Study Of NLRP3 Inflammasome Activation Inhibit Glucose Metabolism Based On PET In Alzheimer’s Disease

Nowadays,Alzheimer’s disease（AD）has become a major challenge to be solved urgently.Abnormal neuroinflammation and glucose metabolism occurs in the early stages and accompanies the entire course of AD.However,most studies have limited the relationship between Aβand tau proteins,and the interaction between neuroinflammation and glucose metabolism is unclear.In recent years,it has been found that the translocation of hexokinase（HK）can cause NLRP3 inflammasome activation,establishing a direct link between neuroinflammation and glucose metabolism.However,it has not been studied whether activation of NLRP3 inflammasome will affect the expression and distribution of HK.In order to fill this gap,this paper takes NLRP3 inflammasome as the research target,explores the effect of NLRP3 inflammasome activation on the expression and distribution of HK and glucose metabolism.It may be useful for a better understanding of the relationship between neuroinflammation and glucose metabolism and then provides new ideas for intervention and treatment of AD.First,the effects of age,sex,and genotype on glucose metabolism of triple-transgenic AD mice（3×Tg AD mice）and Non-transgenic mice（NTg mice）and APP/PS1 mice were studied using ¹⁸F-FDG PET.The differences in glucose metabolism were compared between6-month-old and 9-month-old NTg mice and 3×Tg AD mice,and the differences in glucose metabolism between 9-month-old female and male NTg mice and 3×Tg AD mice,and the differences in glucose metabolism between 9-month-old female NTg mice and 3×Tg AD mice and APP/PS1 mice.Hence,9-month-old female NTg mice and 3×Tg AD mice were selected for pathological studies.Secondly,9-month-old female NTg mice and 3×Tg AD mice were injected with NLRP3-specific inhibitor CY-09.Then using Western Blot,immunofluorescence,Morris Water Maze and other methods to detect the inhibition of CY-09 on NLRP3 and the expression of pathological proteins in AD mice.And using ¹⁸F-FDG PET to detect glucose metabolism levels in the mice brain in each group to assess the effect of CY-09 on glucose metabolism.Results confirmed the inhibitory effect of CY-09 on NLRP3 inflammasome activation,and inhibition of NLRP3 inflammasome activation improved AD pathology and cognitive impairment.At the same time,it was found that inhibiting NLRP3 inflammasome activation could improve glucose metabolism levels in the brains of 3×Tg AD mice.Thirdly,the effects of inhibiting NLRP3 inflammasome activation on glucose transporters,insulin signaling pathways and insulin resistance in the brains of 3×Tg AD mice were explored by insulin tolerance detection,glucose tolerance detection,Western Blot,immunofluorescence,ELISA and other methods.Results showed that inhibiting NLRP3inflammasome activation increased the expression of glucose transporters in the brains of3×Tg AD mice,restored insulin signaling pathway conduction,and eased insulin resistance.Finally,the expression and distribution of hexokinase and openness of mitochondrial permeability transition pore（m PTP）were studied by Western Blot,immunofluorescence,mitochondrial swelling,ELISA and other methods in N2a-sw cells and 3×Tg AD mice.Results showed that inhibiting activation of NLRP3 inflammasome helped improve expression and distribution of HK in N2a-sw cells and 3×Tg AD mice,turn off m PTP and reduce the production of reactive oxygen.On the whole,the results of this paper suggest that inhibition of NLRP3 inflammasome activation can restore glucose metabolism,indicating that the inhibition of NLRP3inflammasome activation on glucose metabolism in AD.It provides evidence for the relationship between neuroinflammation and glucose metabolism and also provides a new theoretical basis for neuroinflammation as a therapeutic target of AD.Next,how to improve the expression of glucose transporter and how to regulate the interaction between HK and m PTP by inhibiting NLRP3 inflammasome activation need further exploration.