Gypenoside XVII Enhances Lysosome Biogenesis and Autophagy Flux and Accelerates Autophagic Clearance of Amyloid-β through TFEB Activation

Abstract

A strategy for activating transcription factor EB (TFEB) to restore autophagy flux may provide neuroprotection against Alzheimer's disease. Our previous study reported that gypenoside XVII (GP-17), which is a major saponin abundant in ginseng and Panax notoginseng, ameliorated amyloid-β (Aβ)25-35-induced apoptosis in PC12 cells by regulating autophagy. In the present study, we aimed to determine whether GP-17 has neuroprotective effects on PC12 cells expressing the Swedish mutant of APP695 (APP695swe) and APP/PS1 mice. We also investigated the underlying mechanism. We found that GP-17 could significantly increase Atg5 expression and the conversion of LC3-I to LC3-II in APP695 cells, which was associated with a reduction in p62 expression. GP-17 also elevated the number of LC3 puncta in APP695 cells transduced with pCMV-GFP-LC3. GP-17 promoted the autophagy-based elimination of AβPP, Aβ40, and Aβ42 in APP695swe cells and prevented the formation of Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Furthermore, spatial learning and memory deficits were cured. Atg5 knockdown could abrogate the GP-17-mediated removal of AβPP, Aβ40, and Aβ42 in APP695swe cells. GP-17 upregulated LAMP-1, increased LysoTracker staining, and augmented LAMP-1/LC3-II co-localization. GP-17 could release TFEB from TFEB/14-3-3 complexes, which led to TFEB nuclear translocation and the induction of autophagy and lysosome biogenesis and resulted in the amelioration of autophagy flux. The knockdown of TFEB could abolish these effects of GP-17. In summary, these results demonstrated that GP-17 conferred protective effects to the cellular and rodent models of Alzheimer's disease by activating TFEB.

Gypenoside XVII Prevents Atherosclerosis by Attenuating Endothelial Apoptosis and Oxidative Stress: Insight into the ERα-Mediated PI3K/Akt Pathway

“…Although ERs is pathways upstream of PI3K [14], the inhibition effect of ICI182780 is worse than LY294002. That’s because GP-17 had other protection mechanism, so the inhibition of ERs downstream targets could result in more effective inhibition against GP-17 protection of HUVECs [36]. What’s more, LDH release is a consequence of damage to cellular integrity during apoptosis, which can indirectly reflect cytotoxicity.…”

Sense Ginsenosides From Ginsengs: Structure-Activity Relationship in Autophagy

“…48 Furthermore, gypenoside XVII is a promising candidate for the prevention of AD due to facilitation of the autophagy-dependent removal of Aβ through TFEB activation in cellular and rodent models of AD. 68 Gypenoside XVII could also attenuate Aβ25-35induced parallel autophagic and apoptotic cell death through the estrogen receptor-dependent activation of Nrf2/ARE pathways. 69…”

Nature’s Derivative(s) as Alternative Anti-Alzheimer’s Disease Treatments

“…A study also reported the potential of GP-17, a novel phytoestrogen isolated from ginseng, in the clearing of A␤ in vivo and in vitro in the AD mouse models, Swedish mutant of APP695 (APP695swe) and APP/PS1. The neuroprotective effect was due to the autophagy-based elimination of A␤ due to the activation of transcription factor EB responsible for lysosome biogenesis [100]. It is useful in the inhibition of formation of A␤, stimulation of soluble A␤PP␣ formation, anti-inflammation, anti-apoptosis, decreasing oxidation stress, and enhancing CNS cholinergic function to counter impairments and implications associated with AD [101,102].…”