NGF gene transfer to intrinsic basal forebrain neurons increases cholinergic cell size and protects from age-related, spatial memory deficits in middle-aged rats.
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.
Klein
R L
RL
Department of Pharmacology and Therapeutics, Campus Box 100267, JHMHC, Gainesville, FL 32610-0267, USA.
Hirko
A C
AC
Meyers
C A
CA
Grimes
J R
JR
Muzyczka
N
N
Meyer
E M
EM
D000375:Aging / Q000523:psychology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D048429:Cell Size; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D015870:Gene Expression; D018014:Gene Transfer Techniques; D008297:Male; D008568:Memory / Q000502:physiology; D008569:Memory Disorders / Q000517:prevention & control*; D020932:Nerve Growth Factor / Q000235:genetics / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D016548:Prosencephalon / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013028:Space Perception / Q000502:physiology*; D019076:Transgenes / Q000502:physiology
D020932:Nerve Growth Factor; D002795:Choline O-Acetyltransferase