Protocatechuic acid alleviates the progression of Alzheimer's disease by regulating p53/GADD45/MAPK signaling pathway.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder worldwide lacking effective treatments. Protocatechuic acid (PCA), a natural polyphenol found in various foods and medicinal herbs, exhibits diverse bioactivities; but its role in AD remains unclear. This study investigated the neuroprotective effects and mechanisms of PCA. In vitro, PCA significantly attenuated glutamic-induced cytotoxicity, oxidative stress, calcium influx, and apoptosis in PC12, SH-SY5Y, and HT22 cells. In vivo, PCA improved cognitive performance in the Morris water maze, open field, and novel object recognition tests in a D-galactose/AlCl₃-induced AD mice, and mitigated hippocampal and cortical histopathological damage. Integrated transcriptomic and network pharmacology analyses identified the apoptosis, p53, and MAPK as key pathways. RT-qPCR and western blot analyses revealed that PCA downregulated p53, GADD45B, GADD45G, and phosphorylated p38. Collectively, these findings demonstrate that PCA alleviates AD progression by inhibiting the p53/GADD45/MAPK axis, positioning it as a promising natural candidate for AD prevention.