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

• Published in: Cell death and differentiation Vol. 27; no. 1; pp. 192 - 209
• Main Authors: Tao, Chih-Chieh, Cheng, Kuang-Min, Ma, Yun-Li, Hsu, Wei-Lun, Chen, Yan-Chu, Fuh, Jong-Ling, Lee, Wei-Ju, Chao, Chih-Chang, Lee, Eminy H. Y.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2020; Nature Publishing Group
• Subjects: 13/109; 13/51; 13/89; 14/19; 38/1; 631/378/2611; 631/443/7; Age Factors; Alzheimer Disease - metabolism; Alzheimer Disease - psychology; Amyloid beta-Peptides; Amyloidogenic Proteins - metabolism; Animals; Apoptosis; Biochemistry; Biomedical and Life Sciences; Blood Proteins - metabolism; Calcium-Binding Proteins; Cell Biology; Cell Cycle Analysis; Disease Models, Animal; Female; Galectin 3 - genetics; Galectin 3 - metabolism; Galectin 3 - physiology; Galectin-3; Galectins - metabolism; Glial Fibrillary Acidic Protein - metabolism; Hippocampus - metabolism; Integrins - metabolism; Life Sciences; Male; Memory; Mice; Mice, Knockout; Mice, Transgenic; Microfilament Proteins; Neprilysin - metabolism; Oligomerization; Peptide Fragments; Plaque, Amyloid; Rats, Sprague-Dawley; Rodents; Signal Transduction; Stem Cells; Toxicity
• ISSN: 1350-9047; 1476-5403; 1476-5403
• DOI: 10.1038/s41418-019-0348-z

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.