Semaglutide administration reduces hippocampal injury, p-tau, and glial activation in STZ-induced Alzheimer's rat model.

While Glucagon-like peptide-1 receptor (GLP1R) agonists like semaglutide show neuroprotective effects in genetic models of Alzheimer's disease (AD), their impact on sporadic AD models, such as those induced by intracerebroventricular streptozotocin (STZ) injection, is less understood, especially regarding delayed and long-term efficacy. A critical gap exists in understanding how long GLP1R agonist effects persist after discontinuation and whether a single course can suppress progressive neurodegeneration. This study specifically aimed to evaluate these delayed effects on hippocampal morphology and cognitive impairment.

Rats received bilateral intracerebroventricular STZ injections (3 mg/kg) to induce an AD-like state. Following this, animals were treated with intraperitoneal semaglutide 0.1 mg/kg every other day for 5 weeks. A control group received STZ without semaglutide. Animals were euthanized 60 days after semaglutide discontinuation. Immunomorphological methods were employed to detect neuronal, astrocytic, and microglial alterations, while a novel object recognition test assessed behavioral effects and cognitive impairment.

STZ-treated animals exhibited significant cognitive impairments, ventriculomegaly, and a 23% decrease in CA1-CA3 field area (p = 0.008). They also showed reduced hippocampal neuronal density, a significant increase in p-tau protein fluorescence intensity (p = 0.02), and decreased levels of TOMM20 (a mitochondrial marker) and synaptophysin. These changes were accompanied by significant glial activation in the hippocampal CA3 field. Semaglutide administration significantly mitigated these effects: it reduced the enlarged ventricular lumen by 43.5% and decreased p-tau fluorescence intensity. Furthermore, semaglutide treatment increased synaptophysin fluorescence intensity and alleviated disrupted AQP4 distribution. Microglial activation was reduced, evidenced by decreased IBA1 cell density and elongation. Importantly, semaglutide also significantly reduced vimentin-positive reactive astrocytes.

Semaglutide administration reduced vimentin-positive reactive astrocytes by 68.4%.