Long-term radiofrequency electromagnetic fields exposure attenuates cognitive dysfunction in 5×FAD mice by regulating microglial function

We have previously found that long-term effects of exposure to radiofrequency electromagnetic fields in 5xFAD mice with severe late-stage Alzheimer’s disease reduced both amyloid-β deposition and glial activation,including microglia.To examine whether this therapeutic effect is due to the regulation of activated microglia,we analyzed mic roglial gene expression profiles and the existence of microglia in the brain in this study.5xFAD mice at the age of 1.5 months were assigned to sham-and radiofrequency electromagnetic fields-exposed groups and then animals were exposed to 1950 MHz radiofrequency electromagnetic fields at a specific absorption rate of 5 W/kg for 2 hours/day and 5 days/week for 6 months.We conducted behavioral tests including the object recognition and Y-maze tests and molecular and histopathological analysis of amyloid precursor protein/a myloid-beta metabolism in brain tissue.We confirmed that radiofrequency electromagnetic field exposure for 6 months ameliorated cognitive impairment and amyloid-β deposition.The expression levels of Iba1(pan-microglial marker) and colony-stimulating factor 1 receptor(CSF1R;regulates microglial prolife ration) in the hippocampus in 5xFAD mice treated with radiofrequency electromagnetic fields were significantly reduced compared with those of the sham-exposed group.Subsequently,we analyzed the expression levels of genes related to mic rogliosis and microglial function in the radiofrequency electromagnetic fields-exposed group compared to those of a CSF1R inhibitor(PLX3397)-treated group.Both radiofrequency electromagnetic fields and PLX3397 suppressed the levels of genes related to microgliosis(Csf1r,CD68,and Ccl6) and pro-inflammatory cytokine interleukin-1β.N otably,the expression levels of genes related to mic roglial function,including Trem2,Fcgr1α,Ctss,and Spi1,were decreased after long-term radiofrequency electromagnetic field exposure,which was also observed in response to microglial suppression by PLX3397.These results showed that radiofrequency electromagnetic fields ameliorated amyloid-β pathology and cognitive impairment by suppressing amyloid-β deposition-induced microgliosis and their key regulator,CSF1R.