Journal
NEUROCHEMISTRY INTERNATIONAL
Volume 62, Issue 4, Pages 433-445Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuint.2013.01.026
Keywords
Atorvastatin; Excitotoxicity; GGTase-I beta; Rac1; alpha N-catenin; Neuroprotection; Neuronal plasticity
Categories
Funding
- CODI Young Researcher Programme
- Colciencias [111545921467]
- CODI
- University of Antioquia, Colombia [TE20075]
- Advanced Microscopy Unit
- Viral Vector Core and Gene Therapy from the Group of Neuroscience of Antioquia, University of Antioquia
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Statins are widely used cholesterol-lowering drugs that may reduce the incidence of stroke and the progression of Alzheimer's disease (AD). However, how statins exert these beneficial effects remains poorly understood. Thus, this study evaluated the roles of Rac1 geranylgeranylation and the relationship between Rac1 and alpha N-catenin in the protective activity of atorvastatin (ATV) in a cortical neuronal culture model of glutamate (GLU) excitotoxicity. We found that ATV-induced neuroprotection and plasticity were blocked by isoprenoids, such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), inhibition of farnesylation (FTI-277) and geranylgeranylation (GGTI-286), down-regulation of GGTase-I beta and Rac activity and promotion of active RhoA. Additionally, ATV rescued the distribution of dendritic alpha N-catenin and increased the number and length of dendritic branches; these effects were reversed by GGTI-286, GGTase-I beta shRNA, Rac1 shRNA and a dominant-negative version of Rac1 (T17N). In summary, our findings suggest that ATV requires GGTase-I beta, prenylation and active Rac1 to induce protection and plasticity. In this regard, a alpha N-catenin is a marker for stable interactions between adhesion proteins and the actin cytoskeleton and is necessary for the neuroprotective action of ATV. (C) 2013 Elsevier Ltd. All rights reserved.
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