• Mazdutide, a novel GLP-1R/GCGR dual agonist, significantly improves spatial, episodic, and working memory in APP/PS1/Tau triple transgenic mice.
• Network pharmacology identifies endothelin receptor A (EDNRA) as the top hub target, linking Mazdutide's action to cerebrovascular function and amyloid/Tau pathology.
• Mazdutide reduces hippocampal β-amyloid deposition and p-Tau181 levels, while suppressing EDNRA overexpression, indicating a multi-target neuroprotective effect.
• The study reveals a 'drug-target-pathway' mechanism involving neuroactive ligand-receptor interaction and calcium signaling, offering a new therapeutic avenue for Alzheimer's disease.