IST1 alleviated acrylamide-induced apoptosis and cognitive impairment through regulating autophagy flux blockage in SH-SY5Y cells and C57BL/6J mice.

Acrylamide (ACR) is a widely used environmental chemical with neurotoxicity. However, the molecular mechanism and intervention targets of ACR have not been fully elucidated. IST1 factor associated with ESCRT-III (IST1) is an important regulatory subunit of endosomal sorting and transport complex III (ESCRT-III). It can promote autophagy flux and accelerate the autophagic clearance of the phosphorylated Tau protein (p-Tau). This study aimed to explore the role of IST1 in ACR-caused apoptosis, autophagy flux blockage, and p-Tau accumulation. SH-SY5Y cells were exposed to ACR for 72 h at 0.5 and 0.75 mmol/L doses. IST1 overexpression (IST1oe) of SH-SY5Y cells and hippocampal IST1oe C57BL/6 J mice was conducted to evaluate the role of IST1 in ACR-caused neurotoxicity. Results showed that ACR treatment could cause apoptosis, autophagy flux blockage, decreased IST1 level, and abnormal expressions of learning and memory-related proteins, including p-CREB, BDNF, and p-Tau. The effect of ACR on IST1 protein was earlier than that of apoptosis- and autophagy-related proteins such as Bax, Bcl-2, LC3-II, and p62. IST1oe alleviated ACR-induced autophagy flux blockage by promoting autophagosome-lysosome fusion, thereby alleviating the changes in p-CREB, BDNF, p-Tau proteins, and cell apoptosis. IST1oe could alleviate ACR-led learning and memory dysfunction, alleviate the reduction of dendritic spines in C57BL/6 J mice. This study helped elucidate the neurotoxic mechanism of ACR and provide potential molecular targets for prevention and treatment.