Change of mTOR/P70S6K/IRS-1 signaling pathway in the brain of Alzheimer’s disease rats induced by streptozotocin

Abstract:

Objective：To investigate the effects of intracerebroventricular injection of streptozotocin on mTOR/P70S6K/IRS-1 signaling pathway. Methods：The 30 male SD rats were randomly divided into control group and model group，fifteen rats in each group. The rats were treated with saline or streptozotocin（STZ，3 mg/kg） intracerebroventricularly（ICV） at the 1st day and the 3rd day of the experi－ment to induce dementia model. Thirty-six days after STZ in－jection，spatial learning and memory of the rats were deter－mined by Morris water maze test. The expression of mammalian target of rapamycin（mTOR），phosphorylated mTOR（p-mTORS－er2448），p70 ribosomal S6 protein kinase（P70S6K），phosphory－lated P70S6K（p-P70S6KThr389），insulin receptor substract-1（IRS-1） and phosphorylated IRS-1（p-IRS-1Ser636） were mea－sured by Western blot. Morphologic changes of neurons in cere－bral cortex and hippocampus were observed by HE staining. Deposition of Aβ in hippocampus was detected by Thioflavin S staining. Results：ICV-STZ can significantly reduce the time spent in the target quadrant（t=8.558，P=0.000） and numbers of platform location crosses（t=6.086，P=0.000）. HE staining demonstrated that some cells were clearly shrank and swelled in cerebral cortex and hip－pocampus of rats treated by STZ. Meanwhile，the deposition of Aβ detected by Thio-flavin S staining was also significantly increased. Compared with that in control group，the expressions of p-P70S6KThr389（t=-8.409，P=0.000），p-IRS-1Ser636（t=-4.417，P=0.002） in the cerebral cortex and p-P70S6KThr389（t=-7.339，P=0.000），p-IRS-1Ser636（t=-5.496，P=0.001） in hippocampus were increased markedly，while the protein levels of P70S6K，mTOR，p-mTORSer2448 and IRS-1 were not affected by ICV- STZ． Conclusion：ICV-STZ results in increased activation of mTOR/P70S6K/IRS-1 signaling pathway，and the increased activation of mTOR/P70S6K/IRS-1 may play important roles in AD pathogenesis．