Simvastatin Therapy Attenuates Memory Deficits that Associate with Brain Monocyte Infiltration in Chronic Hypercholesterolemia

Abstract

Aims: Metabolic and cardiovascular disease is the most prevalent disease burden in the developed world and risk factors for progressive cognitive decline. Effective treatments for cognitive deficits emanating from cardiovascular disease and its risk factors are missing due to limited understanding of underlying mechanisms. Several lines of evidence suggest association of cardiovascular risk factors to unfavorable immune system activation, neuro-inflammation and cognitive decline. Interestingly, cardiovascular therapeutics (e.g., statins and anti-hypertensive drugs) possess immune-modulatory functions in parallel to their principle cholesterol-or blood pressure-lowering properties. How their ability to modify immune responses affects cognitive function is unknown.Methods and Results: By using multi-color flow cytometry, Elisa, qPCR, Western blotting and novel object recognition tasks, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and aged-matched wild-type (WT) controls. Chronic hypercholesterolemia associated to apparent immune system activation characterized by higher proportions of circulating pro-inflammatory Ly6Chi monocytes across different ages. This persistent low-grade immune activation facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE -/but not WT mice, potentially promoting the development of memory dysfunction associated to chronic hypercholesterolemia. Long-term therapeutic administration of an FDA-approved cholesterol-lowering drug (i.e. simvastatin) significantly reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE -/mice. Conclusion:Our study strongly suggests a causative link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment. Cholesterol-lowering therapy provides aged Apolipoprotein E knockout (ApoE -/-) mice. To this end, we therapeutically administered the antihypertensive agent hydralazine, known to reduce leukocyte migration in spontaneously hypertensive rats, 24 and/or the statin simvastatin that has been attributed a strong anti-inflammatory character by regulating proliferation and activation of macrophages. 25,26 Our findings underscore a causative role of myeloid cell activation in the development of neuro-inflammation associated to chronic hypercholesterolemia as well as cell type-specific drug effects that may limit their efficacy.