Memantine inhibits and reverses the Alzheimer type abnormal hyperphosphorylation of tau and associated neurodegeneration.
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.
Li
Liang
L
Department of Neurochemistry, NYS Institute for Basic Research, 1050 Forest Hill Road, Staten Island, NY 10314-6399, USA.
Sengupta
Amitabha
A
Haque
Niloufar
N
Grundke-Iqbal
Inge
I
Iqbal
Khalid
K
D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000544:Alzheimer Disease / Q000503:physiopathology; D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000201:enzymology; D007736:Kynurenic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D008559:Memantine / Q000494:pharmacology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D009454:Neurofibrils / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D019319:Okadaic Acid / Q000494:pharmacology; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D016875:tau Proteins / Q000378:metabolism*
D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008869:Microtubule-Associated Proteins; D018696:Neuroprotective Agents; D016875:tau Proteins; D019319:Okadaic Acid; D018698:Glutamic Acid; D015763:2-Amino-5-phosphonovalerate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D008559:Memantine