CATECHOLAMINES POTENTIATE AMYLOID BETA-PEPTIDE NEUROTOXICITY - INVOLVEMENT OF OXIDATIVE STRESS, MITOCHONDRIAL DYSFUNCTION, AND PERTURBED CALCIUM HOMEOSTASIS

Oxidative stress and mitochondrial dysfunction are implicated in the n euronal cell death that occurs in physiological settings and in neurod egenerative disorders. In Alzheimer's disease (AD) degenerating neuron s are associated with deposits of amyloid beta-peptide (A beta), and t here is evidence for increased membrane lipid peroxidation and protein oxidation in the degenerating neurons. Cell culture studies have show n that A beta can disrupt calcium homeostasis and induce apoptosis in neurons by a mechanism involving oxidative stress. We now report that catecholamines (norepinephrine, epinephrine, and dopamine) increase th e vulnerability of cultured hippocampal neurons to A beta toxicity. Th e catecholamines were effective in potentiating A beta toxicity at con centrations of 10-200 mu M, with the higher concentrations (100-200 mu M) themselves inducing cell death. Serotonin and acetylcholine were n ot neurotoxic and did not modify A beta toxicity. Levels of membrane l ipid peroxidation, and cytoplasmic and mitochondrial reactive oxygen s pecies, were increased following exposure to neurons to A beta, and ca techolamines exacerbated the oxidative stress. Subtoxic concentrations of catecholamines exacerbated decreases in mitochondrial energy charg e and transmembrane potential caused by A beta, and higher concentrati ons of catecholamines alone induced mitochondrial dysfunction. Antioxi dants (vitamin E, glutathione, and propyl gallate) protected neurons a gainst the damaging effects of A beta and catecholamines, whereas the P-adrenergic receptor antagonist propanolol and the dopamine (D1) rece ptor antagonist SCH23390 were ineffective. Measurements of intracellul ar free Ca2+ ([Ca2+](i)) showed that A beta induced a slow elevation o f [Ca2+]i which was greatly enhanced in cultures cotreated with catech olamines. Collectively, these data indicate a role for catecholamines in exacerbating A beta-mediated neuronal degeneration in AD and, when taken together with previous findings, suggest roles for oxidative str ess induced by catecholamines in several different neurodegenerative c onditions, (C) 1998 Academic Press.