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• RK1 exhibits neuroprotective effects in PC12 cells and primary neuron. • RK1 alleviates AD pathology, and the effect is better than the clinical drug donepezil. • The protective effect of RK1 is associated with the activation of AMPK/Nrf2 signaling pathway. • RK1 is expected to be a potential therapeutic drug for AD. The pathogenesis of Alzheimer's disease (AD) is complex, resulting in unsatisfactory effects of single-target therapeutic drugs. Accumulation evidence suggests that low toxicity multi-target drugs may play effective roles in AD. Ginseng is the root and rhizome of Panax ginseng Meyer, which can be used not only as herbal medicine but also as a functional food to support body functions. Ginsenoside RK1 (RK1), obtained from ginseng plants through high-temperature treatment, has antiapoptotic, antioxidant, anti-inflammatory effects and these events are involved in the development of AD. So, we believe that RK1 may be an effective drug for the treatment of AD. We aimed to investigate the potential protective effects and mechanisms of RK1 in AD. Neuronal damage was detected by MTT assay, LDH assay, immunofluorescence and western blotting. Oxidative stress was measured by JC-1 staining, reactive oxygen species (ROS) staining, superoxide dismutase (SOD) and malonaldehyde (MDA). The cognitive deficit was measured through morris water maze (MWM) and novel object recognition (NOR) tests. RK1 attenuated Aβ-induced apoptosis, restored mitochondrial membrane potential (ΔΨm), and reduced intracellular levels of ROS in both PC12 cells and primary cultured neurons. In vivo, RK1 significantly improved cognitive deficits and mitigated AD-like pathological features. Notably, RK1 demonstrated superior efficacy compared to the positive control drug, donepezil. Mechanistically, our study elucidates that RK1 modulates the phosphorylation of AMP-activated protein kinase (AMPK) and its downstream target, NF-E2-related factor 2 (Nrf2), leading to the optimization of mitochondrial membrane potential, reduction of ROS levels, and mitigation of AD-like pathology. It's noteworthy that blocking the AMPK signaling pathway attenuated the protective effects of RK1. RK1 demonstrates superior efficacy in alleviating cognitive deficits and mitigating pathological changes compared to donepezil. These findings suggest the potential utility of RK1-based therapies in the development of treatments for AD. [Display omitted] [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) stands as the predominant age-related neurodegenerative disorder, for which efficacious treatment remains elusive. An auspicious avenue for this disease lies in natural compounds sourced from tranditional medicine and plant origins. Parthenolide (PTN) is a natural product with multiple biological functionsand. Recent investigations have illuminated PTN's protective properties against neurological maladies; however, its potential therapeutic role against AD remains uncharted. This study aims to explore the role of PTN in treating AD. Our in vitro findings underscore PTN's bioactivity, as evidenced by its capacity to curtail apoptosis, reduce reactive oxygen species (ROS) production, and restore mitochondrial membrane potential in PC12 cells. Moreover, PTN treatment demonstrates a capacity to ameliorate deficits in spatial learning and memory in the 3 ×Tg-AD murine model. Notably, PTN's therapeutic efficacy surpasses that of a clinical agent, donepezil. Mechanistically, PTN's neuroprotective effects stem from its adept regulation of the AMPK/GSK3β(ser9)/Nrf2 signaling pathway and protection on neuronal cells from ROS-related apoptosis. Although the molecular target and the pre-clinical evaluations of PTN need to be further explored, this study indicates PTN as a potential agent or lead compound for the drug development against AD. [Display omitted] [ABSTRACT FROM AUTHOR]

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]

In the ancient book "Shen Nong's Herbal Classic," Panax ginseng CA Mey was believed to have multiple benefits, including calming nerves, improving cognitive function, and promoting longevity. Ginsenosides are the main active ingredients of ginseng. Ginsenoside RK3 (RK3), a rare ginsenoside extracted from ginseng, displays strong pharmacological potential. However, its effect on neurogenesis remains insufficiently investigated. This study aims to investigate whether RK3 improves learning and memory by promoting neurogenesis, and to explore the mechanism of RK3 action. The therapeutic effect of RK3 on learning and memory was determined by the Morris water maze (MWM) and novel object recognition test (NORT). The pathogenesis and protective effect of RK3 on primary neurons and animal models were detected by immunofluorescence and western blotting. Protein expression of cAMP response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) signaling pathway was detected by western blotting. Our results showed that RK3 treatment significantly improved cognitive function in APPswe/PSEN1dE9 (APP/PS1) mice and C57BL/6 (C57) mice. RK3 promotes neurogenesis and synaptogenesis in the mouse hippocampus. In vitro , RK3 prevents Aβ-induced injury in primary cultured neurons and promotes the proliferation of PC12 as well as the expression of synapse-associated proteins. Mechanically, the positve role of RK3 on neurogenesis was combined with the activation of CREB/BDNF pathway. Inhibition of CREB/BDNF pathway attenuated the effect of RK3. In conclusion, this study demonstrated that RK3 promotes learning and cognition in APP/PS1 and C57 mice by promoting neurogenesis and synaptogenesis through the CREB/BDNF signaling pathway. Therefore, RK3 is expected to be further developed into a potential drug candidate for the treatment of Alzheimer's disease (AD). [Display omitted] • RK3 improves cognitive impairment in APP/PS1 mice. • RK3 improves the learning and memory ability of C57 mice. • RK3 promotes neurogenesis and synaptogenesis. • The effect of RK3 is associated with activation of the CREB/BDNF signaling pathway. [ABSTRACT FROM AUTHOR]

Protein tyrosine phosphatases (PTPs) are important regulator of neuronal signal transduction and a growing number of PTPs have been implicated in Alzheimer's disease (AD). In the brains of patients with AD, there are a variety of abnormally phosphorylated proteins, which are closely related to the abnormal expression and activity of PTPs. β-Amyloid plaques (Aβ) and hyperphosphorylated tau protein are two pathological hallmarks of AD, and their accumulation ultimately leads to neurodegeneration. Studies have shown that protein phosphorylation signaling pathways mediates intracellular accumulation of Aβ and tau during AD development and are involved in synaptic plasticity and other stress responses. Here, we summarized the roles of PTPs related to the pathogenesis of AD and analyzed their therapeutic potential in AD. [Display omitted] • Protein tyrosine phosphatases (PTPs) are important regulator of neuronal signal transduction. • PTPs related to the pathogenesis of Alzheimer's disease (AD). • Compounds targeting PTPs alleviated pathological features of brain disease. • PTPs is expected to be an important direction and a potential breakthrough for AD research. [ABSTRACT FROM AUTHOR]