Neuron specific toxicity of oligomeric amyloid-β: role for JUN-kinase and oxidative stress.
Recent studies have demonstrated a potential role for oligomeric forms of amyloid-β (Aβ) in the pathogenesis of Alzheimer's disease (AD), although it remains unclear which aspects of AD may be mediated by oligomeric Aβ. In the present study, we found that primary cultures of rat cortical neurons exhibit a dose-dependent increase in cell death following Aβ oligomer administration, while primary cultures of astrocytes exhibited no overt toxicity with even the highest concentrations of oligomer treatment. Neither cell type exhibited toxicity when treated by equal concentrations of monomeric Aβ. The neuron death induced by oligomer treatment was associated with an increase in reactive oxygen species (ROS), altered expression of mitochondrial fission and fusion proteins, and JUN kinase activation. Pharmacological inhibition of JUN kinase ameliorated oligomeric Aβ toxicity in neurons. These data indicate that oligomeric Aβ is sufficient to selectively induce toxicity in neurons, but not astrocytes, with neuron death occurring in a JUN kinase-dependent manner. Additionally, these observations implicate a role for oligomeric Aβ as a contributor to neuronal oxidative stress and mitochondrial disturbances in AD.
Ebenezer
Philip J
PJ
Pennington Biomedical Research Center/Louisiana State University System, Baton Rouge, LA, USA.
Weidner
Adam M
AM
LeVine
Harry
H
Markesbery
William R
WR
Murphy
M Paul
MP
Zhang
Le
L
Dasuri
Kalavathi
K
Fernandez-Kim
Sun Ok
SO
Bruce-Keller
Annadora J
AJ
Gavilán
Elena
E
Keller
Jeffrey N
JN
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology
C511717:AEG 3482; D016229:Amyloid beta-Peptides; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D013830:Thiadiazoles; D048031:JNK Mitogen-Activated Protein Kinases