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 neurodegenerative disease. Recombinant adeno-associated virus vectors, incorporating a neuron-specific promoter driving bicistronic expression of green fluorescent protein and either nerve growth factor or brain-derived neurotrophic factor, transduced 10,000-15,000 neurons in the medial septum for periods 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 immunohistochemical detection of the acetylcholine-synthesizing enzyme in septal neurons ipsilateral to the injection. Increased levels of this enzyme, choline acetyltransferase, persisted for six months with the brain-derived neurotrophic factor vector. The nerve growth factor vector increased Trk receptor immunoreactivity in a volume of brain exceeding that of the transduced cells. Counterstaining for the neuronal marker, NeuN, or Nissl substance did not reveal any vector toxicity at any time-point. It therefore appears that the lasting effects of vector-mediated trophic factor gene transfer will offer a new approach for modulating septal cholinergic transmission and Trk receptor activity.
Klein
R L
RL
Department of Pharmacology and Therapeutics, University of Florida, Gainesville 32610, USA.
Muir
D
D
King
M A
MA
Peel
A L
AL
Zolotukhin
S
S
Möller
J C
JC
Krüttgen
A
A
Heymach
J V
JV
Muzyczka
N
N
Meyer
E M
EM
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000494:pharmacology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins; D008164:Luminescent Proteins / Q000235:genetics; D009414:Nerve Growth Factors / Q000235:genetics / Q000494:pharmacology*; D016548:Prosencephalon / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D011995:Recombination, Genetic; D013997:Time Factors; D019076:Transgenes / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D008164:Luminescent Proteins; D009414:Nerve Growth Factors; D020801:Receptor, Ciliary Neurotrophic Factor; D017475:Receptors, Nerve Growth Factor; D049452:Green Fluorescent Proteins; D002795:Choline O-Acetyltransferase; D020794:Receptor Protein-Tyrosine Kinases