Reversal of age-dependent cognitive impairments and cholinergic neuron atrophy by NGF-secreting neural progenitors grafted to the basal forebrain.

ABSTRACT

A highly NGF-secreting cell line was generated by retroviral transduction of a conditionally immortalized CNS-derived neural progenitor cell line. After transplantation to the nucleus basalis magnocellularis (NBM), the cells continue to express the NGF transgene for at least 10 weeks, producing sufficient NGF to reverse cholinergic neuron atrophy in aged rats and induce cellular hypertrophy in young rats. In cognitively impaired aged rats, transplants of the NGF-secreting cells placed either in the NBM and septum or in only the NBM induced a near-complete reversal of the spatial learning impairment. This was accompanied by a normalization of the size of the cholinergic neurons in the grafted areas. The results demonstrate that locally increased supply of NGF to the basal forebrain cholinergic nuclei has a significant impact on cognitive function and support the usefulness of neural progenitor cells for a long-term localized delivery of neurotrophins to the CNS.