Affiliations: Centro de Biología Molecular “Severo Ochoa”, CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, Madrid, Spain
Correspondence:
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Address for correspondence: Félix Hernández, Centro de Biología Molecular “Severo Ochoa”, CSIC/UAM, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain. Tel.: +34 91 196 45 63; Fax: +34 91 196 44 20; E-mail: fhernandez@cbm.uam.es.
Abstract: Deregulation of glycogen synthase kinase-3 (GSK-3) activity is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). GSK-3 activity is regulated by phosphorylation and through interaction with GSK-3-binding proteins. Previously, we demonstrated that calpain activation produces a truncation of GSK-3. In this study, we show that calpain-mediated GSK-3 truncation, induced by N-methyl-D-aspartic acid (NMDA), depends on extracellular calcium. Primary cultures of cortical neurons treated with NMDA reduce GSK-3 levels up to 75%, although the truncated form of GSK-3 does not accumulate, suggesting that a short-lived product is formed. The data obtained with human AD samples suggest that, although a great variability exists at least in postmortem samples, truncated GSK-3 does not accumulate. However, memantine, a non-competitive NMDA receptor which has been approved for the treatment of moderate to severe AD, is able to inhibit GSK-3 truncation induced by NMDA in primary cultures of cortical neurons in a dose-dependent manner. Thus, memantine modulates GSK-3 signaling, which might explain its protective role in AD. Overall, our data reinforces the important relationship between NMDA receptors and GSK-3 and their involvement as one of the first steps in neurodegenerative diseases such as AD.
