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Updated: Mar 10, 2026
Labeling and Imaging of Amyloid Plaques in Brain Tissue Using the Natural Polyphenol Curcumin
Published on: November 1, 2019
Decrease of Amyloid-β Levels by Curcumin Derivative via Modulation of Amyloid-β Protein Precursor Trafficking
Rina Kotani1, Yasuomi Urano1, Hachiro Sugimoto2
1Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan.
Abstract:
The abnormal production and deposition of amyloid-β (Aβ) peptides is a pathologic hallmark of Alzheimer's disease. Aβ is generated from amyloid-β protein precursor (AβPP) by two sequential proteolytic cleavage steps involving β- and γ-secretases in the trans-Golgi network and endosomes. Since direct inhibition of secretase could induce undesirable side-effects due to inadvertent inhibition of unrelated secretase substrates, it is important to establish methods for inhibiting Aβ production that do not affect secretase activity. It has been suggested that curcumin may have potent anti-amyloidogenic effect. In the present study, we evaluate the effect of curcumin derivatives on Aβ production in human neuroblastoma SH-SY5Y cells and in CHO cells which stably express human AβPP (CHO-AβPP). We found that the curcumin derivative CU6 was more effective than curcumin itself in reducing Aβ secretion. We further found that in SH-SY5Y cells CU6 inhibited neither β- nor γ-secretase activity, and that increased amounts of immature forms of AβPP accumulated in the endoplasmic reticulum (ER). We also found that CU6 induced expression of the ER chaperone glucose-regulated protein 78 (GRP78), and enhanced formation of the AβPP/GRP78 complex. These results suggest that CU6 downregulates intracellular AβPP trafficking, resulting in suppression of Aβ production independently of secretase activity.
Insights
A novel curcumin derivative, CU6, effectively reduces amyloid-β (Aβ) production in Alzheimer
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Alzheimer's disease (AD) is characterized by abnormal amyloid-β (Aβ) peptide production and deposition.
- Aβ is generated from amyloid-β protein precursor (AβPP) via sequential cleavage by β- and γ-secretases.
- Targeting secretase activity directly may cause adverse effects; thus, alternative strategies to inhibit Aβ production are needed.
Purpose of the Study:
- To evaluate the efficacy of curcumin derivatives in reducing Aβ production.
- To investigate the mechanism by which CU6 suppresses Aβ generation.
Main Methods:
- Utilized human neuroblastoma SH-SY5Y cells and CHO cells stably expressing human AβPP (CHO-AβPP).
- Assessed Aβ secretion levels.
- Measured β- and γ-secretase activities.
- Analyzed AβPP processing and localization within cellular compartments (ER, Golgi).
- Investigated the role of ER chaperones, specifically glucose-regulated protein 78 (GRP78).
Main Results:
- The curcumin derivative CU6 demonstrated superior efficacy in reducing Aβ secretion compared to curcumin.
- CU6 did not inhibit β- or γ-secretase activity.
- Accumulation of immature AβPP forms was observed in the endoplasmic reticulum (ER).
- CU6 induced GRP78 expression and enhanced the formation of the AβPP/GRP78 complex.
- These findings indicate that CU6 downregulates intracellular AβPP trafficking.
Conclusions:
- CU6 effectively suppresses Aβ production through a mechanism independent of direct secretase inhibition.
- CU6 modulates AβPP intracellular trafficking and processing.
- This suggests CU6 as a potential therapeutic agent for Alzheimer's disease by targeting AβPP metabolism.
