Different amyloidogenic peptides share a similar mechanism of neurotoxicity involving reactive oxygen species and calcium.
The amyloid beta-peptide (A beta) that accumulates as insoluble plaques in the brains of Alzheimer's victims can be neurotoxic, by a mechanism that may involve generation of reactive oxygen species (ROS) and destabilization of cellular calcium homeostasis. We now provide evidence that the mechanism of neurotoxicity of two other amyloidogenic peptides (APs), human amylin and beta 2-microglobulin, also involves induction of ROS and elevation of [Ca2+]i. Human amylin, beta 2-microglobulin and A beta 1-40 all caused significant death of neurons in rat hippocampal cell cultures during 24-48 h exposure periods. Rat amylin, a non-AP, was not neurotoxic. Each AP caused an elevation of rest [Ca2+]i during a 20 h exposure period, and promoted a sustained elevation of [Ca2+]i following exposure to glutamate which was significantly greater than controls. Each AP induced accumulation of ROS in neurons which preceded elevation of [Ca2+]i. Several antioxidants, including propyl gallate, vitamin E and the spin-trapping compound N-tert-butyl-alpha-phenylnitrone attenuated the elevation of [Ca2+]i and neurotoxicity induced by the peptides. The data indicate that different APs share a common mechanism of neurotoxicity involving free radical accumulation and destabilization of [Ca2+]i homeostasis.
Mattson
M P
MP
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
Goodman
Y
Y
D000682:Amyloid / Q000378:metabolism / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D058228:Islet Amyloid Polypeptide; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D014810:Vitamin E / Q000494:pharmacology; D001613:beta 2-Microglobulin / Q000378:metabolism / Q000494:pharmacology
D000682:Amyloid; D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D017382:Reactive Oxygen Species; D001613:beta 2-Microglobulin; D014810:Vitamin E; D018698:Glutamic Acid; D002118:Calcium