Sex Differences in the Effects of High Fat Diet on Neuroinflammation in a Mouse Model of VCID

Abstract

AbstractBackgroundNeuroinflammation plays a central role in the progression of vascular contributions to cognitive impairment and dementia (VCID). Unfortunately, anti‐inflammatory therapeutics have proven insufficient so far at ameliorating the progression of VCID. This may be because broadly suppressing inflammation prohibits its beneficial functions. Instead, supporting endogenous inflammation resolving programs may prove more effective. Mid‐life metabolic disease is a major risk factor for VCID, particularly in women. Therefore, we examined neuroinflammation at middle‐age in both males and females with VCID. We modeled metabolic disease via long‐term administration of a high fat (HF) diet, and VCID via unilateral carotid artery occlusion surgery which results in chronic cerebral hypoperfusion. We hypothesized that metabolic disease would lead to more adverse cognitive and neuroinflammatory effects in middle‐aged females compared to males in a mouse model of VCID.Method8.5 month old male and female C57BL/6J mice were placed on a HF or control diet for 7 months. At month 3, they received VCID or sham surgery. At month 6, cognitive function was assessed. Half of the brains were collected for histology while the other half were flash frozen for qPCR analysis of pro‐inflammatory and pro‐resolving mediators.ResultHippocampal‐dependent spatial memory was impaired in VCID males, regardless of diet; however, in females, both HF diet and VCID (or a combination of the two) impaired spatial memory. In males, HF diet increased microglial activity in the hippocampus. Additionally, HF diet in combination with VCID surgery increased expression of pro‐inflammatory markers as well as pro‐resolving mediators in males. However, females on a HF diet experienced a suppression of microglia activity in the hippocampus. HF‐fed females, regardless of surgery, had decreased expression of both pro‐inflammatory markers as well as pro‐resolving mediators.ConclusionIn line with clinical findings, these data suggest that metabolic disease increases cognitive deficits to a greater extent in middle‐aged females than males. Further, our data suggest VCID with metabolic disease increases neuroinflammation and its resolution in males, while metabolic disease suppresses neuroinflammation and its resolution in females. This highlights the need for a better understanding of the sex differences in neuroinflammation following vascular injury.