Up-regulation of Bcl-xL in response to subtoxic β-amyloid: role in neuronal resistance against apoptotic and oxidative injury

Neuron death in Alzheimer’s disease is believed to be triggered by an increased production of amyloidogenic β-amyloid peptides, involving both increased oxidative stress and activation of a conserved death program. Bcl-xL, an anti-apoptotic protein of the Bcl-2 family, is expressed at high levels in the adult nervous system. Exposure of neuronal cultures to subtoxic concentrations of β-amyloid peptide 1–40 (1–10 μM) or the fragment 25–35 (1–10 μM) up-regulated both bcl-xL mRNA and Bcl-xL protein levels, determined by reverse transcriptase–polymerase chain reaction and western blot analysis. Bcl-xL protein was also up-regulated during oxidative stress induced by exposure to hydrogen peroxide (3–100 μM) or ferric ions (1–10 μM). In contrast, apoptotic stimuli (exposure to staurosporine or serum withdrawal) actually decreased neuronal Bcl-xL expression. To investigate the role of Bcl-xL in cell death relevant to Alzheimer’s disease, we stably overexpressed Bcl-xL in human SH-SY5Y neuroblastoma cells. Cells overexpressing Bcl-xL were significantly protected from β-amyloid neurotoxicity and staurosporine-induced apoptosis compared to vector-transfected controls. In contrast, Bcl-xL overexpression only confered a mild protection against oxidative injury induced by hydrogen peroxide. We conclude that up-regulation of Bcl-xL expression in response to subtoxic concentrations of β-amyloid is a stress response that increases the resistance of neurons to β-amyloid neurotoxicity primarily by inhibiting apoptotic processes.