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Microglia as a Surrogate Biosensor to Determine Nanoparticle Neurotoxicity
Published on: October 25, 2016
The Lnc_000151/microRNA-96-5p/insulin receptor substrate 1 axis mediates aluminum-induced neurotoxicity
Chanting He1, Qian Hu2, Yafen Chu3
1Academy of Medical Sciences, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Occupational Health, School of Public Health, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Anatomy, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Lab of Environmental Pollution Pathogenicity and Prevention of Shanxi Province, Shanxi Medical University, Taiyuan, Shanxi 030001, China; MOE Key Laboratory of Coal Environmental Pathogenicity and Prevention (Shanxi Medical University), Ministry of Education, China.
None:
Aluminum causes learning and memory impairments, and is an environmental and occupational toxicant. This in vivo and in vitro study assessed the implications of Lnc_000151 on aluminum-induced neurotoxicity through competitive binding to miR-96-5p. Fifty-six male SpragueDawley rats were randomly divided into eight groups: untreated, sham-operated, saline + sham-operated, Al(mal)₃ + sham-operated, saline + AAV-NC, Al(mal)₃ + AAV-NC, saline + AAV-Lnc_000151 shRNA, and Al(mal)₃ + AAV-Lnc_000151 shRNA. PC12 cells were separated into groups of 0, 100, 200, and 400 µM Al (mal)₃, and transfection groups including Lnc_000151 NC/siRNA, miR-96-5p NC/inhibitor, and IRS1 NC/siRNA. The learning and memory functions of rats were assessed via Morris water maze. Hippocampal CA1 neuronal count and synaptic structure were detected with hematoxylin-eosin staining and transmission electron microscopy. Cell apoptosis was measured using flow cytometry. Relative expression of Lnc_000151, miR-96-5p, and the IRS1/AKT/GSK3β pathway was determined using RT-PCR and Western blotting. The dual-luciferase assay confirmed targeted binding of Lnc_000151 to miR-96-5p and miR-96-5p to IRS1. In vivo and in vitro experiments demonstrated that under aluminum exposure, inhibition of Lnc_000151 expression exacerbated learning and memory impairments, neuronal loss, synaptic damage, increased Tau and p-Tau (Ser396) expression, and cell apoptosis. In vitro experiments further verified that under aluminum exposure and Lnc_000151 inhibition, suppressing miR-96-5p expression reduced Tau and p-Tau (Ser396) expression and cell apoptosis, while activating the IRS1/AKT/GSK3β pathway. However, further inhibition of IRS1 expression abrogated these ameliorative effects. In conclusion, this study demonstrates that Lnc_000151 can competitively bind to miR-96-5p in a competing endogenous RNA (ceRNA)-dependent manner, thereby regulating IRS1 expression, modulating the AKT/GSK3β pathway, and affecting aluminum-induced neurotoxicity.