Research Square · Feb 10, 2026
GLP-1/GLP-1R-mediated glycolytic reprogramming drives AP neuronal hyperactivity in NMOSD
By Yang L, Hao Q, Wang C et al.
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.