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

ABSTRACT: Amyloid-? (A?) 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 A? oligomerization and A? 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 A? oligomerization is reduced in Gal-3 KO mice injected with A?, whereas overexpression of Gal-3 enhances A? oligomerization in the hippocampi of A?-injected mice. Gal-3 expression shows an age-dependent increase that parallels endogenous A? oligomerization in APP/PS1 mice. Moreover, A? 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 A? oligomerization, we found that Gal-3 primarily co-localizes with Iba1, and that microglia-secreted Gal-3 directly interacts with A?. 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 A? in APP/PS1 mice and partially overlaps with that of amyloid plaque. Moreover, the expression of the A?-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 A? oligomerization. Because Gal-3 expression is dramatically increased as early as 3 months of age in APP/PS1 mice and anti-A? oligomerization is believed to protect against A? toxicity, Gal-3 could be considered a novel therapeutic target in efforts to combat AD.

SUBMITTER: Tao CC 

PROVIDER: S-EPMC7206130 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature