Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration

FEBS Lett. 2004 May 21;566(1-3):261-9. doi: 10.1016/j.febslet.2004.04.047.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 2-Amino-5-phosphonovalerate / pharmacology
  • Alzheimer Disease / physiopathology
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases / antagonists & inhibitors
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Enzyme Inhibitors / pharmacology
  • Excitatory Amino Acid Antagonists / pharmacology
  • Glutamic Acid / pharmacology
  • Hippocampus / enzymology
  • Kynurenic Acid / analogs & derivatives*
  • Kynurenic Acid / pharmacology
  • Memantine / pharmacology*
  • Microtubule-Associated Proteins / metabolism
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / metabolism*
  • Nerve Degeneration / physiopathology
  • Neurofibrils / drug effects
  • Neurofibrils / pathology
  • Neuroprotective Agents / pharmacology*
  • Okadaic Acid / pharmacology
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism
  • Phosphorylation / drug effects
  • Rats
  • Rats, Wistar
  • tau Proteins / metabolism*

Substances

  • Enzyme Inhibitors
  • Excitatory Amino Acid Antagonists
  • Microtubule-Associated Proteins
  • Neuroprotective Agents
  • tau Proteins
  • Okadaic Acid
  • Glutamic Acid
  • 2-Amino-5-phosphonovalerate
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Phosphoprotein Phosphatases
  • Kynurenic Acid
  • 5,7-dichlorokynurenic acid
  • Memantine