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 expre... More
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.
