Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation

Abstract

Normal aging is associated with a significant reduction in cognitive function across primate species. However, the structural and molecular basis for this age-related decline in neural function has yet to be defined clearly. Extensive cell loss does not occur as a consequence of normal aging in human and nonhuman primate species. More recent studies have demonstrated significant reductions in functional neuronal markers in subcortical brain regions in primates as a consequence of aging, including dopaminergic and cholinergic systems, although corresponding losses in cortical innervation from these neurons have not been investigated. In the present study, we report that aging is associated with a significant 25% reduction in cortical innervation by cholinergic systems in rhesus monkeys (P < 0.001). Further, these age-related reductions are ameliorated by cellular delivery of human nerve growth factor to cholinergic somata in the basal forebrain, restoring levels of cholinergic innervation in the cortex to those of young monkeys (P ‫؍‬ 0.89). Thus, (i) aging is associated with a significant reduction in cortical cholinergic innervation; (ii) this reduction is reversible by growth-factor delivery; and (iii) growth factors can remodel axonal terminal fields at a distance, representing a nontropic action of growth factors in modulating adult neuronal structure and function (i.e., administration of growth factors to cholinergic somata significantly increases axon density in terminal fields). These findings are relevant to potential clinical uses of growth factors to treat neurological disorders.aging ͉ Alzheimer's disease ͉ gene therapy ͉ plasticity ͉ cholinergic systems

Increased encapsulated cell biodelivery of nerve growth factor in the brain by transposon-mediated gene transfer

“…NGF also induces sprouting of cholinergic fibres. 4,6 As shown in Figure 3b, we observed a significant increase in sprouting of p75NGFR-immunoreactive fibres around devices with NGF-producing cells. Quantification by image analysis showed significantly more sprouting around devices with NGC0211 cells (2.281 ± 0.142 mm 2 p75NGFR-immunoreactive area per section) than around devices with ARPE-19 cells (0.349±0.027 mm 2 per section) and NGC-0295 cells (1.186 ± 0.063 mm 2 per section), Po0.05.…”

Modulation of neuronal survival and axonal growth in vivo by tetracycline-regulated neurotrophin expression

“…16 To investigate if regulated delivery of neurotrophic factors has effects on neuronal rescue and axonal growth in vivo, we utilized a well-established model of basal forebrain neuron degeneration, the fim- bria-fornix transection, which mimics the cholinergic component of cell loss in Alzheimer's disease. 3,9,[18][19][20][21] Following fimbria-fornix lesions, cholinergic neurons of the medial septal nucleus undergo degeneration over a 2-week period; this degeneration is entirely prevented by grafts of NGF-secreting cells adjacent to the degenerating somata; 3,9,17,22 further, the grafts become penetrated by cholinergic axons, providing an assay of axonal growth responses.…”

“…First, the safety profile of ex vivo gene therapy is improved if the transgene can be turned on and off by oral administration of doxycycline. For certain applications, such as growth factor delivery in Alzheimer's disease, 3,7,9 Parkinson's disease 2 and motor neuron disease (amyotrophic lateral sclerosis), 5,10 the presence of regulatable expression systems would facilitate the translation of these approaches to clinical trials by providing a means of discontinuing gene therapy in the event that adverse effects occur. A clinical trial of ex vivo NGF gene therapy is currently underway in Alzheimer's disease, because adverse effects of long-term constitutive NGF delivery have not been observed in extensive primate studies (M Tuszynski and A Blesch, unpublished data).…”

“…Gene therapy is a potentially effective means of achieving these goals. [1][2][3][4][5][6][7][8] However, the availability of a safe and effective means of controlling transgene expression is a highly desirable feature that would potentially facilitate the translation of gene therapy approaches from promising findings in animal models to humans with Alzheimer's disease, 3,9 Parkinson's disease, 2 and motor neuron disease. 5,10 Such regulatable expression would permit the doses of gene product to be reduced and, if necessary, discontinued in the event that adverse events occurred in the clinical setting.…”

“…Previously in unregulated vector systems, we reported that ex vivo NGF gene delivery prevents the death and reverses the age-related atrophy of adult basal forebrain cholinergic neurons in rodents and primates. 1,3,9,17 In the present study, we examined whether NGF gene delivery using the tetracycline regulatable system would lead to accurate control of cell death and axon growth in the in vivo cholinergic model system in rodents, a correlational model of Alzheimer's disease. In addition, we examined whether long-term control of gene expression in vivo was sustainable in the injured CNS environment.…”