Gastrodin Ameliorates Tau Pathology and BBB Dysfunction in 3xTg‐AD Transgenic Mice by Regulating the ADRA1/NF‐κB/NLRP3 Pathway to Reduce Neuroinflammation

ABSTRACT Background and aim: Gastrodin, an active compound derived from the traditional Chinese herbal medicine Gastrodia, demonstrates a variety of pharmacological effects, particularly in the enhancement of neural functions. Thus, the aim of this study is to explore the therapeutic effects of gastrodin on Alzheimer's disease (AD) and its underlying molecular mechanisms. Experimental procedure: Cognitive function was assessed via Morris water maze and Y‐maze tests. Tau pathology, neuroinflammation, and BBB dysfunction were analyzed using various techniques, including Western blot, immunohistochemistry, and ELISA. ADRA1 overexpression was induced by lentiviral infection, and gastrodin's impact on NF‐κB p65, NLRP3, IL‐1β, and IL‐18 levels was evaluated. Key results: In the in vivo experiment, gastrodin enhanced learning and spatial memory in 3xTg‐AD mice, as well as reducing p‐Tau protein expression in the hippocampus and cortex. Gastrodin inhibited the ADRA1/NF‐κB/NLRP3 pathway, which decreased glial cell activation and inflammatory cytokines IL‐1β and IL‐18, improving neuron and BBB function. In the in vitro experiment, gastrodin inhibited the activation of the NF‐κB/NLRP3 pathway due to ADRA1 overexpression and prevented the Aβ42‐induced increase in ADRA1/NF‐κB/NLRP3 protein expression in SH‐SY5Y cells. It also reduced IL‐1β and IL‐18 cytokine release, restoring tight junction protein expression in bEnd.3 cells. Conclusions and implications: gastrodin ameliorates learning and memory abilities by alleviating neuroinflammation and tau pathology, restoring the structure and function of neurons and BBB, suggesting that gastrodin may serve as an effective drug for the treatment of AD.