GLP-1/GLP-1R-mediated glycolytic reprogramming drives AP neuronal hyperactivity in NMOSD

Background Neuromyelitis optica spectrum disorder (NMOSD) with area postrema syndrome (APS) manifests as intractable nausea, vomiting, and hiccups, yet the underlying mechanisms remain poorly understood. Recent evidence suggests a potential role of metabolic dysregulation in autoimmune neurological disorders, but the involvement of glucagon-like peptide-1 receptor (GLP-1R) signaling in APS pathogenesis has not been explored. Methods We conducted a clinical study involving 248 AQP4-IgG+ NMOSD patients, including 57 with APS, alongside healthy controls and RRMS patients. Serum and cerebrospinal fluid (CSF) levels of GLP-1 and GLP-1R were measured and correlated with clinical severity. Mechanistic studies employed a dual-antigen (AQP4 + MOG) experimental autoimmune encephalomyelitis (EAE) mouse model and SH-SY5Y neuronal cultures. Techniques included non-targeted metabolomics, patch-clamp electrophysiology, transmission electron microscopy (TEM), and pharmacological interventions with the GLP-1R antagonist Exendin-(9–39) and IL-6 inhibitor satralizumab. Results APS patients exhibited elevated GLP-1 and GLP-1R levels in serum and CSF, which correlated with symptom severity and APS symptom. In EAE _AQP4+MOG mice, gut-derived GLP-1 crossed the compromised blood-brain barrier, activating GLP-1R in area postrema (AP) neurons. This triggered cAMP-PKA-dependent glycolytic reprogramming, lactate accumulation, mitochondrial dysfunction, and neuronal hyperexcitability. In vitro studies using SH-SY5Y neuronal cells demonstrated that LPS-induced inflammation or direct GLP-1R agonism similarly upregulated glycolytic enzymes and lactate production while impairing mitochondrial respiratory chain function. Importantly, both in vivo and in vitro experiments showed that pharmacological blockade of GLP-1R with Exendin-(9–39) or inhibition of IL-6 signaling with satralizumab effectively reversed these pathological changes, normalizing neuronal excitability and resolving APS-like symptoms in the EAE model. Conclusion Our study identifies a novel gut-brain metabolic axis in APS pathogenesis, driven by GLP-1/GLP-1R-mediated glycolytic reprogramming and neuronal hyperactivity. These findings highlight GLP-1R as a potential therapeutic target for NMOSD, offering a dual approach to address both neuroinflammatory and metabolic disorder of the disease.