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 (APPSs) which are secreted from many cell types. These APPSs have neuritogenic and neuroprotective activities; indeed, APPSs can protect primary neurons from the toxicity of A beta itself. To begin to explore the regulation of gene expression by APPS, 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 APPS. Furthermore, we effected direct activation of NF-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 NF-kappa B may exist as a common agent inducing a neuroprotective pattern of gene expression in response to either trophic cytokines or stress itself.
Barger
S W
SW
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536, USA.
Mattson
M P
MP
D016229:Amyloid beta-Peptides / Q000506:poisoning*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004586:Electrophoresis; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D015345:Oligonucleotide Probes / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D010446:Peptide Fragments / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016328:NF-kappa B; D018696:Neuroprotective Agents; D015345:Oligonucleotide Probes; D016376:Oligonucleotides, Antisense; D010446:Peptide Fragments