Neurotrophic factors tactivity-dependent nenrotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)l interrupt excitotoxic neurodegenerative cascades promoted by a PSI mutation

摘要

AlthoUgh an excitotoxic mechanism of neuro- nal injury has been proposed to play a role in chronic neuro- degenerative disorders such as Alzheimer's disease, and neuro- trophic factors have been put forward as potential therapeutic agents, direct evidence is lacking. Taking advantage of the fact that mutations in the presenilin-1 (PSI) gene are causally linked to many cases of earlyonset inherited Alzheimer's disease, we generated PSI mutant knock-in mice and directly tested the excitotoxic and neurotrophic hypotheses of Alzheimer's disease. Primary hippocampal neurons from PSI mutant knock-in mice exhibited increased production of amyloid p-peptide 42/43 and ,increased vulnerability to excitotoxicity, which occurred in a gene dosage-dependent mannen Neurons expressing mutant PSI exhibited enhanced calcium responses to glutamate and in- creased oxyradical production and mitochondrial dysfunction. Pretreatment with either basic fibroblast growth factor or ac- tivity-dependent neurotrophic factor protected neurons express- ing mutant PSI against excitotoxicity. Both basic fibroblast growth factor and activity-dependent neurotrophic factor stabi. Iized intracellular calcium levels and abrogated the increased oxyradical production and mitochondrial dyslitnction otherwise caused by the PSI mutation. Our data indicate that neurotrophic factors can interrupt excitotoxic neurodegenerative cascades promoted by PSI mutations.