Simvastatin Therapy Attenuates Memory Deficits that Associate to Brain
Monocyte Infiltration in Chronic Hypercholesterolemic ApoE-/- Mice
Abstract
Background and Purpose: Metabolic and cardiovascular disease is the most
prevalent disease burden in the world and risk factor for progressive
cognitive decline. Evidence associates cardiovascular risk factors to
unfavorable systemic and neuro-inflammation and to cognitive decline.
Cardiovascular therapeutics (e.g., statins and anti-hypertensives)
possess immune-modulatory functions in parallel to their cholesterol- or
blood pressure (BP)-lowering properties. How their ability to modify
immune responses affects cognitive function is unknown. Experimental
Approach: By using flow cytometry, Elisa, qPCR, Western blotting and
object recognition tasks, we examined the effect of chronic
hypercholesterolemia on inflammation and memory function in
Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type
mice. Key results: Chronic hypercholesterolemia associated to moderate
BP elevations and apparent immune system activation characterized by
increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/-
mice. The persistent low-grade immune activation associated to chronic
hypercholesterolemia facilitates the infiltration of pro-inflammatory
Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice,
linking to memory dysfunction. Therapeutic administration of
cholesterol-lowering simvastatin reduced BP, systemic and
neuro-inflammation, and the occurrence of memory deficits in aged
ApoE-/- mice. BP-lowering therapy alone (i.e. hydralazine) attenuated
some neuro-inflammatory signatures but not the occurrence of memory
deficits. When administered in combination, it reduced effectiveness of
statin therapy in some instances. Conclusions and Implications: Our
study suggests a link between chronic hypercholesterolemia, myeloid cell
activation and neuro-inflammation with memory impairment.
Cholesterol-lowering therapy provides effectiveness to attenuate memory
impairment and inflammatory events and hence, emerges as safe
therapeutic strategy to control hypercholesterolemia-associated memory
decline.