Lithium chloride increases the production of amyloid-beta peptide independently from its inhibition of glycogen synthase kinase 3.
Glycogen synthase kinase 3 (GSK3) is able to phosphorylate tau at many sites that are found to be phosphorylated in paired helical filaments in Alzheimer disease. Lithium chloride (LiCl) efficiently inhibits GSK3 and was recently reported to also decrease the production of amyloid-beta peptide (Abeta) from its precursor, the amyloid precursor protein. Therefore, lithium has been proposed as a combined therapeutic agent, inhibiting both the hyperphosphorylation of tau and the production of Abeta. Here, we demonstrate that the inhibition of GSK3 by LiCl induced the nuclear translocation of beta-catenin in Chinese hamster ovary cells and rat cultured neurons, in which a decrease in tau phosphorylation was observed. In both cellular models, a nontoxic concentration of LiCl increased the production of Abeta by increasing the beta-cleavage of amyloid precursor protein, generating more substrate for an unmodified gamma-secretase activity. SB415286, another GSK3 inhibitor, induced the nuclear translocation of beta-catenin and slightly decreased Abeta production. It is concluded that the LiCl-mediated increase in Abeta production is not related to GSK3 inhibition.
Feyt
Christine
C
Laboratory of Experimental Pharmacology, Université catholique de Louvain, 1200 Brussels, Belgium.
Kienlen-Campard
Pascal
P
Leroy
Karelle
K
N'Kuli
Francisca
F
Courtoy
Pierre J
PJ
Brion
Jean-Pierre
JP
Octave
Jean-Noël
JN
D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D006224:Cricetinae; D003412:Cricetulus; D003720:Densitometry; D000229:Dependovirus / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D007150:Immunohistochemistry; D018021:Lithium Chloride / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis; D010766:Phosphorylation; D011233:Precipitin Tests; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C093597:amyloid beta-protein precursor 695 (18-38); D016875:tau Proteins; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride