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Background Alzheimer’s Disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. Peroxisome Proliferator-Activated Receptor-γ (PPARγ) play a crucial role in regulating insulin sensitivity and may serve as potential therapeutic targets for AD. Pioglitazone (PIOG), as a PPARγ agonist, reduces β-amyloid and tau proteins, and inhibits neuroinflammation. Objective This study aims to evaluate the effects of PIOG chronic administration on learning and memory in rat model of Streptozotocin (STZ)-induced AD Methods Forty-two male Wistar rats were divided into two groups: A. Normal rats divided into three subgroups of Control, Dimethyl Sulfoxide (DMSO), and PIOG; and B. AD rats divided into four subgroups of Vehicle, STZ, STZ+DMSO and STZ+PIOG. The last two AD subgroups received 0.2 mL DMSO and PIOG (10 mg/kg per day) for 21 days. For induction of AD, STZ (3 mg/kg, 10 μl per injection site) were administered into lateral ventricles. All rates were trained under the Morris water maze task. Findings PIOG impaired the spatial learning and memory in normal rats. Intracerebroventricular injection of STZ significantly increased escape latency and swimming time to find the hidden platform compared to the control group (P<0.05). The amnesic effect of STZ was prevented by PIOG administration such that the escape latency and swimming time to find the hidden platform in the STZ+PIOG group were significantly lower than in the STZ+DMSO group (P<0.05). Conversely, the percentage of time spent and distance swimming in the target quadrant in the probe test in the STZ+ PIOG group rats were significantly higher than those in the STZ + DMSO group. Conclusion PIOG administration impaired spatial learning and memory in normal rats, but improved learning and memory in rats with STZ-induced AD. It can be useful for treatment of cognitive impairment in AD patients.