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Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation
Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Aβ production, aggregation, and clearance are thought to be important therapeutic targets for AD. Curcumin has been known to have an anti-amyloidogenic effect on AD. In the present study, we performed screen...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072163/ https://www.ncbi.nlm.nih.gov/pubmed/32028683 http://dx.doi.org/10.3390/cells9020349 |
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author | Urano, Yasuomi Takahachi, Mina Higashiura, Ryo Fujiwara, Hitomi Funamoto, Satoru Imai, So Futai, Eugene Okuda, Michiaki Sugimoto, Hachiro Noguchi, Noriko |
author_facet | Urano, Yasuomi Takahachi, Mina Higashiura, Ryo Fujiwara, Hitomi Funamoto, Satoru Imai, So Futai, Eugene Okuda, Michiaki Sugimoto, Hachiro Noguchi, Noriko |
author_sort | Urano, Yasuomi |
collection | PubMed |
description | Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Aβ production, aggregation, and clearance are thought to be important therapeutic targets for AD. Curcumin has been known to have an anti-amyloidogenic effect on AD. In the present study, we performed screening analysis using a curcumin derivative library with the aim of finding derivatives effective in suppressing Aβ production with improved bioavailability of curcumin using CHO cells that stably express human amyloid-β precursor protein and using human neuroblastoma SH-SY5Y cells. We found that the curcumin derivative GT863/PE859, which has been shown to have an inhibitory effect on Aβ and tau aggregation in vivo, was more effective than curcumin itself in reducing Aβ secretion. We further found that GT863 inhibited neither β- nor γ-secretase activity, but did suppress γ-secretase-mediated cleavage in a substrate-dependent manner. We further found that GT863 suppressed N-linked glycosylation, including that of the γ-secretase subunit nicastrin. We also found that mannosidase inhibitors that block the mannose trimming step of N-glycosylation suppressed Aβ production in a similar fashion, as was observed as a result of treatment with GT863. Collectively, these results suggest that GT863 downregulates N-glycosylation, resulting in suppression of Aβ production without affecting secretase activity. |
format | Online Article Text |
id | pubmed-7072163 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70721632020-03-19 Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation Urano, Yasuomi Takahachi, Mina Higashiura, Ryo Fujiwara, Hitomi Funamoto, Satoru Imai, So Futai, Eugene Okuda, Michiaki Sugimoto, Hachiro Noguchi, Noriko Cells Article Amyloid-β (Aβ) peptides play a crucial role in the pathogenesis of Alzheimer’s disease (AD). Aβ production, aggregation, and clearance are thought to be important therapeutic targets for AD. Curcumin has been known to have an anti-amyloidogenic effect on AD. In the present study, we performed screening analysis using a curcumin derivative library with the aim of finding derivatives effective in suppressing Aβ production with improved bioavailability of curcumin using CHO cells that stably express human amyloid-β precursor protein and using human neuroblastoma SH-SY5Y cells. We found that the curcumin derivative GT863/PE859, which has been shown to have an inhibitory effect on Aβ and tau aggregation in vivo, was more effective than curcumin itself in reducing Aβ secretion. We further found that GT863 inhibited neither β- nor γ-secretase activity, but did suppress γ-secretase-mediated cleavage in a substrate-dependent manner. We further found that GT863 suppressed N-linked glycosylation, including that of the γ-secretase subunit nicastrin. We also found that mannosidase inhibitors that block the mannose trimming step of N-glycosylation suppressed Aβ production in a similar fashion, as was observed as a result of treatment with GT863. Collectively, these results suggest that GT863 downregulates N-glycosylation, resulting in suppression of Aβ production without affecting secretase activity. MDPI 2020-02-03 /pmc/articles/PMC7072163/ /pubmed/32028683 http://dx.doi.org/10.3390/cells9020349 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Urano, Yasuomi Takahachi, Mina Higashiura, Ryo Fujiwara, Hitomi Funamoto, Satoru Imai, So Futai, Eugene Okuda, Michiaki Sugimoto, Hachiro Noguchi, Noriko Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation |
title | Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation |
title_full | Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation |
title_fullStr | Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation |
title_full_unstemmed | Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation |
title_short | Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation |
title_sort | curcumin derivative gt863 inhibits amyloid-beta production via inhibition of protein n-glycosylation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072163/ https://www.ncbi.nlm.nih.gov/pubmed/32028683 http://dx.doi.org/10.3390/cells9020349 |
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