Amyloid beta-mediated oxidative and metabolic stress in rat cortical neurons: no direct evidence for a role for H2O2 generation.
H2O2 and free radical-mediated oxidative stresses have been implicated in mediating amyloid beta (1-40) [A beta (1-40)] neurotoxicity to cultured neurons. In this study, we confirm that addition of the H2O2-scavenging enzyme catalase protects neurons in culture against A beta-mediated toxicity; however, it does so by a mechanism that does not involve its ability to scavenge H2O2. A beta-mediated elevation in intracellular H2O2 production is suppressed by addition of a potent H2O2 scavenger without any significant neuroprotection. Three intracellular biochemical markers of H2O2-mediated oxidative stress were unchanged by A beta treatment: (a) glyceraldehyde-3-phosphate dehydrogenase activity, (b) hexose monophosphate shunt activity, and (c) glucose oxidation via the tricarboxylic acid cycle. lonspray mass spectra of A beta in the incubation medium indicated that A beta itself is an unlikely source of reactive oxygen species. In this study we demonstrate that intracellular ATP concentration is compromised during the first 24-h exposure of neurons to A beta. Our results challenge a pivotal role for H2O2 generation in mediating A beta toxicity, and we suggest that impairment of energy homeostasis may be a more significant early factor in the neurodegenerative process.
Zhang
Z
Z
Division of CNS Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
Rydel
R E
RE
Drzewiecki
G J
GJ
Fuson
K
K
Wright
S
S
Wogulis
M
M
Audia
J E
JE
May
P C
PC
Hyslop
P A
PA
D000255:Adenosine Triphosphate / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000704:Analysis of Variance; D000818:Animals; D052160:Benzothiazoles; D002374:Catalase / Q000037:antagonists & inhibitors; D002470:Cell Survival; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D004396:Coloring Agents; D005333:Fetus; D005452:Fluoresceins; D016166:Free Radical Scavengers; D005947:Glucose / Q000378:metabolism*; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000378:metabolism; D006019:Glycolysis / Q000187:drug effects; D006038:Glyoxylates / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000494:pharmacology; D010078:Oxazines; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D013844:Thiazoles; D014966:Xanthenes
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D004396:Coloring Agents; D005452:Fluoresceins; D016166:Free Radical Scavengers; D006038:Glyoxylates; D009498:Neurotoxins; D010078:Oxazines; D010446:Peptide Fragments; D017382:Reactive Oxygen Species; D013844:Thiazoles; D014966:Xanthenes; C078592:amyloid beta-protein (1-40); C085925:calcein AM; C101912:4-nitrophenylglyoxylic acid; C005843:resazurin; C009462:thioflavin T; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D005947:Glucose