Zanthoxylum alkylamides activate the Shh/Ptch1/Smo signaling pathway to ameliorate cognitive impairment in Alzheimer’s disease mice

• ZAs derived from Zanthoxylum bungeanum exhibit a beneficial effect on AD mice. • ZAs administration can enhance the levels of anti-inflammatory factors in AD mice. • ZAs exert regulatory control over the levels of arachidonic acid, 5-HIAA, DHA, and cholesterol. • ZAs exert a beneficial effect on AD pathology by modulating the Shh/Ptch1/Smo signaling pathway. This study aimed to investigate the neuroprotective effects of Zanthoxylum alkylamides (ZAs) in a mouse model of Alzheimer’s disease (AD) induced by D-galactose/aluminum chloride (D-gal/AlCl 3 ). ZAs improved cognitive function, increased body weight, food intake, water consumption and organ indices, antioxidant enzymes activities in both the serum and brain tended normal conditions, while the malondialdehyde (MDA) concentration was reduced. The levels of the inflammatory cytokines were significantly reduced. Histopathological revealed that ZAs repaired damaged brain tissue. Transcriptomic revealed ZAs regulated Shh, Ptch1, Smo, and Gli1 gene expression to mitigate apoptosis. Metabolomic revealed ZAs regulated the levels of arachidonic acid, 5-hydroxyindoleacetic acid, docosahexaenoic acid, and cholesterol. Integrated omics analysis revealed that ZAs can activate the Shh/Ptch1/Smo signaling pathway to affect nerve cell proliferation and improve neuronal dysfunction. This study provides biomarkers for AD and reveals the signaling pathways through which ZAs ameliorate AD in mice, providing a potential treatment strategy for AD.