Long-term actions of vector-derived nerve growth factor or brain-derived neurotrophic factor on choline acetyltransferase and trk receptor levels in the adult rat basal forebrain

Trophic factor gene therapy may provide a rational treatment strategy for n eurodegenerative disease. Recombinant adeno-associated virus vectors, incor porating a neuron-specific promoter driving bicistronic expression of green fluorescent protein and either nerve growth factor or brain-derived neurot rophic factor, transduced 10,000-15,000 neurons in the medial septum for pe riods of at least six months. Both cholinergic and non-cholinergic neurons expressed green fluorescent protein. Nerve growth factor and brain-derived neurotrophic factor vectors produced up to 50% increases in immunohistochem ical detection of the acetylcholine-synthesizing enzyme in septal neurons i psilateral to the injection. Increased levels of this enzyme, choline acety ltransferase, persisted for six months with the brain-derived neurotrophic factor vector. The nerve growth factor vector increased Trk receptor immuno reactivity in a volume of brain exceeding that of the transduced cells. Cou nterstaining for the neuronal marker, NeuN, or Nissl substance did not reve al any vector toxicity at any time-point. It therefore appears that the lasting effects of vector-mediated trophic fa ctor gene transfer will offer a new approach for modulating septal choliner gic transmission and Trk receptor activity. (C) 1999 IBRO. Published by Els evier Science Ltd.