IGF2BP2 Regulates the Progression of Alzheimer's Disease Through m6A-Mediated NLRP3 Inflammasome

Background: Recent studies show that N6-methyladenosine (m6A) plays an important role in the pathogenesis of the Alzheimer's disease (AD), while the mechanisms involved were studied insufficiently. Aims: The present study aimed to explore the effect of human insulin-like growth factor 2 (IGF2) mRNA binding proteins 2 (IGF2BP2), one of the m6A-binding proteins on the progression of AD. Materials & Methods: The mRNA and protein expression level were determined using RT-qPCR and western blot, respectively. MTT assay was carried out to evaluate cell viability. The content of ROS, antioxidant enzymes, IL-1 beta and pyroptosis, as well as m6A contents were determined using relative commercial kit. The AD models were built using A beta 1-42 -stimulated hippocampal neuron in vitro and AD mice in vivo. Results: Our results showed that IGF2BP2 was significantly upregulated in the A beta 1-42 -stimulated hippocampal neuron. IGF2BP2 inhibition reversed the decreased cell viability and the increased cell apoptosis induced by A beta 1-42. IGF2BP2 siRNA transfection alleviated A beta 1-42 induced pyroptosis and pyroptosis-related proteins upregulation. we also found that IGF2BP2 inhibition downregulated the expression of NLRP3 through m6A methylation. Furthermore, overexpression of NLRP3 partly reversed the effect of IGF2BP2 inhibition on A beta 1-42 -induced hippocampal neuron injury. In addition, IGF2BP2 improved cognitive function and alleviated A beta 1-42 neuronal injury in vivo. Conclusion: Knockdown of IGF2BP2 inhibit neuronal damage and pyroptosis in the hippocampus cells, and improve cognitive function in AD partly through m6A-mediated NLRP3 inflammasome.