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

Neuron death in Alzheimer's disease is believed to be triggered by an incre ased production of amyloidogenic beta -amyloid peptides, involving both inc reased oxidative stress and activation of a conserved death program. Bcl-xL , an anti-apoptotic protein of the Bcl-2 family, is expressed at high level s in the adult nervous system. Exposure of neuronal cultures to subtoxic co ncentrations of beta -amyloid peptide 1-40 (1-10 muM) or the fragment 25-35 (1-10 muM) up-regulated both bcl-xL mRNA and Bcl-xL protein levels, determ ined by reverse transcriptase-polymerase chain reaction and western blot an alysis. Bcl-xL protein was also up-regulated during oxidative stress induce d by exposure to hydrogen peroxide (3-100 muM) or ferric ions (1-10 muM). I n contrast, apoptotic stimuli (exposure to staurosporine or serum withdrawa l) actually decreased neuronal Bcl-xL expression. To investigate the role o f Bcl-xL in cell death relevant to Alzheimer's disease, we stably overexpre ssed Bcl-xL in human SH-SY5Y neuroblastoma cells. Cells overexpressing Bcl- xL were significantly protected from beta -amyloid neurotoxicity and stauro sporine-induced apoptosis compared to vector-transfected controls. In contr ast, Bcl-xL overexpression only confered a mild protection against oxidativ e injury induced by hydrogen peroxide. We conclude that up-regulation of Bcl-xL expression in response to subtoxic concentrations of beta -amyloid is a stress response that increases the re sistance of neurons to beta -amyloid neurotoxicity primarily by inhibiting apoptotic processes. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.