Synergistic trophic actions on rat basal forebrain neurons revealed by a synthetic NGF/BDNF chimaeric molecule.
Basal forebrain cholinergic neurons, which degenerate in Alzheimer's disease, respond to multiple trophic factors, including the neurotrophins, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). This dual responsiveness prompted us to investigate the effects of a synthetic chimaeric molecule, containing the active domains of both NGF and BDNF. The NGF/BDNF chimaeric factor exhibited synergistic actions, and was 100-fold more potent than wild-type BDNF in enhancing survival of cultured dissociated basal forebrain cholinergic neurons. This effect was apparently due to true BDNF/NGF synergy, since addition of the two wild-type trophins simultaneously reproduced the effect of the chimaera. Synergy was selective for neurons which respond to both factors; substantia nigra dopaminergic neurons, which respond to BDNF but not NGF, exhibited no potentiation. The chimaeric factor thus revealed a synergy that may normally occur in the brain, and constitutes a potentially novel therapeutic agent with greater potency than naturally occurring individual trophins.
Friedman
W J
WJ
Department of Neuroscience and Cell Biology, UMDNJ/Robert Wood Johnson Medical School, Piscataway, USA.
Black
I B
IB
Persson
H
H
Ibáñez
C F
CF
D000818:Animals; D001479:Basal Ganglia / Q000166:cytology / Q000502:physiology*; D019208:Brain-Derived Neurotrophic Factor; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D006651:Histocytochemistry; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009620:Nodose Ganglion / Q000166:cytology; D010275:Parasympathetic Nervous System / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D010641:Phenotype; D010766:Phosphorylation; D011247:Pregnancy; D016548:Prosencephalon / Q000166:cytology / Q000502:physiology*; D011487:Protein Conformation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011993:Recombinant Fusion Proteins; D005680:gamma-Aminobutyric Acid; D011505:Protein-Tyrosine Kinases