Abstract
Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, reduces the clinical deterioration in moderate-to-severe Alzheimer disease (AD) for which other treatments are not available. The activity of protein phosphatase (PP)-2A is compromised in AD brain and is believed to be a cause of the abnormal hyperphosphorylation of tau and the consequent neurofibrillary degeneration. Here we show that memantine inhibits and reverses the PP-2A inhibition-induced abnormal hyperphosphorylation and accumulation of tau in organotypic culture of rat hippocampal slices. Such restorative effects of memantine were not detected either with 5,7-dichlorokynurenic acid or with D(-)-2-amino-5-phosphopentanoic acid, NMDA receptor antagonists active at the glycine binding site and at the glutamate binding site, respectively. These findings show (1) that memantine inhibits and reverses the PP-2A inhibition-induced abnormal hyperphosphorylation of tau/neurofibrillary degeneration and (2) that this drug might be useful for the treatment of AD and related tauopathies.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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2-Amino-5-phosphonovalerate / pharmacology
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Alzheimer Disease / physiopathology
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Animals
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Enzyme Inhibitors / pharmacology
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Excitatory Amino Acid Antagonists / pharmacology
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Glutamic Acid / pharmacology
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Hippocampus / enzymology
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Kynurenic Acid / analogs & derivatives*
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Kynurenic Acid / pharmacology
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Memantine / pharmacology*
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Microtubule-Associated Proteins / metabolism
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Nerve Degeneration / drug therapy*
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Nerve Degeneration / metabolism*
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Nerve Degeneration / physiopathology
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Neurofibrils / drug effects
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Neurofibrils / pathology
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Neuroprotective Agents / pharmacology*
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Okadaic Acid / pharmacology
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Phosphoprotein Phosphatases / antagonists & inhibitors
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Phosphoprotein Phosphatases / metabolism
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Phosphorylation / drug effects
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Rats
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Rats, Wistar
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tau Proteins / metabolism*
Substances
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Enzyme Inhibitors
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Excitatory Amino Acid Antagonists
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Microtubule-Associated Proteins
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Neuroprotective Agents
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tau Proteins
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Okadaic Acid
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Glutamic Acid
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2-Amino-5-phosphonovalerate
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Calcium-Calmodulin-Dependent Protein Kinase Type 2
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Calcium-Calmodulin-Dependent Protein Kinases
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Phosphoprotein Phosphatases
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Kynurenic Acid
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5,7-dichlorokynurenic acid
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Memantine