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Open AccessArticle

Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation

1
Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, 1–3 Miyakodani, Tatara, Kyotanabe, Kyoto 610 0394, Japan
2
Department of Molecular and Cell Biology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramakiazaaoba, Aobaku, Sendai, Miyagi 980-0845, Japan
3
Green Tech Co., Ltd., 1–7–7 Yaesu, Chuo-ku, Tokyo 103-0028, Japan
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 349; https://doi.org/10.3390/cells9020349 (registering DOI)
Received: 27 December 2019 / Revised: 29 January 2020 / Accepted: 31 January 2020 / Published: 3 February 2020
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. View Full-Text
Keywords: Alzheimer’s disease; amyloid-β peptides; curcumin derivatives; glycosylation Alzheimer’s disease; amyloid-β peptides; curcumin derivatives; glycosylation
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Urano, Y.; Takahachi, M.; Higashiura, R.; Fujiwara, H.; Funamoto, S.; Imai, S.; Futai, E.; Okuda, M.; Sugimoto, H.; Noguchi, N. Curcumin Derivative GT863 Inhibits Amyloid-Beta Production via Inhibition of Protein N-Glycosylation. Cells 2020, 9, 349.

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