Abstract
A large-scale epidemiology study on statins previously showed that simvastatin was unique among statins in reducing the incidence of dementia. Since amyloid beta (Aβ42) is the protein that is most associated with Alzheimer’s disease, this study has focused on how simvastatin influences the turnover of native Aβ42 and Aβ42 fused with green fluorescent protein (GFP), in the simplest eukaryotic model organism, Saccharomyces cerevisiae. Previous studies have established that yeast constitutively producing Aβ42 fused to GFP offer a convenient means of analyzing yeast cellular responses to Aβ42. Young cells clear the GFP fusion protein and do not have green fluorescence while the older population of cells retains the fusion protein and exhibits green fluorescence, offering a fast and convenient means of studying factors that affect Aβ42 turnover. In this study the proportion of cells having GFP fused to Aβ after exposure to simvastatin, atorvastatin and lovastatin was analyzed by flow cytometry. Simvastatin effectively reduced levels of the cellular Aβ42 protein in a dose-dependent manner. Simvastatin promoted the greatest reduction as compared to the other two statins. A comparison with fluconazole, which targets that same pathway of ergosterol synthesis, suggests that effects on ergosterol synthesis do not account for the reduced amounts of Aβ42 fused to GFP. The levels of native Aβ42 following treated with simvastatin were also examined using a more laborious approach, quantitative MALDI TOF mass spectrometry. Simvastatin efficiently reduced levels of native Aβ42 from the population. This work indicates a novel action of simvastatin in reducing levels of Aβ42 providing new insights into how simvastatin exerts its neuroprotective role. We hypothesize that this reduction may be due to protein clearance.
Highlights
IntroductionWidely-prescribed drugs that bind to and inhibit HMG-CoA reductase (HMGCR) reducing the liver’s synthesis of cholesterol (see Figure 1, cholesterol biosynthesis pathway)
Statins are highly effective, widely-prescribed drugs that bind to and inhibit HMG-CoA reductase (HMGCR) reducing the liver’s synthesis of cholesterol
An unpredicted effect was found in a large-scale epidemiology study: simvastatin halved the incidence of Alzheimer’s Disease while there was no similar effect in users of atorvastatin or lovastatin [1,2]
Summary
Widely-prescribed drugs that bind to and inhibit HMG-CoA reductase (HMGCR) reducing the liver’s synthesis of cholesterol (see Figure 1, cholesterol biosynthesis pathway). There has been interest in understanding how simvastatin might exert this effect. The question relates to the mechanism of simvastatin action, and some studies have looked at the effects of statins on Aβ42 production. Inhibition of HMGCR affects some additional pathways, including protein prenylation [3]. One of the proteases leading to the production of Aβ42, BACE, is a prenylated protein. Studies of mammalian cells in culture show that numerous statins inhibit BACE prenylation resulting in less Aβ42 production [4]. In the brain simvastatin may be inhibiting Aβ42 production
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