Recent studies mentioned that
Andrographolide (Andro), the main bioactive component of
traditional Chinese medicine Andrographis paniculata, 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 the β-
amyloid (Aβ)
peptide. Our results revealed that Andro protected and rescued PC12 cells from Aβ1⁻42-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 Aβ1⁻42-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 Aβ1⁻42 insult through the activation of autophagy and the Nrf2-mediated p62 signaling pathway.