Memantine inhibits calpain-mediated truncation of GSK-3 induced by NMDA: implications in Alzheimer's disease.
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.
Goñi-Oliver
Paloma
P
Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Fac. Ciencias, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain.
Avila
Jesús
J
Hernández
Félix
F
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D002154:Calpain / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D008875:Middle Aged; D016202:N-Methylaspartate / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D038362:Glycogen Synthase Kinase 3; D002154:Calpain; D008559:Memantine