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. 2005 Jan 12;25(2):299-307.
doi: 10.1523/JNEUROSCI.2544-04.2005.

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses

Andrew Cordle  1 , Gary Landreth
Affiliations

3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors attenuate beta-amyloid-induced microglial inflammatory responses

Andrew Cordle et al. J Neurosci. .

Abstract

Alzheimer's disease (AD) is characterized by extracellular deposits of fibrillar beta-amyloid (Abeta) in the brain, a fulminant microglial-mediated inflammatory reaction, and neuronal death. The use of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) is associated with a reduced risk of AD, which has been attributed to the cholesterol-lowering actions of these drugs. Statins have been reported recently to have anti-inflammatory actions in addition to their classic lipid-lowering effects. We report that statins robustly inhibited the Abeta-stimulated expression of interleukin-1beta and inducible nitric oxide synthase and the production of nitric oxide by microglia and monocytes. Statin treatment also blocked the rac1-dependent activation of NADPH oxidase and superoxide production. The anti-inflammatory actions of the statins were attributable to their ability to reduce the levels of isoprenyl intermediates in the cholesterol biosynthetic pathway. The effect of statins could not be reversed by exogenous cholesterol supplementation, indicating that the anti-inflammatory actions are distinct from their cholesterol-lowering actions. The addition of the isoprenyl precursors, mevalonic acid, and geranylgeranyl pyrophosphate (GGpp) attenuated the statin-mediated downregulation of inflammatory markers. Prevention of protein isoprenylation by the GGpp transferase inhibitor (GGTI-286) or inhibition of Rho-family function with Clostridium difficile Toxin A blocked the inflammatory response similar to the effect of statin treatment. We argue that the statin-mediated decrease in AD risk arises from their pleiotropic actions, effecting a reduction in neuronal Abeta production and microglia-directed inflammation.

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Figures

Figure 1.
Figure 1.
Statins attenuate IL-1β induction after Aβ stimulation. A, THP-1 cells (3 × 106/condition) were pretreated with increasing concentration of simvastatin for 6 h. After pretreatment, Aβ25-35 (50 μm), LPS (1 μg/ml), or Aβ25-35 and LPS were added to the cells and incubated for 18 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. B, Quantification of pooled experiments was performed (n = 3; *p < 0.05, **p < 0.001 compared with Aβ25-35 plus LPS). C, THP-1 cells (3 × 106/condition) were pretreated with increasing concentration of simvastatin for 18 h. After pretreatment, Aβ25-35 (60 μm) and LPS (500 ng/ml) were added to the cells and incubated for 6 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. D, Quantification of pooled experiments was performed (n = 2; *p < 0.05 compared with Aβ25-35 plus LPS). E, THP-1 cells (3 × 106/condition) were pretreated with increasing concentration of lovastatin for 18 h. After pretreatment, Aβ25-35 (50 μm) and LPS (500 ng/ml) were added to the cells and incubated for 6 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. F, THP-1 cells (3 × 106/condition) were pretreated with increasing concentration of lovastatin for 18 h. After pretreatment, Aβ1-42 (1 μm) and LPS (500 ng/ml) were added to the cells and incubated for 6 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. Veh, Vehicle.
Figure 2.
Figure 2.
Statins attenuate iNOS expression and activity after Aβ stimulation. A, BV-2 cells (1 × 106/condition) were pretreated with increasing concentration of simvastatin for 6 h. After pretreatment, Aβ25-35 (50 μm) and LPS (1 μg/ml) were added to the cells and incubated for 18 h. Cell lysates were separated by Western blotting and probed with anti-iNOS antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. B, Quantification of pooled experiments was performed (n = 3; *p < 0.05 compared with Aβ plus LPS). C, BV-2 cells (5 × 105/condition) were pretreated with increasing concentration of simvastatin for 6 h. After pretreatment, Aβ25-35 (50 μm) and LPS (1 μg/ml) were added to the cells and incubated for 18 h. NO production was measured by Griess reagent and normalized by MTT assay (n = 3; *p < 0.01, **p < 0.001 compared with Aβ plus LPS). Veh, Vehicle.
Figure 3.
Figure 3.
Statins attenuate reactive oxygen species production after Aβ stimulation. BV-2 cells (3.5 × 106/condition) were pretreated with increasing concentration of simvastatin (1-20 μm) for 18 h. After pretreatment, Aβ25-35 (60 μm) and LPS (500 ng/ml) were added to the cells and incubated for 30 min. Production of ROS was determined by NBT assay (n = 2; *p < 0.001 compared with Aβ plus LPS). Veh, Vehicle.
Figure 4.
Figure 4.
Mevalonic acid, but not cholesterol, reverses the anti-inflammatory effects of statins. A, C, THP-1 cells (3 × 106/condition) were pretreated with simvastatin (25 μm) and increasing concentrations of cholesterol (A) or mevalonic acid (C) for 6 h. After pretreatment, Aβ25-35 (50 μm) and LPS (1 μg/ml) were added to the cells and incubated for 18 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. B, D, Quantification of pooled experiments was performed for A and C, respectively (B, n = 3; D, n = 2). Veh, Vehicle.
Figure 5.
Figure 5.
GGpp, but not Fpp, reverses the anti-inflammatory effects of statins. A, C, THP-1 cells (3 × 106/condition) were pretreated with simvastatin (25 μm) and increasing concentrations of GGpp (A) or Fpp (C) for 6 h. After pretreatment, Aβ25-35 (50 μm) and LPS (1 μg/ml) were added to the cells and incubated for 18 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. B, D, Quantification of pooled experiments was performed for A and C, respectively (B, n = 6; *p < 0.05; **p < 0.01; D, n = 2). Veh, Vehicle.
Figure 6.
Figure 6.
Inhibition of isoprenylation attenuates IL-1β induction after Aβ stimulation. A, THP-1 cells (3 × 106/condition) were pretreated with GTI for 6 h. After pretreatment, Aβ25-35 (50 μm) and LPS (1 μg/ml) were added to the cells and incubated for 18 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. B, Quantification of pooled experiments was performed (n = 2; *p < 0.01 compared with Aβ plus LPS). Veh, Vehicle.
Figure 7.
Figure 7.
Inhibition of Rho-family small G-protein function attenuates IL-1β induction after Aβ stimulation. A, THP-1 cells (3 × 106/condition) were pretreated with increasing concentrations of Clostridium difficile Toxin A for 2 h. After pretreatment, the cells were incubated with Aβ25-35 (50 μm) and LPS (1 μg/ml) for an additional 6 h. Cell lysates were separated by Western blotting and probed with anti-IL-1β antibodies. Blots were stripped and reprobed with anti-Erk2 antibodies to monitor protein loading. B, Quantification of pooled experiments was performed (n = 2; *p < 0.05 compared with Aβ plus LPS). Veh, Vehicle.
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