Andrographolide derivative Andro-III modulates neuroinflammation and attenuates neuropathological changes of Alzheimer's disease via GSK-3β/NF-κB/CREB pathway

Andrographolide has anti-inflammatory and neuroprotective effects, making it a potential therapeutic option for Alzheimer's disease (AD). Our research group optimized its structure in a previous study to minimize the risk of renal toxicity, which would beneficial for future clinical research. This study aims to examine the impact of Andro-III on enhancing cognitive learning ability in 3xTg-AD mice, as well as the mechanisms involved. Andro-III improved spatial learning ability, prevented the loss of Nysted's vesicles, reduced the accumulation of β-amyloid (Aβ) and tau proteins, and suppressed microglial activation. Further research found that the expression of nuclear factor kappa-B RelA (NF-κB p65) expression and glycogen synthase kinase-3β (GSK-3β) activity were inhibited, while CREB was upregulated in brain tissue treated with Andro-III. Moreover, Andro-III downregulated the expression of IBA1 and inflammatory factors in microglial cells of mice induced by Aβ. The regulation of the GSK-3β/NF-κB/CREB pathway was similar to that observed in 3xTg-AD mice. Therefore, Andro-III modulates neuroinflammation and attenuates neuropathological changes of AD via the GSK-3β/NF-κB/CREB pathway.