NGF gene transfer to intrinsic basal forebrain neurons increases cholinergic cell size and protects from age-related, spatial memory deficits in middle-aged rats

• Published in: Brain research Vol. 875; no. 1; pp. 144 - 151
• Main Authors: Klein, Ronald L, Hirko, Aaron C, Meyers, Craig A, Grimes, Jeremy R, Muzyczka, Nicholas, Meyer, Edwin M
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 01-09-2000; Amsterdam Elsevier; New York, NY
• Subjects: Adeno-associated virus; Aging - psychology; Animals; Behavior, Animal - drug effects; Behavior, Animal - physiology; Biological and medical sciences; Biotechnology; Cell Size; Choline acetyltransferase; Choline O-Acetyltransferase - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression; Gene therapy; Gene transfer; Gene Transfer Techniques; Health. Pharmaceutical industry; Industrial applications and implications. Economical aspects; Male; Memory - physiology; Memory Disorders - prevention & control; Morris water task; Nerve Growth Factor - genetics; Nerve Growth Factor - pharmacology; Neurons - cytology; Neurons - drug effects; Neurons - enzymology; NGF; Prosencephalon - cytology; Prosencephalon - drug effects; Rats; Rats, Sprague-Dawley; Space Perception - physiology; Transgenes - physiology; Morris water task; Disorders of the nervous system; Adeno-associated virus; Gene transfer; Choline acetyltransferase; Gene therapy; NGF; Cholinergic neuron; Memory disorder; Senescence; Rat; Rodentia; Nerve growth factor; Prosencephalon; Genetic transfer; Vertebrata; Mammalia; Animal; Spatial memory
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/S0006-8993(00)02634-2

Administration of nerve growth factor (NGF) by intracerebroventricular infusion or transplantation of NGF-secreting cells to the basal forebrain improves spatial memory in aged animals. Using the adeno-associated virus (AAV) vector system, basal forebrain neurons were transduced to produce NGF ectopically for long intervals (at least 9 months). Rats received intraseptal injections of either the control vector, pTR-UF4, or the pTR-NGFmyc at 3 months of age, prior to testing their performance in the Morris water task. An age-related decrease in the acquisition of the hidden platform location was found at 12 months of age in the pTR-UF4 control group, but not in the pTR-NGFmyc group. Further, when compared to 3 month old untreated animals, the control group, but not the pTR-NGFmyc group, was impaired at 12 months of age. Concomitant to preventing age-related memory deficits, the NGF gene transfer increased cholinergic neuron size by 34% in the medial septum. This approach may therefore represent a viable therapy for age-related dementia involving dysfunction in cholinergic activity and memory, such as Alzheimer’s disease.