Abstract
Aluminum neurotoxicity impairs learning and memory ability, but the molecular mechanism has not been elucidated. The aim of this study was to examine the role of phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling in regulating the expression of synaptic plasticity-related proteins (PRPs) and p-tau deposition to explore the mechanism underlying aluminum-induced neurotoxicity. We constructed a sub-chronic aluminum-exposed Sprague Dawley (SD) rat model to assess aluminum neurotoxicity in vivo. The learning and memory abilities of rats were examined using the Morris water maze test. We also assessed the effect of aluminum in vitro using rat pheochromocytoma (PC12) cells. To explore the role of PI3K/Akt/mTOR signaling in aluminum neurotoxicity, we used the PI3K inhibitor wortmannin and the mTOR inhibitor rapamycin in aluminum-treated PC12 cells. Protein expression was examined by western blotting. Aluminum disrupted the learning and memory abilities of SD rats. Mechanistically, aluminum reduced the levels of the synaptic PRPs (cAMP-response element binding protein (CREB), glutamate receptor 1 (GluR1), glutamate receptor 2 (GluR2), and postsynaptic density protein 95 (PSD-95), and it increased p-tau deposition in the hippocampus of SD rats. We observed similar results in aluminum-treated PC12 cells. Further, PI3K/Akt/mTOR signaling was abnormally activated in aluminum-treated PC12 cells, and treatment with rapamycin reversed the decrease in synaptic PRPs levels and the increase in p-tau deposition. In conclusion, the activation of PI3K/Akt/mTOR signaling reduces the levels of synaptic PRPs and increases p-tau deposition induced by aluminum. Therefore, the PI3K/Akt/mTOR pathway participates in the mechanism of aluminum neurotoxicity.
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Funding
This work was supported by the National Natural Science Foundation of China NSCF (Grant number 81803208) and the Science Foundation Shanxi Province University (Grant number 2019L0997).
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Material was prepared by Guangheng Zhang and Yingying Zhao, experiments were performed by Yirong Xu and Yingying Zhao, and data collection and analysis were performed by Fan Bu and Yeping Zhang. The first draft of the manuscript was written by Yirong Xu, and all authors commented on previous versions of the manuscript. All authors have read and approved the final manuscript.
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Xu, Y., Zhang, G., Zhao, Y. et al. Activation of PI3k/Akt/mTOR Signaling Induces Deposition of p-tau to Promote Aluminum Neurotoxicity. Neurotox Res 40, 1516–1525 (2022). https://doi.org/10.1007/s12640-022-00573-9
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DOI: https://doi.org/10.1007/s12640-022-00573-9