Oxidized low-density lipoprotein induces neuronal death: implications for calcium, reactive oxygen species, and caspases.
Low-density lipoprotein (LDL) exists within the brain and is highly vulnerable to oxidative modifications. Once formed, oxidized LDL (oxLDL) is capable of eliciting cytotoxicity, differentiation, and inflammation in nonneuronal cells. Although oxLDL has been studied primarily for its role in the development of atherosclerosis, recent studies have identified a possible role for it in neurological disorders associated with oxidative stress. In the present study application of oxLDL, but not LDL, resulted in a dose- and time-dependent death of cultured rat embryonic neurons. Studies using pharmacological inhibitors implicate the involvement of calcium, reactive oxygen species, and caspases in oxLDL-induced neuronal death. Coapplication of oxLDL with either amyloid beta-peptide or glutamate, agents that enhance oxidative stress, resulted in increased neuronal death. Taken together, these data demonstrate that oxLDL induces neuronal death and implicate a possible role for oxLDL in conditions associated with increased levels of reactive oxygen species, including Alzheimer's disease.
Keller
J N
JN
Sanders-Brown Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Hanni
K B
KB
Markesbery
W R
WR
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*
D015853:Cysteine Proteinase Inhibitors; D008077:Lipoproteins, LDL; D009842:Oligopeptides; D017382:Reactive Oxygen Species; C108637:aspartyl-glutamyl-valyl-aspartal; C099252:oxidized low density lipoprotein; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; C096429:L 709049; D004533:Egtazic Acid; D016291:Dizocilpine Maleate; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D020169:Caspases; D002118:Calcium