Short-term exposure to dietary cholesterol is associated with downregulation of interleukin-15, reduced thigmotaxis and memory impairment in mice

Alzheimer's disease (AD) is a neurodegenerative condition associated with loss of memory function, depression and anxiety. The etiology of AD is poorly understood, but both cholesterol dyshomeostasis and dysregulation of the immune system are contributing factors. Current evidence is consistent with a detrimental effect of excess cholesterol on neuroinflammation, both in mouse models of memory loss and in dementia in humans. However, whether the impact of cholesterol on neuroinflammation occurs early and contributes to pathogenesis of the disease or simply reflects a pleiotropic impact at advanced stages of disease is unclear. To explore this question, we measured, in 9–13 week-old mice, cognitive status and changes in brain inflammatory mediators in response to a short-term high-cholesterol diet. We hypothesized that short-term exposure to excess dietary cholesterol would alter the early inflammatory responses associated with cognitive and/or behavioral impairment. We report that short-term exposure to a high-cholesterol diet led to decreased thigmotaxis and short-term spatial memory impairment without affecting long-term recognition memory. Furthermore, cognitive and behavioral phenotypes in these mice were associated with a reduction in interleukin-15 levels in the absence of changes in other inflammatory mediators. Our findings indicate that interleukin-15 may play a role in early stages of cognitive impairment secondary to hypercholesterolemia. Consequently, optimization of interleukin-15 signaling may be a viable effective cognitive therapy in the population susceptible to developing dementia due to risk factors associated with cholesterol dysregulation.