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bioRxiv · 10.1101/2021.09.14.460251

Crocin inhibited amyloid-beta (Aβ) generation via promoting non-amyloidogenic APP processing and suppressed ER stress UPR signaling in N2a/APP cells

Lin, C.·Yue, Q.·Liang, Z.·Lee, S. M. Y.·Zhang, Z.·Hoi, M. P. M.
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Abstract

BackgroundCrocin is a major active component of saffron (Crocus sativus) with many beneficial effects. More recently, crocin has been proposed for management of neurodegenerative diseases such as Alzheimers disease (AD). Here, we demonstrated for the first time that crocin reduced amyloid-beta (A{beta}) generation through promoting -cleavage of APP processing and inhibited ER stress by attenuating UPR signaling in N2a/APP cells. MethodologyMouse neuroblastoma N2a cells stably transfected with the Swedish mutant APP (N2a/APP) was used as a cellular model for AD pathogenesis. Vector transfected cells (N2a/vector) were employed to serve as control. The toxicity of crocin was first evaluated and non-toxic treatment of crocin (>30 {micro}M for 24 h) was used for further investigations. A{beta} levels were determined by ELISA. Expression levels of UPR signaling proteins were determined by using Western blot. ResultsCrocin significantly inhibited the protein expression of total APP in N2a/APP cells and promoted -cleavage of APP processing to increase sAPP generation, but only modestly reduced BACE-1 and PS1, suggesting A{beta} reduction by crocin was mainly associated with the non-amyloidogenic APP processing. Further investigation on ER stress related protein expressions showed that GRP78, CHOP, p-PERK, p-eIF2, p-IRE1, XBP1, ATF6 and PDI were all significantly elevated in N2a/APP cells compared to N2a/vector. Crocin effectively reduced the levels of GRP78 and CHOP, and significantly inhibited p-PERK/p-eIF2 amd AT6 while slightly reduced p-IRE1. ConclusionThe present study showed that crocin was effective at blocking A{beta} generation and inhibiting ER stress associated overactivation of UPR signaling in AD cell model N2a/APP. The results provided evidence for crocin as useful natural product for the treatment of AD.

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Lin, C., Yue, Q., Liang, Z., Lee, S. M. Y., Zhang, Z., Hoi, M. P. M.. 2021-09-16. Crocin inhibited amyloid-beta (Aβ) generation via promoting non-amyloidogenic APP processing and suppressed ER stress UPR signaling in N2a/APP cells. https://doi.org/10.1101/2021.09.14.460251

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