Abstract
Lithium is one of the most widely used mood-stabilizing agents for the treatment of bipolar disorder. Lithium is also a potent inhibitor of glycogen synthase kinase-3β (GSK3β) activity, which is linked to Alzheimer's disease (AD). In experiments with cultured HEK293T cells, we show here that GSK3β stabilizes synaptic acetylcholinesterase (AChE-S), a critical component of AD development. Cells treated with lithium exhibited rapid proteasomal degradation of AChE-S. Furthermore treatment of the cells with MG132, an inhibitor of the 26S proteasome, prevented the destabilizing effect of lithium on AChE-S. Taken together, these findings suggest that regulation of AChE-S protein stability may be an important biological target of lithium therapy.
Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acetylcholinesterase / genetics*
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Acetylcholinesterase / metabolism*
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Alzheimer Disease / drug therapy
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Alzheimer Disease / enzymology
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Amino Acid Substitution
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Animals
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Enzyme Inhibitors / pharmacology
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Enzyme Stability / drug effects
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GPI-Linked Proteins / genetics
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GPI-Linked Proteins / metabolism
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 beta
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HEK293 Cells
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Humans
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Leupeptins / pharmacology
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Lithium / pharmacology*
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Mutagenesis, Site-Directed
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PC12 Cells
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Proteasome Endopeptidase Complex / metabolism*
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Rats
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
Substances
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Enzyme Inhibitors
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GPI-Linked Proteins
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Leupeptins
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Recombinant Proteins
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Lithium
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Gsk3b protein, rat
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Glycogen Synthase Kinase 3
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ACHE protein, human
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Acetylcholinesterase
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Ache protein, rat
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Proteasome Endopeptidase Complex
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benzyloxycarbonylleucyl-leucyl-leucine aldehyde