NaF induced excessive autophagy of rat hippocampal neurons and NG108-15 cells via epigenetic upregulation of miR-183-5p.

In environments with high levels of fluoride (F) due to industrial pollution or high natural background values, long-term exposure to excessive F has been linked to a heightened likelihood of cognitive deterioration among humans, but the full mechanism needs to be explored. MiR-183-5p may be implicated in the formation of learning and memory within the mammalian brain and also in the regulation of autophagy. Numerous studies have reported that sodium fluoride (NaF) induces dysfunctional autophagy, and 3-methyladenine (3-MA) is a commonly recognized autophagy inhibitor. Based on database predictions and confirmed by dual-luciferase reporter assays, miR-183-5p binds to the distinct 3'-UTR of PLCβ4, thereby modulating the expression of this gene. This study investigated how miR-183-5p regulates the autophagy response induced by F in SD rats and evaluated the regulatory effect of 3-MA on F-induced autophagy in NG108-15 cells. In this study, autophagy was confirmed through transmission electron microscopy and dansylcadaverine staining. Our findings demonstrated that F promotes autophagy of nerve cells both in vivo and in vitro by upregulating miR-183-5p, which subsequently suppresses the PLCβ4 and Wnt/Ca²⁺ signaling pathways and activates calcineurin (CaN). Conversely, 3-MA alleviated excessive autophagy by downregulating miR-183-5p, activating the Wnt/Ca2 + pathway and inhibiting CaN. This study is the earliest to testify that upregulation of miR-183-5p contributes to F-induced neurotoxicity by aggravating defective autophagy via negatively targeting PLCβ4.