Transgenic murine cortical neurons expressing human Bcl-2 exhibit increased resistance to amyloid β-peptide neurotoxicity

Abstract

The generation of reactive oxygen species has been implicated in the neurotoxicity of amyloid β-peptide, the main constituent of the senile plaques that accumulates in the brain of Alzheimer's disease victims. In this study, we have compared the toxicity of amyloid β-peptide on cultured cortical neurons from control mice and transgenic mice expressing either human copper–zinc superoxide dismutase or human Bcl-2, two proteins that protect cells against oxidative damage. Copper–zinc superoxide dismutase overexpression failed to protect cortical neurons against the toxicity of amyloid β-peptide(25–35) [the minimal cytotoxic fragment of amyloid β-peptide(1–42)] as assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction and an enzyme-linked immunoabsorbent assay using an antibody directed against microtubule-associated protein-2 (a specific neuronal protein), ruling out a role for superoxide anion and peroxynitrite in amyloid β-peptide-evoked neurotoxicity. On the contrary, cortical neurons expressing human copper–zinc superoxide dismutase exhibited increased apoptotic nuclei in both untreated and amyloid β-peptide(25–35)-exposed neurons. Transgenic neurons expressing human Bcl-2 were partially protected against amyloid β-peptide-induced neuronal death. This neuroprotection appears to be related to the complete inhibition of apoptosis induced by both amyloid β-peptide(25–35) and amyloid β-peptide(1–42). This study may be relevant for developing neuroprotective gene therapy to inhibit neuronal apoptosis in Alzheimer's disease.