Isolinderalactone Ameliorates the Pathology of Alzheimer's Disease by Inhibiting the JNK Signaling Pathway.

Neuronal cell damage is a major cause of cognitive impairment in Alzheimer's disease (AD). Multiple factors, such as amyloid deposition, tau hyperphosphorylation, and neuroinflammation, can lead to neuronal cell damage. Therefore, the development of multi-target drugs with broad neuroprotective effects may be an effective strategy for the treatment of AD. Natural products have become an important source of drug discovery because of their good pharmacological activity, multiple targets, and low toxicity. In this study, we screened a natural compound library and found that the fat-soluble sesquiterpene natural compound isolinderalactone (Iso) extracted from the dried root pieces of Lindera aggregata had the ability to alleviate cellular damage induced by ß-amyloid-1-42 (Aß1-42). The role and mechanism of Iso in AD have not yet been reported. Herein, we demonstrated that Iso significantly reduced the level of apoptosis in PC12 cells. Besides, Iso treatment reduced amyloid deposition, neuron apoptosis, and neuroinflammation, ultimately improving the cognitive dysfunction of APP/PS1 (APPswe/PSEN 1dE9) mice. Notably, Iso-10 mg/kg showed superior improved effects in APP/PS1 mice compared with the positive control drug donepezil-5 mg/kg. Mechanistically, the results of RNA sequencing combined with Western blots showed that Iso exerted its therapeutic effect by inhibiting the c-Jun N-terminal kinase (JNK) signaling pathway. Taken together, our findings suggest that Iso is a potential drug candidate for the treatment of AD.

Ginsenoside RK3 promotes neurogenesis in Alzheimer's disease through activation of the CREB/BDNF pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: 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. AIM OF THE STUDY: This study aims to investigate whether RK3 improves learning and memory by promoting neurogenesis, and to explore the mechanism of RK3 action. MATERIALS AND METHODS: 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. RESULTS: 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 Aß-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. CONCLUSION: 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).

Norboldine improves cognitive impairment and pathological features in Alzheimer's disease by activating AMPK/GSK3ß/Nrf2 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: 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. AIM OF THE STUDY: This study aims to investigate the effect and mechanism of Nor therapy in improving the cognitive impairment and pathological features of 3 × Tg mice. MATERIALS AND METHODS: 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/GSK3ß/Nrf2 signaling pathway at animal and cellular levels. RESULTS: 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 Aß 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/GSK3ß/Nrf2 signaling pathway. CONCLUSION: Our data provide some evidence that Nor exerts a neuroprotective effect through the AMPK/GSK3ß/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.

Ginsenoside Rk3 ameliorates Aß-induced neurotoxicity in APP/PS1 model mice via AMPK signaling pathway.

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.

Parthenolide alleviates cognitive dysfunction and neurotoxicity via regulation of AMPK/GSK3ß(Ser9)/Nrf2 signaling pathway.

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/GSK3ß(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.

ß-amyloid binds to microglia Dectin-1 to induce inflammatory response in the pathogenesis of Alzheimer's disease.

Microglia-mediated neuroinflammation is closely related to the development of Alzheimer's disease (AD). In the early stages of the inflammation response, pattern recognition receptors (PRRs) play a key role in clearing damaged cells and defending against infection by recognizing endogenous and exogenous ligands. However, the regulation of pathogenic microglial activation and its role in AD pathology remains poorly understood. Here we showed that a pattern recognition receptor called Dectin-1, expressed on microglia, mediates the pro-inflammatory responses of beta-amyloid (Aß). Knockout of Dectin-1 reduced Aß1-42 (Aß42)-induced microglial activation, inflammatory responses, and synaptic and cognitive deficits in Aß42-infused AD mice. Similar results were obtained in the BV2 cell model. Mechanistically, we showed that Aß42 could directly bind to Dectin-1, causing Dectin-1 homodimerization and activating downstream spleen tyrosine kinase (Syk)/nuclear factor-κB (NF-κB) signaling pathway to induce the expression of inflammatory factors and, in turn, AD pathology. These results suggest the important role of microglia Dectin-1 as a new direct receptor for Aß42 in microglial activation and AD pathology and provide a potential therapeutic strategy for neuroinflammation in AD.

The role and therapeutic implication of protein tyrosine phosphatases in Alzheimer's disease.

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. ß-Amyloid plaques (Aß) 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 Aß 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.