Abstract
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.
Highlights
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides in senile plaques and by intracellular accumulation of hyperphosphorylated tau [1]
We further found that GT863 suppressed protein N-glycosylation, including that of γ-secretase subunit nicastrin, and observed that Aβ production was inhibited by mannosidase inhibitors of the type that cause abnormal N-glycan processing
We first performed a WST-8 assay to evaluate the effect of curcumin derivatives on cell viability, with the results showing that 0.5–20 μM GT832, GT855, or GT857 did not affect cell viability, but that an amount greater than 15 μM of GT934, 5 μM of GT935, or 4 μM of GT863 had a significant cytotoxic effect (Figure 1a)
Summary
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β (Aβ) peptides in senile plaques and by intracellular accumulation of hyperphosphorylated tau [1]. CU6/CNB-001 promotes Aβ clearance and improves memory in animal models of AD [14] These results might suggest that CU6/CNB-001 should have beneficial effect on AD pathology, we observed that CU6/CNB-001 had little inhibitory effect on the production of Aβ42, which is much more neurotoxic than Aβ40 [13]. We further found that GT863 suppressed protein N-glycosylation, including that of γ-secretase subunit nicastrin, and observed that Aβ production was inhibited by mannosidase inhibitors of the type that cause abnormal N-glycan processing We believe that these results provide insight into how GT863 and mannosidase inhibitors might be used to beneficial effect in the context of AD pathologies
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