Neurotrophic factors [activity-dependent neurotrophic factor (ADNF) and basic fibroblast growth factor (bFGF)] interrupt excitotoxic neurodegenerative cascades promoted by a PS1 mutation

Although an excitotoxic mechanism of neuronal injury has been proposed to p lay a role in chronic neurodegenerative disorders such as Alzheimer's disea se, and neuro trophic factors have been put forward as potential therapeuti c agents, direct evidence is lacking. Taking advantage of the fact that mut ations in the presenilin-1 (PS1) gene are causally linked to many cases of early-onset inherited Alzheimer's disease, we generated PS1 mutant knock-in mice and directly tested the excitotoxic and neurotrophic hypotheses of Al zheimer's disease. Primary hippocampal neurons from PSI mutant knock-in mic e exhibited increased production of amyloid beta-peptide 42/43 and increase d vulnerability to excitotoxicity, which occurred in a gene dosage-dependen t manner. Neurons expressing mutant PS1 exhibited enhanced calcium response s to glutamate and increased oxyradical production and mitochondrial dysfun ction, Pretreatment with either basic fibroblast growth factor or activity- dependent neurotrophic factor protected neurons expressing mutant PSI again st excitotoxicity, Both basic fibroblast growth factor and activity-depende nt neurotrophic factor stabilized intracellular calcium levels and abrogate d the increased oxyradical production and mitochondrial dysfunction otherwi se caused by the PSI mutation, Our data indicate that neurotrophic factors can interrupt excitotoxic neurodegenerative cascades promoted by PS1 mutati ons.