Norboldine improves cognitive impairment and pathological features in Alzheimer's disease by activating AMPK/GSK3β/Nrf2 signaling pathway

Abstract

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/GSK3β/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 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.

Conclusion: 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.

Keywords: AMPK/GSK3β/Nrf2 signaling pathway; Alzheimer's disease; Apoptosis; Cognitive function; Norboldine.