miR-181c-5p suppresses neuronal pyroptosis via NLRP1 in Alzheimer’s disease

Alzheimer's disease (AD) is neurodegenerative disease common in the elderly, whose pathological mechanism is the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. Pyroptosis is a programmed cell death mediated by Gasdermin protein. After the activation of inflammasomes, the cleaved caspase⁃ 1/4/5/11 activates GSDMD, which promotes the release of inflammatory substances and eventually causes cell swelling and death. Pyroptosis caused by inflammasomes plays a role in AD. However, the specific regulatory mechanism of pyroptosis in AD still needs more experimental studies. To further study the effects of NLRP1-induced pyroptosis on AD, miR-181c-5p, which could targeted bind to NLRP1, was knocked down or overexpression in HT22 cells to detect cell apoptosis with Tunel assay, the expression of inflammasome-related proteins with Western blot and the content of inflammatory factors with ELISA. miR-181c-5p was overexpressed in AD model mice to detect the learning and cognitive ability with morris water maze testing and the expression of inflammasoma-related proteins with Western blot. The results showed that miR-181c-5p mimic attenuated Aβ1–42-induced neuronal pyroptosis in HT22 cells, while up-regulation of NLRP1 aggravated neuronal pyroptosis in HT22 cells. In mice, miR-181c-5p agomir attenuated neuronal pyroptosis in both hippocampal and cortical tissues, and miR-181c-5p antagomir improved neuronal pyroptosis and cognitive impairment through NLRP1. Therefore, the study suggests that miR-181c-5p can alleviated AD process by targeted downregulation of NLRP1, which is expected to be a target site for AD treatment.