Functional mitochondria are required for amyloid β-mediated neurotoxicity

The role of mitochondria. in amyloid betapeptide (Abeta)-induced cytotoxicity is unclear. We therefore exposed NT2 cells, a clonal human teratocarcinoma cell line capable of differentiation into terminal neurons, to Abeta 25-35 or to Abeta 1-42 to evaluate cell viability and altered mitochondrial function. A 24-h incubation of native NT2 cells (rho+ cells) with Abeta 25-35 or with Abeta 1-42 produced a dose-dependent decline in MTT reduction. Abeta 1-42 was shown to be more toxic compared with Abeta 25-35. Abeta 25-35 toxicity was prevented or diminished by a 22-h preincubation with antioxidants (vitamin E, metatonin, and idebenone), as well as by simultaneous incubation with GSH or the nicotinic receptor agonist nicotine. Abeta 25-35 exposure was also associated with (1) inhibition of mitochondrial respiratory chain complexes (I, NADH-ubiquinone oxidoreductase; II/III, succinate-cytochrome c oxidoreductase; and IV, cytochrome c oxidase), (2) ATP depletion, and (3) reduction of the mitochondrial membrane potential. In contrast, NT2 cells rendered incapable of oxidative phosphorylation via depletion of their mitochondrial DNA (rho0 cells) were unaffected by exposure to Abeta 25-35 or Abeta 1-42. These data indicate that Abeta can disrupt mitochondrial function and that such disruption causes oxidative stress. It is further suggested that a functional mitochondrial respiratory chain is required for Abeta toxicity.