Statins of Different Brain Penetrability Differentially Affect CSF PLTP Activity

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Abstract
Background/Aims: Phospholipid transfer protein (PLTP) and apolipoprotein E (apoE) are key proteins involved in lipoprotein metabolism in the peripheral circulation and in the brain. Several epidemiological studies suggested that use of 3-hydroxyl-3-methylglutaryl-coenzyme A reductase inhibitors (statins) reduces risk of Alzheimer’s disease (AD). However, the effects of statins of differing blood-brain barrier (BBB) penetrability on brain-derived molecules in cognitively normal individuals are largely unknown. Methods: To assess the effect of statins on these indices as a function of BBB penetration, cerebrospinal fluid (CSF) and plasma PLTP activity and apoE concentration were measured in cognitively intact, modestly hypercholesterolemic adults randomly allocated to treatment with either pravastatin, which does not penetrate BBB (80 mg/day, n = 13), or simvastatin, which penetrates BBB (40 mg/day, n = 10). Results: Simvastatin significantly increased CSF PLTP activity (p = 0.005). In contrast, pravastatin had no such effect. In the pravastatin-treated group, CSF apoE concentration decreased significantly (p = 0.026), while the simvastatin-treated group showed a tendency towards lower CSF apoE levels, with CSF apoE concentration lowered in 8 of 10 subjects. Conclusion: Our data indicate that statins differentially affect two key lipid transfer proteins in the brain, and that effect on PLTP activity depends on statin BBB penetrability.