Semaglutide reduces hypothalamic glial cell damage in a streptozocin-induced model of Alzheimer's disease

Introduction: Reactive changes in glial cells, as well as their dysfunction, particularly cerebrospinal fluid dynamics disturbances, are associated with multiple neurodegenerative diseases and Alzheimer’s disease (AD). Intraventricular administration of streptozotocin (STZ) is considered a model of sporadic AD, though data on hypothalamic glial cell changes, ependymal glia, and tanycytes in this model remain limited. Of particular interest is the potential for glucagon-like peptide-1 (GLP-1) receptor agonists to address STZ-induced changes following intraventricular administration. Material and Methods: Using immunomorphological methods, this study assessed changes in staining density and distribution of glial proteins (GFAP, aquaporine-4, connexin 43, vimentin) and neuronal alterations in hypothalamic structures following intraventricular STZ administration (3 mg/kg) and course treatment with intraperitoneal semaglutide (0.1 mg/kg, 16 injections). Results: STZ caused neuronal damage in the ventromedial hypothalamic nucleus, disrupted the ependymal lining and tanycytes of the third ventricle, induced reactive astrogliosis, and altered the distribution of aquaporin-4 and connexin-43. Semaglutide administration reduced astroglial activation, normalized aquaporin and connexin distribution, decreased neuronal death, and suppressed caspase-3 activation in the ventromedial hypothalamic nucleus. Conclusion: Intraventricular single-dose STZ administration causes long-term impairment of glial functions related to cerebrospinal fluid exchange. The course treatment GLP-1R agonist semaglutide (started 5 days after streptozocin administration, 16 injections every other day) demonstrated normalizing effects on both glial and neuronal parameters in the STZ-induced AD model.