Statin's excitoprotection is mediated by sAPP and the subsequent attenuation of calpain-induced truncation events, likely via rho-ROCK signaling.

Abstract

The widely used cholesterol-lowering drugs, statins, were reported to reduce the incidence of stroke and the progression of Alzheimer's disease. However, little is known on how statins exert these beneficial effects. In this study, we investigated the molecular mechanisms underlying the neuroprotective actions of statins in primary cultured cortical neurons. We found that chronic treatment of neurons with a low dosage of two CNS-permeable statins (lovastatin and simvastatin) selectively reduced NMDA-induced cell death but not the caspase-mediated apoptosis. The protective effects of stains were inhibited by mevalonate, a PI3K inhibitor, and tyrphostin AG538, suggesting roles for cholesterol and insulin/IGF-1 signaling in the neurotoxic response. We further demonstrate that statins block calcium-dependent calpain activation, resulting in complete suppression of protein truncation events on multiple calpain substrates that are involved in neuronal death including CDK5 coactivator p35 cleavage to p25, GSK3 and beta-catenin. This is followed by reduced and increased nuclear translocation of p25 and beta-catenin, respectively. Under excitotoxic conditions, the activities of CDK5 and beta-catenin are exclusively regulated by calpain-mediated cleavage while apoptosis modulates beta-catenin mainly through phosphorylation. Strikingly, our data demonstrate that the calpain-blocking effect of statins is largely mediated by stimulation of alpha-secretase cleavage of APP, resulting in increased secretion of its soluble form, sAPP. Finally, our data suggest that statin-regulated sAPP secretion occurs via activation of the PI3K pathway and inhibition of ROCK signaling. Altogether, our study provides novel insights into statin-mediated neuronal excitoprotection through both cholesterol-dependent and -independent mechanisms and links them to calpain-mediated neuronal death.

• Authors: Tao Ma, YongBo Zhao, Young-Don Kwak, Zhangmin Yang, Robert Thompson, Zhijun Luo, Huaxi Xu, Francesca-Fang Liao
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 29 Issue 36 Pg. 11226-36 (Sep 09 2009) ISSN: 1529-2401 [Electronic] United States
• PMID: 19741129 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Excitatory Amino Acid Agonists
• GRP78 protein, rat
• Heat-Shock Proteins
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Molecular Chaperones
• rho-Associated Kinases
• Calpain

Topics

• Animals
• Calpain (antagonists & inhibitors, pharmacology)
• Cell Line
• Cells, Cultured
• Excitatory Amino Acid Agonists (pharmacology)
• Heat-Shock Proteins (physiology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Molecular Chaperones (physiology)
• Neurons (drug effects, enzymology, physiology)
• Rats
• Rats, Sprague-Dawley
• Signal Transduction (drug effects, physiology)
• rho-Associated Kinases (physiology)