Andrographolide Protects PC12 Cells Againstβ-Amyloid-Induced Autophagy-Associated Cell Death Through Activation of the Nrf2-Mediated p62 Signaling Pathway.
Int J Mol Sci. 2018 Sep 19 ;19(9). Epub 2018 Sep 19. PMID: 30235892
Recent studies mentioned that Andrographolide (Andro), the main bioactive component of traditional Chinese medicine, may be a potential natural product for treating Alzheimer's disease, but the underlining mechanism remains to be discovered. In this study, we investigated whether Andro regulates the nuclear factor E2-related factor 2 (Nrf2)/Sequestosome 1 (p62) signaling pathway and activates autophagy to protect neuronal PC12 cells from the toxicity of theβ-amyloid (Aβ) peptide. Our results revealed that Andro protected and rescued PC12 cells from Aβ-induced cell death and restored abnormal changes in nuclear morphology, lactate dehydrogenase, malondialdehyde, intracellular reactive oxygen species, and mitochondrial membrane potential. RT-PCR and Western blotting analysis demonstrated that Andro activated autophagy-related genes and proteins (Beclin-1 and LC3); meanwhile, it also augmented the Nrf2 and p62 expression in mRNA and protein levels, and reduced p-tau and p21 protein expression in Aβ-stimulated cells. Then, further study showed that the pre-transfection of cells with Nrf2 small interfering RNA (siRNA) resulted in the downregulation of p62, Beclin-1, and LC3 proteins expression, as well as the upregulation of p21. Furthermore, the pre-transfection of cells with p62 siRNA didn't block the Nrf2 protein expression, accompanying with an elevated p21. Taken together, these results showed that Andro significantly ameliorated cell death due to Aβinsult through the activation of autophagy and the Nrf2-mediated p62 signaling pathway.