Simple SummaryAn early time course study of the proteins associated to synaptic dynamics and cognitive behavior. Study evaluated the expression levels and activation state of markers in hippocampal synaptosomes. Changes in enzymatic activities and proteins levels were detected early during the disease. Study used two different models of impaired insulin signaling in the brain. The two models used exhibited different effects on the parameters tested.AbstractsIn hyperglycemia/diabetes, impaired insulin signaling in the brain causes a cerebral pathology and cognitive impairments as in sporadic Alzheimer’s disease (sAD). To improve our understanding of the role of impaired insulin signaling in cognitive dysfunction, we examined the expression levels and activation states of mediators of neuronal survival and cytoskeletal dynamics/plasticity in the hippocampus in rats treated with intraperitoneal (IP) and intracerebroventricular (ICV) streptozotocin (STZ). We studied early changes (1, 3, or 6 weeks) in response to STZ treatment. Cognitive function was assessed using the novel object recognition (NOR) test and T-maze. The activity of acetylcholine esterase (AChE) and Na+/K+-ATPase was measured biochemically and the expression levels and phosphorylation states of mediators of neuronal survival and synaptosomal dynamics/plasticity (PI3K, Akt, GSK-3β, PAK, LIMK-1, and cofilin-1) were examined by immunoblotting. Significant cognitive losses were observed in STZ-injected rats, together with elevated AChE and reduced Na+/K+-ATPase activity. STZ administration reduced the ratio of phosphorylated/total PI3K, Akt, and GSK-3β and increased the ratio of phosphorylated/total PAK, LIMK-1, and coflin-1. Significant differences between the IP and ICV administration of STZ were observed in the expression levels and phosphorylation states of different markers. Cognitive impairments at 3W and 6W were significantly correlated with changes in the ratio of phosphorylated/total proteins. We conclude that impaired insulin signaling causes early deleterious changes in mediators of synaptic dynamics/plasticity. This study provides mechanistic insights into early events involved in mediating sAD and highlights potential intervention opportunities.