TY - JOUR T1 - Statin's Excitoprotection Is Mediated by sAPP and the Subsequent Attenuation of Calpain-Induced Truncation Events, Likely via Rho-ROCK Signaling JF - The Journal of Neuroscience JO - J. Neurosci. SP - 11226 LP - 11236 DO - 10.1523/JNEUROSCI.6150-08.2009 VL - 29 IS - 36 AU - Tao Ma AU - YongBo Zhao AU - Young-Don Kwak AU - Zhangmin Yang AU - Robert Thompson AU - Zhijun Luo AU - Huaxi Xu AU - Francesca-Fang Liao Y1 - 2009/09/09 UR - http://www.jneurosci.org/content/29/36/11226.abstract N2 - 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 β-catenin. This is followed by reduced and increased nuclear translocation of p25 and β-catenin, respectively. Under excitotoxic conditions, the activities of CDK5 and β-catenin are exclusively regulated by calpain-mediated cleavage while apoptosis modulates β-catenin mainly through phosphorylation. Strikingly, our data demonstrate that the calpain-blocking effect of statins is largely mediated by stimulation of α-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. ER -