Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Urano, Yasuomi, Takahachi, Mina, Higashiura, Ryo, Fujiwara, Hitomi, Funamoto, Satoru, Imai, So, Futai, Eugene, Okuda, Michiaki, Sugimoto, Hachiro, Noguchi, Noriko
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783506342003081216
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
work_keys_str_mv AT uranoyasuomi curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT takahachimina curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT higashiuraryo curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT fujiwarahitomi curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT funamotosatoru curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT imaiso curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT futaieugene curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT okudamichiaki curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT sugimotohachiro curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation
AT noguchinoriko curcuminderivativegt863inhibitsamyloidbetaproductionviainhibitionofproteinnglycosylation