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| Title | Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer’s disease |
| Creator | 趙知章 Chao, Chih-Chang CC, Tao KM, Cheng YL, Ma WL, Hsu YC, Chen JL, Fuh WJ, Lee EHY*, Lee |
| Contributor | 神科所 |
| Date | 2019-05 |
| Date Issued | 20-Feb-2020 11:56:07 (UTC+8) |
| Summary | 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. |
| Relation | Cell Death & Differentiation, pp.e1-e18 |
| Type | article |
| DOI | https://doi.org/10.1038/s41418-019-0348-z |
| dc.contributor | 神科所 | |
| dc.creator (作者) | 趙知章 | |
| dc.creator (作者) | Chao, Chih-Chang | |
| dc.creator (作者) | CC, Tao | |
| dc.creator (作者) | KM, Cheng | |
| dc.creator (作者) | YL, Ma | |
| dc.creator (作者) | WL, Hsu | |
| dc.creator (作者) | YC, Chen | |
| dc.creator (作者) | JL, Fuh | |
| dc.creator (作者) | WJ, Lee | |
| dc.creator (作者) | EHY*, Lee | |
| dc.date (日期) | 2019-05 | |
| dc.date.accessioned | 20-Feb-2020 11:56:07 (UTC+8) | - |
| dc.date.available | 20-Feb-2020 11:56:07 (UTC+8) | - |
| dc.date.issued (上傳時間) | 20-Feb-2020 11:56:07 (UTC+8) | - |
| dc.identifier.uri (URI) | http://nccur.lib.nccu.edu.tw/handle/140.119/128686 | - |
| dc.description.abstract (摘要) | 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. | |
| dc.format.extent | 2980906 bytes | - |
| dc.format.mimetype | application/pdf | - |
| dc.relation (關聯) | Cell Death & Differentiation, pp.e1-e18 | |
| dc.title (題名) | Galectin-3 promotes Aβ oligomerization and Aβ toxicity in a mouse model of Alzheimer’s disease | |
| dc.type (資料類型) | article | |
| dc.identifier.doi (DOI) | 10.1038/s41418-019-0348-z | |
| dc.doi.uri (DOI) | https://doi.org/10.1038/s41418-019-0348-z |