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bioRxiv · 10.1101/2020.05.15.098236

Simvastatin Therapy Attenuates Memory Deficits that Associate to Brain Monocyte Infiltration in Chronic Hypercholesterolemic ApoE-/- Mice

Don-Doncow, N.·Matthes, F.·Matuskova, H.·Rattik, S.·Kragh Petersen, S.·Hartlova, A.·Meissner, A.
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Abstract

Evidence associates cardiovascular risk factors with unfavorable systemic and neuro-inflammation and cognitive decline in the elderly. 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. Here, we examined the effect of chronic hypercholesterolemia on inflammation and memory function in Apolipoprotein E (ApoE) knockout mice and normocholesterolemic wild-type mice. Chronic hypercholesterolemia that was accompanied by moderate blood pressure elevations associated with apparent immune system activation characterized by increases in circulating pro-inflammatory Ly6Chi monocytes in ApoE-/- mice. The persistent low-grade immune activation that is associated with chronic hypercholesterolemia facilitates the infiltration of pro-inflammatory Ly6Chi monocytes into the brain of aged ApoE-/- but not wild-type mice, and links to memory dysfunction. Therapeutic cholesterol-lowering through simvastatin reduced systemic and neuro-inflammation, and the occurrence of memory deficits in aged ApoE-/- mice with chronic hypercholesterolemia. BP-lowering therapy alone (i.e., hydralazine) attenuated some neuro-inflammatory signatures but not the occurrence of memory deficits. Our study suggests a link between chronic hypercholesterolemia, myeloid cell activation and neuro-inflammation with memory impairment and encourages cholesterol-lowering therapy as safe strategy to control hypercholesterolemia-associated memory decline during ageing.

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Don-Doncow, N., Matthes, F., Matuskova, H., Rattik, S., Kragh Petersen, S., Hartlova, A., Meissner, A.. 2020-05-16. Simvastatin Therapy Attenuates Memory Deficits that Associate to Brain Monocyte Infiltration in Chronic Hypercholesterolemic ApoE-/- Mice. https://doi.org/10.1101/2020.05.15.098236

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