The aged monkey basal forebrain: rescue and sprouting of axotomized basal forebrain neurons after grafts of encapsulated cells secreting human nerve growth factor.

Abstract

Six Rhesus monkeys between 24 and 29 years of age received unilateral transections of the fornix. Three monkeys then received intraventricular transplants of polymer-encapsulated baby hamster kidney (BHK) fibroblasts that had been genetically modifled to secrete human nerve growth factor (hNGF). The remaining three monkeys received identical grafts except the cells were not modified to secrete hNGF.Monkeys receiving the fornix transection and control grafts displayed extensive reductions in the number of choline aceyltranserase-(57-75%) and p75 NGF receptor-(53%) immunoreactive medial septal neurons ipsilateral to the lesion/ implant. In contrast, monkeys receiving transplants of encapsulated hNGF-secreting cells display only a modest loss of choline acetyltransferase-(0-36%) and p75 NGF receptor-(7-22.4%) immunoreactive septal neurons. Additionally, all monkeys receiving the hNGF-secreting Implants, but none receiving control inats, displayed robust sprouting of cholinergic fibers within the septum ipsilateral to the transplant. Just prior to sacrifice, the capsules were retrieved and found to contain viable BHK cells releasing biologically relevant levels of hNGF. These data demonstrate that hNGF can provide trophic and tropic influences to aged primate basal forebrain neurons undergoing lesion-induced degeneration, supporting the contention that hNGF may prevent the degeneration of basal forebrain neurons in Alzheimer disease.In the central nervous system, converging lines of evidence indicate that nerve growth factor (NGF) provides trophic and tropic influences for cholinergic neurons of the basal forebrain. For instance, injections of radiolabeled NGF into the hippocampus or cerebral cortex results in the specific retrograde transport to cholinergic neurons within the septal diagonal band complex and nucleus basalis, respectively (1, 2). NGF enhances cholinergic tone in normal and developing rats (3) and cholinergic basal forebrain (CBF) neurons are the only cells in the brain shown to express both the low-affinity p75 NGF receptor (NGFr) and the high-affinity trkA receptor

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.…”

Human adipose tissue‐derived mesenchymal stem cells improve cognitive function and physical activity in ageing mice

“…Notably, BDNF is also involved in the development of motor coordination (Strand et al, 2007). Several studies have demonstrated that age-and AD-related dysfunctions of the cholinergic system related to physical activity as well as cognitive function are ameliorated by NGF and BDNF treatment (Williams et al, 1986;Casamenti et al, 1994;Kordower et al, 1994;Murray et al, 1994).…”