Mazdutide improves cognitive function in APP/PS1/Tau triple transgenic mice

Abstract

BACKGROUND: The pathological process of Alzheimer's disease is closely related to β-amyloid/Tau deposition and cerebrovascular dysfunction, and existing therapies are difficult to effectively intervene. In recent years, research on glucagon-like peptide-1 receptor agonists for the treatment of Alzheimer's disease has gained increasing popularity. As a novel dual agonist of the glucagon-like peptide-1 receptor and glucagon receptor, the therapeutic mechanism of Mazdutide in Alzheimer’s disease remains to be elucidated. OBJECTIVE: To systematically explore the mechanism by which Mazdutide improves cognitive function in Alzheimer's disease using network pharmacology and experimental validation, and to identify potential core molecular targets, providing a theoretical basis for new therapeutic strategies. METHODS: A multi-omics integration strategy was employed. Co-localization targets of Alzheimer's disease and Mazdutide were screened using DisGeNET and SEA databases. A protein-protein interaction network was constructed via STRING, and hub genes were identified by Cytoscape topological analysis. In APP/PS1/Tau triple transgenic Alzheimer's disease mice, Mazdutide (30 nmol/kg) was administered intraperitoneally. Cognitive function was assessed using Morris water maze, novel object recognition, and Y maze tests. Western blot was used to detect hippocampal β-amyloid (6E10), p-Tau181, and endothelin receptor A expression. RESULTS AND CONCLUSION: ① Fifty-two co-localized targets were identified, with endothelin receptor A (EDNRA) as the top hub gene. ② Mazdutide significantly improved cognition in 3xTg mice: shortened spatial memory latency, increased novel object recognition index, increased spontaneous alternation in Y maze, and reduced hippocampal pathological burden, with decreased p-Tau181 and EDNRA overexpression. ③ Gene Ontology and KEGG enrichment revealed core pathways: biological processes included blood pressure regulation, amine transport regulation, and amine transport; cellular components included symmetric synapses, sperm head, and pseudopodia; molecular functions included G protein-coupled peptide receptor activity, peptide receptor activity, and neuropeptide receptor activity. KEGG pathways included neuroactive ligand-receptor interaction, calcium signaling, and hormone signaling. ④ This study confirms that Mazdutide may improve cognitive deficits in Alzheimer's disease by targeting and inhibiting EDNRA overexpression, reducing neuronal pathological damage, and acting through multiple dimensions. The discovery of EDNRA provides a novel therapeutic target for Alzheimer's disease.

1. Introduction

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders, characterized by β-amyloid plaque deposition, hyperphosphorylated Tau neurofibrillary tangles, and progressive neuronal loss [1-4]. Currently, FDA-approved drugs such as cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists only provide symptomatic relief without halting disease progression [5]. In recent years, glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as a promising therapeutic strategy for AD due to their multifaceted effects on glucose regulation, neuroinflammation suppression, and neurotrophic factor secretion [6]. Mazdutide, a novel dual agonist of GLP-1R and glucagon receptor (GCGR), has shown significant improvements in body weight and metabolic parameters in phase II clinical trials for obesity, but its regulatory mechanisms on AD core pathology remain unclear [7].

Extensive studies have demonstrated that GLP-1R agonists such as liraglutide and semaglutide exert neuroprotective effects in AD animal models, including reducing β-amyloid plaques, lowering Tau phosphorylation, improving synaptic function, and attenuating neuroinflammation [8-10]. These effects may involve crossing the blood-brain barrier and directly acting on GLP-1Rs on neurons and glial cells [11]. However, as a dual GLP-1R/GCGR agonist, Mazdutide may offer enhanced neuroprotective potential through synergistic activation of both receptors, improving energy metabolism and insulin sensitivity, yet this remains unexplored in AD research [12]. GCGR activation is thought to benefit neuronal survival and function, possibly by increasing brain-derived neurotrophic factor expression [13-14]. Therefore, investigating the efficacy and mechanisms of Mazdutide in AD not only helps understand the therapeutic potential of dual-target agonists but also may provide new strategies for AD treatment.