Abstract
Epidemiological studies suggest that statins (hydroxymethylglutaryl-CoA reductase inhibitors) could reduce the risk of Alzheimer disease. Although one possible explanation is through an effect on beta-amyloid (Abeta) metabolism, its effect remains to be elucidated. Here, we explored the molecular mechanisms of how statins influence Abeta metabolism. Fluvastatin at clinical doses significantly reduced Abeta and amyloid precursor protein C-terminal fragment (APP-CTF) levels among APP metabolites in the brain of C57BL/6 mice. Chronic intracerebroventricular infusion of lysosomal inhibitors blocked these effects, indicating that up-regulation of the lysosomal degradation of endogenous APP-CTFs is involved in reduced Abeta production. Biochemical analysis suggested that this was mediated by enhanced trafficking of APP-CTFs from endosomes to lysosomes, associated with marked changes of Rab proteins, which regulate endosomal function. In primary neurons, fluvastatin enhanced the degradation of APP-CTFs through an isoprenoid-dependent mechanism. Because our previous study suggests additive effects of fluvastatin on Abeta metabolism, we examined Abeta clearance rates by using the brain efflux index method and found its increased rates at high Abeta levels from brain. As LRP1 in brain microvessels was increased, up-regulation of LRP1-mediated Abeta clearance at the blood-brain barrier might be involved. In cultured brain microvessel endothelial cells, fluvastatin increased LRP1 and the uptake of Abeta, which was blocked by LRP1 antagonists, through an isoprenoid-dependent mechanism. Overall, the present study demonstrated that fluvastatin reduced Abeta level by an isoprenoid-dependent mechanism. These results have important implications for the development of disease-modifying therapy for Alzheimer disease as well as understanding of Abeta metabolism.
Highlights
On the other hand, from basic and clinical reports, statins, which are widely used for the treatment of hypercholesterolemic patients, might be beneficial in Alzheimer disease (AD)
Dual Effects of Statin on A Metabolism effects affects A metabolism in vivo more strongly? Secondly, because the concentration of statin might be important [17], what are the physiological levels of statins at clinically relevant doses and how do statins affect A metabolism at those levels? Thirdly, we previously demonstrated that the protective effect of fluvastatin in an A-induced memory impairment mouse model was associated with reduced A accumulation, suggesting additional effects on A metabolism other than A production [25]
Reduction of A Production by Fluvastatin in Brain through the Lysosomal Degradation of Endogenous amyloid precursor protein C-terminal fragment (APP-CTF) via Enhanced Trafficking of APP-CTFs to Lysosomes—Initially, we investigated the in vivo effects of fluvastatin on A production
Summary
Animals—C57BL/6 mice as well as APP23 transgenic mice were used in this study. APP23 transgenic mice overexpress human APP with Swedish double mutation (KM670/671NL) under the control of Thy-1 promoter [26]. Following centrifugation at 10,000 ϫ g for 15 min at 4 °C, the precipitate was suspended with ice-cold culture medium (10% fetal bovine serum in Dulbecco’s modified Eagle’s medium) and filtered through sterilized glass beads (425– 600 m, acid-washed; Sigma-Aldrich) on a 70-m nylon cell strainer (BD Biosciences, Tokyo, Japan). These glass beads were washed with the culture medium and transferred onto a plastic dish. The density of protein bands was standardized to the density of loading controls and compared with those for control mice, to which 100% was assigned
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