Memantine prevents sensitivity to excitotoxic cell death of rat cortical neurons expressing human truncated tau protein.
We have previously shown that human misfolded tau proteins strongly perturb mitochondrial transport and induce accumulation of free radicals in neurons. This interference is underlying cause of increased susceptibility to oxidative stress and could be linked to excitotoxic pathways. In order to understand integral mechanisms of misfolded tau driven neurodegeneration, we have investigated the role of human truncated tau protein, derived from Alzheimer's disease, in rat cortical neurons under the conditions of excitotoxic stress induced by glutamate. We found that primary neurons expressing truncated tau protein are highly susceptible to glutamate-induced cell death. Pre-treatment with memantine (N-methyl-D-aspartate receptor antagonist) significantly improved survival of rat neurons exposed to glutamate and its effect was associated with overall decrease of reactive oxygen species (ROS) in both transgenic and nontransgenic neurons. Interestingly, despite of this overall effect, memantine was not able to decrease misfolded tau-induced ROS level specifically in transgenic cells. Our data suggest that memantine does not interfere with specific pathological pathways induced by misfolded tau protein nevertheless is able to attenuate oxidative stress in neurons.
Cente
Martin
M
Institute of Neuroimmunology, Slovak Academy of Sciences, 845 10 Bratislava, Slovakia.
Mandakova
Stanislava
S
Filipcik
Peter
P
D000818:Animals; D018929:Cell Culture Techniques; D016923:Cell Death / Q000187:drug effects*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology*; D018698:Glutamic Acid / Q000633:toxicity; D006624:Hippocampus / Q000473:pathology*; D008559:Memantine / Q000494:pharmacology*; D009474:Neurons / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000633:toxicity; D051381:Rats; D055647:Rats, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism*
D018696:Neuroprotective Agents; D009498:Neurotoxins; D017382:Reactive Oxygen Species; D016875:tau Proteins; D018698:Glutamic Acid; D008559:Memantine