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.