Induction of neuroprotective κB-dependent transcription by secreted forms of the Alzheimer's β-amyloid precursor

A significant fraction of the β-amyloid precursor protein is proteolytically processed to yield large secreted forms (sAPP). These proteins have pleiotropic effects which potentially involve control of gene expression. We have investigated the influence of sAPP on the class of transcription factors which bind κB enhancer sequences. Transcription dependent on a κB element was enhanced by sAPP in several cell lines, as measured by expression of a transfected chloramphenicol acetyltransferase reporter gene. Secreted APP also induced an increase in κB DNA-binding activity in hippocampal neurons treated with sAPP. Both effects were mimicked by an analog of cyclic GMP and inhibited by an antagonist of cyclic GMP-dependent protein kinase. Such activation of κB-dependent transcription was correlated in two ways with the ability of sAPP to protect neuronal cells against calcium-mediated damage: (1) tumor necrosis factor β also protected against calcium-mediated insults and induced κB-dependent transcription; (2) antisense oligonucleotide-mediated reduction of an endogenous inhibitor of NF-κB activated κB-binding activity and attenuated calcium-mediated toxicity in both a neuronal cell line and in primary neurons. These findings suggest that a κB-binding transcription factor can act as a coordinator of neuroprotective gene expression in response to cytokines.