INVOLVEMENT OF TOLL LIKE RECEPTOR 4 (TLR4) IN THE EFFECT OF HIGH-FAT DIET AND/OR CHRONIC STRESS

QUIROGA SOFIA; MARCONE, MARÍA PAULA; GONZALEZ MURANO, MA ROSA; VIDAL, MARÍA AGUSTINA; GENARO, ANA MARIA; BURGUEÑO, ADRIANA LAURA

Congreso; REUNIÓN CONJUNTA SAIC SAI SAFIS 2022; 2022

High fat diet (HFD) or chronic stress (CS) lead to low-grade inflammation, promoting neuroinflammation and memory impairment in rodents. To analyze the role of the inflammasome NLRP3 in these alterations we compared the effect of HFD and CS in C57Bl/6J (WT) and TLR4 KO mice. We previously found that HFD in WT increases body weight and basal glycemia levels. These results were not observed in KO mice. The aim of this study was to analyze the effect of HFD and/or CS on cognition and gene expression in hippocampus from WT and KO mice. At 4 weeks of age, males received standard diet (SD) or HFD. After 12 weeks, they were exposed (or not) to CS for 8 weeks, resulting in 4 groups for each strain: 1) SD, 2) SD+CS, 3) HFD, and 4) HFD+CS. To assess cognitive performance, we conducted the Object location test (OLT). Hippocampal mRNA expression levels of PYCARD, NLRP3 (components of NLRP3 inflammasome) and NGF, BDNF and SIRT1 (as markers for cognitive deficits) were assess by qPCR. We found that OLT was altered in WT HFD or CS (p<0.05) whereas in KO mice only CS produced a decrease in the discrimination index (DI) (p<0.01). However, the DI in KO was higher than WT in all groups, denoting a better spatial memory. WT HFD showed higher levels of NLRP3 and PYCARD (p<0,01), also CS per se increased levels of both genes (p<0,05). In KO HFD and CS individually produced an increase in NLRP3 mRNA levels (p<0,01 and p<0,05 respectively). In KO NLRP3 showed higher levels of mRNA than in WT (p<0,001), while the opposite occurred with PYCARD (p<0,001). KO HFD+CS showed higher levels of BDNF (p<0,05). In KO SD+CS we observed lower levels of NGF (p<0,01) than KO SD. Also, SIRT1 levels were higher in KO SD and HFD+CS compared with WT mice (p<0,05). These results suggest the involvement of TLR4 in HFD and/or CS in the development of cognitive deficits in WT mice. Further analysis of protein expression will be necessary for a better understanding of the role of TLR4 in this animal model