Impact of Semaglutide on Hippocampal Injury in a Streptozotocin-Induced Model of Alzheimer’s Disease

Background: Glucagon-like peptide-1 receptor (GLP1R) agonists, particularly semaglutide, show neuroprotective effects in genetic models of Alzheimer’s disease (AD). However, their delayed and long-term effects in sporadic AD, such as the intracerebroventricular streptozotocin (STZ) injection, remain insufficient. It is unclear how long the effects of GLP1R agonists persist after discontinuation and whether a single course can suppress progressive neurodegeneration. This study aimed to evaluate the delayed effects of semaglutide administration on morphological changes in neurons and glial cells in the hippocampus associated with cognitive impairment in an STZ-induced rat model of AD. Methods: Rats received bilateral intracerebroventricular STZ injections (3 mg/kg) followed by a 5-week course of intraperitoneal administration of semaglutide (0.1 mg/kg, every other day), and were euthanized 60 days after discontinuation of semaglutide administration. Immunomorphological methods were used to detect neuronal, astrocytic and microglial alterations. A novel object recognition test was performed to assess behavioral effects. Results: STZ-treated animals demonstrated cognitive impairments, ventriculomegaly, a significant increase in p-tau protein fluorescence intensity (p = 0.02), a decrease in CA1–CA3 field area (by 23%, p = 0.008), and reduced hippocampal neuronal density. Decreases in TOMM20 (mitochondrial marker) and synaptophysin levels were accompanied by significant glial activation in the hippocampal CA3 field. Semaglutide administration significantly reduced the enlarged ventricular lumen (by 43.5%), decreased p-tau fluorescence intensity, reduced vimentin-positive reactive astrocytes (by 68.4%), and increased synaptophysin fluorescence intensity. Furthermore, it reduced microglial activation (decreasing IBA1 cell density and elongation) and alleviated the disrupted AQP4 distribution. However, semaglutide did not completely halt the neurodegenerative process and showed no effect on the number of doublecortin-positive cells in the dentate gyrus. Conclusions: Hippocampal changes assessment revealed that course administration of semaglutide exerts prolonged effects, attenuating the severity of pathomorphological alterations and behavioral changes in a sporadic AD model after drug discontinuation.