Participation of gene expression in the protection against amyloid β-peptide toxicity by the β-amyloid precursor protein

The amyloid β-peptide (Aβ) is a toxic derivative of the β-amyloid precursor protein. Alternative processing of this precursor also yields large soluble forms (APP(S)s) which are secreted from many cell types. These APP(S)s have neuritogenic and neuroprotective activities; indeed, APP(S)s can protect primary neurons from the toxicity of Aβ itself. To begin to explore the regulation of gene expression by APP(S), we have focused on the NF-κB transcription factor family. NF-κB is induced by conditions of stress, including cellular oxidation. We report that NF-κB can also be induced by APP(S). Furthermore, we effected direct activation of NF-κB through disinhibition using antisense oligonucleotide technology. This means of activating NF-κB resulted in protection of neuroblastoma cells from the toxicity of a calcium ionophore and protection of primary hippocampal neurons from the toxicity of Aβ. Together, these data suggest that NF-κB may exist as a common agent inducing a neuroprotective pattern of gene expression in response to either trophic cytokines or stress itself.