Quercetagitrin Ameliorates Alzheimer-Like Pathologies Associated with TNFα/NFκB Pathway in APP/PS1 Mice

Background: Alzheimer's disease (AD) is a neurodegenerative disease with two pathological features in the brain: amyloid β (Aβ) plaques and tau tangles. Neuroinflammation plays an important role in the development of AD, closely related to both Aβ and tau pathologies. Tumor necrosis factor α (TNFα) and nuclear factor-κB (NFκB) behave as key regulators of neuroinflammation in AD. It is pressing to develop effective AD drugs. Objective: This study aimed to explore the effects and mechanisms of quercetagitrin in AD using a combination of network pharmacology analyses and in vivo experiments. Methods: The potential target of quercetagitrin in AD was predicted by network pharmacology. The interaction between the compound and the target protein was measured by molecular docking. The in vivo effects were performed in APP/PS1 mice via mouse behavior tests, Western blotting, ThS staining, immunohistochemical staining, and immunofluorescence staining. Results: First, network pharmacology analyses were conducted to predict the primary target of the compound, which is TNFα. Then, molecular docking showed that quercetagitrin interacts with TNFα with a high affinity. Finally, the level of TNFα was reduced, and the activation of NFκB signaling was inhibited by quercetagitrin in APP/PS1 mice. Meanwhile, quercetagitrin treatment ameliorated Aβ pathology, cognitive impairments, and neuroinflammation in the AD mice. Conclusions: These findings demonstrate quercetagitrin as a potential therapeutic drug for AD.