Presentations

Abstract

Background:

Neutrophils are myeloid cells involved in every step of atherosclerosis. The Galkina Lab has shown STAT4, a transcription factor known for driving Th1 and Th17 differentiation, to be critical for neutrophil activation. Recently, we demonstrated that myeloid-specific Stat4 deficient Ldlr-/- mice (Stat4LysMLdlr-/-) have improved plaque stability compared to controls. Increasing evidence suggests that atherosclerosis may be an important risk factor for cognitive impairment. While innate immunity is a known driver for atherosclerosis, its involvement in cognitive decline remains poorly understood. Therefore, we investigated myeloid specific effects of STAT4 deficiency on cognitive performance in atherosclerotic mice. Methods: Stat4LysMLdlr-/- and control Stat4fl/fl Ldlr-/- female and male mice were fed a high- fat/cholesterol diet (DDC) for 28 or 32 weeks. Behavioral analyses, open field, (OF) and Y-maze, were conducted to assess memory and anxiety via Noldus Ethovision XT. During the OF tests, fecal boli counts were collected to measure as an additional anxiety measure.

Results:

32 weeks DDC fed Stat4LysMLdlr-/- female mice showed a significant increase in correct alternations on the Y-maze in comparison with age- and diet- matched Stat4fl/flLdlr-/- controls. Interestingly, DDC feeding for 4 additional weeks resulted in a significant decrease in correct alternations among female Stat4fl/flLdlr-/- mice, implying a decline in spatial recognition memory following extended DDC feeding. It is important to note that male mice showed no significant differences in correct alternations between genotype and/or diet duration. Mice naturally avoid open areas and prefer to stay along the periphery. Decreased center/periphery duration implies increased anxiety. No significant difference was observed in the center/periphery duration among all groups. Additionally, no differences were observed in fecal boli count between groups. Together, these data suggest similar anxiety levels across groups.

Conclusion:

Overall, Stat4LysMLdlr-/- female mice made more correct alternations on the Y-maze compared to control Stat4fl/flLdlr-/- group, which indicates improved cognitive function and memory. Thus, our data suggests that STAT4 in myeloid cells and/or potentially other cells of the brain plays a pathological role for cognitive health that is likely connected with an increased neuroinflammation. Future experiments will be focused on an identification of cell-specific mechanisms by which STAT4 is involved in neuroinflammation in the conditions of atherosclerosis.