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Alzheimer's disease (AD) has become a major public health problem affecting the elderly population, and there is currently no effective treatment. Although the pathogenesis of AD is unclear, neurotoxicity induced by oxidative stress plays an important role in the progression of AD. Ginseng, the root and rhizome of Panax ginseng C. A. Meyer, is used not only as an herbal medicine but also as a functional food to support bodily functions. Ginsenoside Rk3 (Rk3), the main bioactive component in ginseng, has a strong antioxidant effect and has not been reported in AD. In this study, we showed that Rk3 improved neuronal apoptosis, decreased intracellular reactive oxygen species (ROS) production and restored mitochondrial membrane potential in PC12 and primary neuronal cells. In vivo, we found that Rk3 improved spatial learning and memory deficit in precursor protein (APP)/presenilin 1 (PS1) double transgenic mouse model of AD. Additionally, Rk3 increases glutathione reductase (GSH) and superoxide dismutase (SOD) levels while inhibits malondialdehyde (MDA) production, apoptosis and activation of glial cells in APP/PS1 mice. Mechanistically, we found that the protective effect of Rk3 is in correlation with the activation of AMPK/Nrf2 signaling pathway. In conclusion, the findings of this study provide support for Rk3 as a new strategy for the treatment of AD. [Display omitted] • Ginsenoside Rk3, a bioactive component in ginseng, exhibits neuroprotective effects in PC12 cells and primary neuronal cells. • Rk3 significantly alleviates AD pathology with the therapeutic effect better than that of donepezil. • The protective effect of Rk3 is associated with the activation of AMPK/Nrf2 signaling pathway. • Ginsenoside Rk3 is expected to be a potential therapeutic drug for AD. [ABSTRACT FROM AUTHOR]

Lindera aggregata (Sims) Kosterm is a common traditional herb that has multiple bioactivities. Radix Linderae (LR), the dry roots of Lindera aggregata (Sims) Kosterm, is a traditional Chinese herbal medicine with antioxidant, anti-inflammatory and immunomodulatory properties, first found in Kaibao Era. Norboldine (Nor) is an alkaloid extracted from LR and is one of the primary active ingredients of LR. However, the pharmacological functions and mechanism of Nor in Alzheimer's disease (AD) are still unknown. This study aims to investigate the effect and mechanism of Nor therapy in improving the cognitive impairment and pathological features of 3 × Tg mice. 3 × Tg mice were treated with two concentrations of Nor for one month and then the memory and cognitive abilities of mice were assessed by novel object recognition experiment and Morris water maze. The impact of Nor on the pathology of ADwere examined in PC12 cells and animal tissues using western blotting and immunofluorescence. Finally, western blotting was used to verify the anti-apoptotic effect of Nor by activating AMPK/GSK3β/Nrf2 signaling pathway at animal and cellular levels. In this study, we showed that Nor treatment improved the capacity of the learning and memory of 3 × Tg mice and alleviated AD pathology such as Aβ deposition. In addition, Nor restored the abnormalities of mitochondrial membrane potential, significantly reduced the production of intracellular ROS and neuronal cell apoptosis. Mechanistically, we combined network pharmacology and experimental verification to show that Nor may exert antioxidant stress and anti-apoptotic through the AMPK/GSK3β/Nrf2 signaling pathway. Our data provide some evidence that Nor exerts a neuroprotective effect through the AMPK/GSK3β/Nrf2 pathway, thereby improving cognitive impairment in AD model mice. Natural products derived from traditional Chinese medicines are becoming increasingly popular in the process of new drug development and discovery, and our findings provide new perspectives for the discovery of improved treatment strategies for AD. The mechanism of Norboldine improving neuronal apoptosis by activating AMPK/GSK3β/Nrf2 pathway, Nor can restore mitochondrial membrane potential, reduce intracellular ROS concentration, and then decrease the downstream cleaved-caspase3 protein level and alleviate neuronal apoptosis, and finally improve the pathology of AD. [Display omitted] • Norboldine reduces Aβ-induced PC12 cell injury. • Norboldine alleviates cognitive impairment and pathology in AD model mice. • The effect of Norboldine is related to the activation of AMPK/GSK3β/Nrf2 signaling pathway. • Norboldine is expected to be a potential therapeutic drug for the treatment of AD. [ABSTRACT FROM AUTHOR]