AIMS: Insulin signaling malfunction has recently been suggested as a preliminary event involved in the etiology of Sporadic Alzheimer's disease (SAD). In order to develop insulin resistance-related SAD model, rats were treated with streptozotocin, intracerebroventricularly (icv-STZ). Nevertheless, given the lack of knowledge regarding sub-clinical stages of SAD, the current challenging issue is establishing a practical pre-clinical SAD model. Despite some proposed mechanisms, such as insulin malfunction, neuroinflammation, and gliosis, icv-STZ mechanism of action is not fully understood yet and Streptozotocin-induced rat model of Alzheimer has still major shortcomings. MAIN METHODS: Using three STZ doses (0.5, 1, and 3mg/kg) and three testing time (short-term, medium-term and long-term), we sought the best dose of STZ in order to mimic the characteristic feature of sAD in rats. So, we conducted a series of fifteen-week follow-up cognitive and non-cognitive studies. Besides, IR, tau and ChAT mRNA levels were measured, along with histological analysis of astrocyte, dark neuron numbers, and pyramidal layer thickness, in order to compare the effects of different doses of icv-STZ. KEY FINDINGS: STZ 3mg/kg caused cognitive and insulin signaling disturbance from the very first testing-time. STZ1-injected animals, however, showed an augmented hippocampal astrocyte numbers in a short time; they, also, were diagnosed with disturbed insulin signaling in medium-term post icv-STZ-injection. Moreover, behavioral, molecular and histological impairments induced by 0.5mg/kg icv-STZ were slowly progressing in comparison to high doses of STZ. SIGNIFICANCE: STZ1 and 0.5mg/kg-treated animals are, respectively, suggested as a suitable experimental model of MCI, and sub-clinical stage.

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