TMEM16F is involved in many physiological processes such as blood coagulation, cell membrane fusion and bone mineralization. Activation of TMEM16F has been studied in various
central nervous system diseases. High TMEM16F level has been also found to participate in microglial phagocytosis and transformation. Microglia-mediated
neuroinflammation is a key factor in promoting the progression of
Alzheimer's disease. However, few studies have examined the effects of TMEM16F on
neuroinflammation in
Alzheimer's disease. In this study, we established TMEM16F-knockdown AD model in vitro and in vivo to investigate the underlying regulatory mechanism about TMEM16F-mediated
neuroinflammation in AD. We performed a Morris water maze test to evaluate the spatial memory ability of animals and detected markers for the microglia M1/M2 phenotype and NLRP3
inflammasome. Our results showed that TMEM16F was elevated in 9-month-old APP/PS1 mice. After TMEM16F knockdown in mice, spatial memory ability was improved, microglia polarization to the M2 phenotype was promoted, NLRP3
inflammasome activation was inhibited, cell apoptosis and Aβ plaque deposition in brain tissue were reduced, and
brain injury was alleviated. We used
amyloid-beta (Aβ25-35) to stimulate human microglia to construct microglia models of
Alzheimer's disease. The levels of TMEM16F,
inducible nitric oxide synthase (iNOS), proinflammatory
cytokines and NLRP3
inflammasome-associated
biomarkers were higher in Aβ25-35 treated group compared with that in the control group. TMEM16F knockdown enhanced the expression of the M2 phenotype
biomarkers Arg1 and Socs3, reduced the release of proinflammatory factors
interleukin-1,
interleukin-6 and
tumor necrosis factor-α, and inhibited NLRP3
inflammasome activation through reducing downstream proinflammatory factors interleukin-1β and
interleukin-18. This inhibitory effect of TMEM16F knockdown on M1 microglia was partially reversed by the NLRP3 agonist
Nigericin. Our findings suggest that TMEM16F participates in
neuroinflammation in
Alzheimer's disease through participating in polarization of microglia and activation of the NLRP3
inflammasome. These results indicate that TMEM16F inhibition may be a potential therapeutic approach for
Alzheimer's disease treatment.