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

First Author  Tao CC Year  2020
Journal  Cell Death Differ Volume  27
Issue  1 Pages  192-209
PubMed ID  31127200 Mgi Jnum  J:288672
Mgi Id  MGI:6429867 Doi  10.1038/s41418-019-0348-z
Citation  Tao CC, et al. (2020) Galectin-3 promotes Abeta oligomerization and Abeta toxicity in a mouse model of Alzheimer's disease. Cell Death Differ 27(1):192-209
abstractText  Amyloid-beta (Abeta) 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 Abeta oligomerization and Abeta 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 Abeta oligomerization is reduced in Gal-3 KO mice injected with Abeta, whereas overexpression of Gal-3 enhances Abeta oligomerization in the hippocampi of Abeta-injected mice. Gal-3 expression shows an age-dependent increase that parallels endogenous Abeta oligomerization in APP/PS1 mice. Moreover, Abeta 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 Abeta oligomerization, we found that Gal-3 primarily co-localizes with Iba1, and that microglia-secreted Gal-3 directly interacts with Abeta. 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 Abeta in APP/PS1 mice and partially overlaps with that of amyloid plaque. Moreover, the expression of the Abeta-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 Abeta oligomerization. Because Gal-3 expression is dramatically increased as early as 3 months of age in APP/PS1 mice and anti-Abeta oligomerization is believed to protect against Abeta toxicity, Gal-3 could be considered a novel therapeutic target in efforts to combat AD.
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