SYNERGISTIC TROPHIC ACTIONS ON RAT BASAL FOREBRAIN NEURONS REVEALED BY A SYNTHETIC NGF BDNF CHIMERIC MOLECULE/

Basal forebrain cholinergic neurons, which degenerate in Alzheimer's d isease, respond to multiple trophic factors, including the neurotrophi ns, nerve growth factor (NGF) and brain-derived neurotrophic factor (B DNF), This dual responsiveness prompted us to investigate the effects of a synthetic chimaeric molecule, containing the active domains of bo th NGF and BDNF. The NGF/BDNF chimaeric factor exhibited synergistic a ctions, 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 additio n of the two wildtype 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 rev ealed a synergy that may normally occur in the brain, and constitutes a potentially novel therapeutic agent with greater potency than natura lly occurring individual trophins.