Functional mitochondria are required for amyloid β‐mediated neurotoxicity

Abstract

ABSTRACT The role of mitochondria in amyloid βpeptide (Aβ)‐induced cytotoxicity is unclear. We therefore exposed NT2 cells, a clonal human teratocarcinoma cell line capable of differentiation into terminal neurons, to Aβ 25–35 or to Aβ 1–42 to evaluate cell viability and altered mitochondrial function. A 24‐h incubation of native NT2 cells (ρ+ cells) with Aβ 25–35 or with Aβ 1–42 produced a dose‐dependent decline in MTT reduction. Aβ 1–42 was shown to be more toxic compared with Aβ 25–35. Aβ 25–35 toxicity was prevented or diminished by a 22‐h preincubation with antioxidants (vitamin E, melatonin, and idebenone), as well as by simultaneous incubation with GSH or the nicotinic receptor agonist nicotine. Aβ 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 (ρ0 cells) were unaffected by exposure to Aβ 25–35 or Aβ 1–42. These data indicate that Aβ can disrupt mitochondrial function and that such disruption causes oxidative stress. It is further suggested that a functional mitochondrial respiratory chain is required for Aβ toxicity.