A role for 4-hydroxynonenal, an aldehydic product of lipid peroxidation, in disruption of ion homeostasis and neuronal death induced by amyloid beta-peptide.
Peroxidation of membrane lipids results in release of the aldehyde 4-hydroxynonenal (HNE), which is known to conjugate to specific amino acids of proteins and may alter their function. Because accumulating data indicate that free radicals mediate injury and death of neurons in Alzheimer's disease (AD) and because amyloid beta-peptide (A beta) can promote free radical production, we tested the hypothesis that HNE mediates A beta 25-35-induced disruption of neuronal ion homeostasis and cell death. A beta induced large increases in levels of free and protein-bound HNE in cultured hippocampal cells. HNE was neurotoxic in a time- and concentration-dependent manner, and this toxicity was specific in that other aldehydic lipid peroxidation products were not neurotoxic. HNE impaired Na+, K(+)-ATPase activity and induced an increase of neuronal intracellular free Ca2+ concentration. HNE increased neuronal vulnerability to glutamate toxicity, and HNE toxicity was partially attenuated by NMDA receptor antagonists, suggesting an excitotoxic component to HNE neurotoxicity. Glutathione, which was previously shown to play a key role in HNE metabolism in nonneuronal cells, attenuated the neurotoxicities of both A beta and HNE. The antioxidant propyl gallate protected neurons against A beta toxicity but was less effective in protecting against HNE toxicity. Collectively, the data suggest that HNE mediates A beta-induced oxidative damage to neuronal membrane proteins, which, in turn, leads to disruption of ion homeostasis and cell degeneration.
Mark
R J
RJ
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Lovell
M A
MA
Markesbery
W R
WR
Uchida
K
K
Mattson
M P
MP
D000447:Aldehydes / Q000378:metabolism / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D005978:Glutathione / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D007477:Ions; D008054:Lipid Peroxides / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology; D009498:Neurotoxins / Q000494:pharmacology; D011435:Propyl Gallate / Q000494:pharmacology; D051381:Rats / Q000196:embryology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism
D000447:Aldehydes; D016229:Amyloid beta-Peptides; D007477:Ions; D008054:Lipid Peroxides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D011435:Propyl Gallate; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; C027576:4-hydroxy-2-nonenal