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

The amyloid beta-peptide (A beta) is a toxic derivative of the beta-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 A beta itself. To begin to explore the regulation of gene expression by APP(s), we have focused on the NF-kappa B transcription factor family. NF-kappa B is induced by conditions of stress, including cellular oxidation. We report that NF-kappa B can also be induced by APP(s). Furthermore, we effected direct activation of NE-kappa B through disinhibition using antisense oligonucleotide technology. This means of activating NF-kappa B resulted in protection of neuroblastoma cells from the toxicity of a calcium ionophore and protection of primary hippocampal neurons from the toxicity of A beta. Together, these data suggest that NP-kappa B may exist as a common agent inducing a neuroprotective pattern of gene expression in response to either trophic cytokines or stress itself.