The ICV administration of STZ is a well-established, validated, and widely accepted animal model of sAD, which develops many AD-like neuropathological features, including synaptic damage, amyloid-b deposition and tau hyperphosphorylation. Magnesium is required for many physiological processes, including insulin sensitivity, inflammatory responses, glucose metabolism, the regulation of cell proliferation and apoptosis, and defense against oxidative stress. Magnesium deficiency or imbalance has been implicated in AD pathogenesis, and an increase in brain magnesium improves learning and memory functions in aged rats. Our study found that the simultaneous supplementation of magnesium sulfate effectively increased the brain magnesium levels and rescued ICV-STZ-induced learning and memory deficits. Synaptic plasticity is a prerequisite of learning and memory and can be measured using alterations in LTP or synaptic morphology. Increasing extracellular magnesium in the physiological range enhances synaptic plasticity in cultured hippocampal neurons, suggesting its role as positive regulator of synaptic plasticity. Synaptic VE-821 degeneration in AD was correlated with cognitive decline. We showed that the simultaneous supplementation of magnesium sulfate rescued LTP, preserved the morphological complexity of synapses and up-regulated the expression of synaptic proteins in ICV-STZ rats. Tau hyperphosphorylation is the prelude of neurofibrillary tangle formation, which is positively correlated with the degree of clinical dementia. The ICV-STZ model shows neurodegenerative pathologies, including amyloid-b and hyperphosphorylated tau, which are similar to the brains of AD patients. Magnesium favors a-secretase cleavage pathways, which reduce amyloid-b, and we found that magnesium inhibited tau hyperphosphorylation in the sAD model. The protein kinase and protein phosphatase GSK-3b and PP2A are the most implicated regulators of tau phosphorylation. As previously reported, ICV-STZ induced the activation of GSK-3b. Tyr216 and Ser9 phosphorylation regulate GSK-3b activity. We identified that magnesium arrested STZ-induced GSK-3b activation via an increase in inhibitory phosphorylation at Ser9. A previous study also showed that magnesium, similar to zinc and lithium, is a potent inhibitor of GSK-3b. GSK-3b is a downstream target of the PI3K/Akt signaling pathway, and PI3K/Akt inactivation increases GSK-3b activity. Magnesium significantly enhances the activity of the PI3K/Akt pathway. Our data are consistent with recent studies, which showed that ICV-STZ treatment decreases PI3K and Akt phosphorylation. We also found that the simultaneous supplementation of magnesium sulfate was prone to activate the PI3K/Akt pathway and inactivate GSK-3b. ICV-STZ can induce an insulin resistant state in the brain and other similarities with human sAD. In addition, deregulation of brain insulin and insulin receptor has been linked to the pathogenesis of AD. In humans and in animal models, magnesium deficiency modulates insulin sensitivity, and may be associated with impaired insulin secretion. The present results showed that magnesium could promote the protein expression of INSR, the mRNA levels of INS and INSR in ICV-STZ-induced rats.