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Objective The mammalian target of rapamyein (mTOR) kinase is an inhibitor of macroautophagy, which is a conserved intracellular system designed for the degradation of long-lived proteins and organelles in lysosomes.Recent evidence suggested that chronic increase in mTOR function occurring during aging may promote the development of Tau pathology.The senescence accelerated mouse prone 8 (SAMP8) is a mice strain widely used as a rodent model of aging and senile dementia.The present study aimed to explore whether mTOR signaling pathway has effect in the neurodegenerative changes of SAMP8 mice and whether rapamycin administration could alleviate the neurodegenerative disorders.Methods The primary neurons were obtained from the hippocampus of newborn SAMP8 and SAMR1 mice, and at the seventh day of culture, 0.5 or 1.0 μM rapamycin was added into the culture medium, and at the tenth day, neurons were observed after immunofluorenscence staining.The levels of phosphorylated p70S6K, phosphorylated mTOR, Tau [pS199] and Tau [pS396] were detected with Western blot.Results In SAMP8 hippocampal neurons, the levels of phosphorylated p70S6K at Thr389 and mTOR (pSer2448) were significantly higher than in the control SAMR1.mTOR activity signaling was upregulated in the neurons of SAMP8 at the tenth day.The neurons extracted from SAMP8 were in a poor state in contrast to the SAMPR1, most processes broken and presented "bead-like" changes.Rapamycin administration significantly reduced the levels of phosphorylated p70S6K at Thr389 in SAMP8 contrast to SAMR1 in both treated groups.When treated with 0.5 tM rapamycin for 3 d, a mTOR inhibitor, the neurons from SAMP8 seems better than non-treated group, part of processes were smooth and slender, although part of neurons almost all processes broken and absence.The presentation of Tau [pS199] and Tau [pS396] both decreased significantly contrast to the control SAMR1.When treated with 1.0 μM rapamycin, cell state was worse than the untreated group, most neurons were lacked of projections.In the SAMP8 group, the levels of Tau [pS199] and Tau [pS396]) were significantly higher than SAMR1 group.Conclusion mTOR signaling participates in the neurodegenerative process of SAMP8 mice and rapamycin administration could protect neurons and alleviate Tau phosphorylation of SAMP8 mice.Rapamycin might have a potential role in curing the cognitive decline of SAMP8 mice.