transduction

Substances

  • Aif1 protein, mouse
  • Amyloid beta-Peptides
  • Amyloidogenic Proteins
  • Blood Proteins
  • Calcium-Binding Proteins
  • Galectin 3
  • Galectins
  • Glial Fibrillary Acidic Protein
  • Integrins
  • LGALS3 protein, human
  • Lgals3 protein, mouse
  • Microfilament Proteins
  • Peptide Fragments
  • amyloid beta-protein (1-42)
  • glial fibrillary astrocytic protein, mouse
  • Neprilysin