Ex vivo nerve growth factor gene transfer to the basal forebrain in presymptomatic middle-aged rats prevents the development of cholinergic neuron atrophy and cognitive impairment during aging.

Abstract

Nerve growth factor (NGF) is able to restore spatial learning and reverse forebrain cholinergic neuron atrophy when administered intracerebrally to behaviorally impaired aged rats. In the present study, behaviorally unimpaired, middle-aged rats (14-16 months old) received transplants of ex vivo transduced, clonal NGF-secreting immortalized neural progenitor cells, bilaterally in the nucleus basalis and septum. During the subsequent 9 months the aged control animals developed the expected impairment in spatial learning in the water maze task, whereas the animals with NGF-secreting grafts maintained a performance level not different from the 12-month-old control rats. The marked age-induced atrophy (-25%) of the cholinergic neurons in medial septum and nucleus basalis, seen in the aged control rats, was not present in the NGF-treated aged animals. 3H-labeled thymidine autoradiography showed that the transduced cells survived well and had become integrated into the host tissue surrounding the injection sites, and reverse transcription-PCR analysis revealed expression of the NGF transgene, at both 4 and 9 months postgrafting, in the grafted tissue. The results show that long-term supply of NGF from ex vivo transduced immortalized neural progenitor cells locally within the nucleus basalis and septum can prevent the subsequent development of age-dependent neuronal atrophy and behavioral impairments when the animals reach advanced age.