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CELLULAR AND MOLECULAR

HMG-CoA Reductase Inhibitor Simvastatin Inhibits Cell Cycle Progression at the G₁/S Checkpoint in Immortalized Lymphocytes from Alzheimer's Disease Patients Independently of Cholesterol-Lowering Effects

Department of Cellular and Molecular Pathophysiology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Cientificas, Madrid, Spain (S.G.S., U.M., F.B., A.M.R.); and Hospital Doce de Octubre, Madrid, Spain (F.B.)

Recent work has suggested that statins may exert beneficial effects on patients suffering from Alzheimer's disease (AD). The pharmacological effects of statins extend beyond their cholesterol-lowering properties. Based on the antineoplastic and apoptotic effects of statins in several cell types, we hypothesized that statins may be able to protect neurons by controlling the regulation of cell cycle. A growing body of evidence indicates that neurodegeneration involves the activation of cell cycle machinery in postmitotic neurons. We and others have presented direct evidence to support the hypothesis that the failure of cell cycle control is not restricted to neurons in AD patients, but that it occurs in peripheral cells as well. For these reasons, we found it worthy to study the role of simvastatin on cell proliferation in immortalized lymphocytes from AD patients. We report here that simvastatin (SIM) inhibits the serum-mediated enhancement of cell proliferation in AD by blocking the events critical for G₁/S transition. SIM induces a partial blockade of retinoblastoma protein phosphorylation and inhibition of cyclin E/cyclin-dependent kinase (CDK)2 activity associated with increased levels of the CDK inhibitors p21^Cip1 and p27^kip1. These effects of SIM on AD lymphoblasts are dependent on inhibition of the proteasome-mediated degradation of p21 and p27 proteins. The antiproliferative effect of this natural statin may provide a therapeutic approach for AD disease.

Address correspondence to: Dr.Ángeles Martín-Requero, Centro de Investigaciones Biológicas, Ramiro de Maeztu 9, 28040 Madrid, Spain. E-mail: amrequero{at}cib.csic.es