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 play a role in chronic neurodegenerative disorders such as Alzheimer's disease, and neurotrophic factors have been put forward as potential therapeutic agents, direct evidence is lacking. Taking advantage of the fact that mutations 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 Alzheimer's disease. Primary hippocampal neurons from PS1 mutant knock-in mice exhibited increased production of amyloid beta-peptide 42/43 and increased vulnerability to excitotoxicity, which occurred in a gene dosage-dependent manner. Neurons expressing mutant PS1 exhibited enhanced calcium responses to glutamate and increased oxyradical production and mitochondrial dysfunction. Pretreatment with either basic fibroblast growth factor or activity-dependent neurotrophic factor protected neurons expressing mutant PS1 against excitotoxicity. Both basic fibroblast growth factor and activity-dependent neurotrophic factor stabilized intracellular calcium levels and abrogated the increased oxyradical production and mitochondrial dysfunction otherwise caused by the PS1 mutation. Our data indicate that neurotrophic factors can interrupt excitotoxic neurodegenerative cascades promoted by PS1 mutations.
Guo
Q
Q
Sanders-Brown Research Center on Aging and Department of Anatomy and Neurobiology, University of Kentucky, Lexington, KY 40536, USA.
Sebastian
L
L
Sopher
B L
BL
Miller
M W
MW
Glazner
G W
GW
Ware
C B
CB
Martin
G M
GM
Mattson
M P
MP
D000544:Alzheimer Disease / Q000235:genetics* / Q000517:prevention & control*; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000235:genetics*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003433:Crosses, Genetic; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D005786:Gene Expression Regulation; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D017354:Point Mutation; D053764:Presenilin-1; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005609:Free Radicals; D008565:Membrane Proteins; D009498:Neurotoxins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D017382:Reactive Oxygen Species; D018698:Glutamic Acid; D002118:Calcium