Neural Transplantation in Animal Models of Dementia

Abstract

Neural transplantation provides a powerful novel technique for investigating the neurobiological basis and potential strategies for repair of a variety of neurodegenerative conditions. The present review considers applications of this technique to dementia. After a general introduction (section 1), attempts to replace damaged neural systems by transplantation are considered in the context of distinct animal models of dementia. These include grafting into aged animals (section 2), into animals with neurotransmitter-selective lesions of subcortical nuclei, in particular involving basal forebrain cholinergic systems (section 3), and into animals with non-specific lesions of neocortical and hippocampal systems (section 4). The next section considers the alternative use of grafts as a source of growth/trophic factors to inhibit degeneration and promote regeneration in the aged brain (section 5). Finally, a number of recent studies have employed transplanted tissues to model and study the neurodegenerative processes associated with ageing and Alzheimer's disease taking place within the transplant itself (section 6). It is concluded (section 7) that although neural transplantation does not offer any immediate prospect of therapeutic repair in clinical dementia, the technique does offer a powerful neurobiological tool for studying the neuropathological processes involved in both spontaneous degeneration and specific diseases of ageing. New understandings derived from neural transplantation may be expected to lead to rational development of novel strategies to inhibit the neurodegenerative process and to promote regeneration in the aged brain.

Central neuronal loss and behavioral impairment in mice lacking neurotrophin receptor p75

“…Fimbria-fornix lesions have demonstrated the crucial role played by the basal forebrain in the performance of complex learning and memory tasks (Brito and Brito, 1990;Dunnett, 1990). Lesion-induced deficits in spatial memory performance can be attenuated by acetylcholineproducing grafts to the hippocampus (Dickinson-Anson et al, 1998) or NGF-producing fibroblast grafts to the lesion cavity serving as a bridge for hippocampal reinnervation (Eagle et al, 1995).…”

“…These neurons retrogradely transport NGF (Schwab et al, 1979;Seiler and Schwab, 1984) and appear to be NGF dependent based on their vulnerability to the loss of NGF and their subsequent rescue by exogenous NGF (Hefti, 1986;Williams et al, 1986;Kromer, 1987;Rosenberg et al, 1988). Lesion of these projections interferes in the performance of complex learning and memory tasks (Dunnett, 1990), which can be attenuated following regeneration of cholinergic projections across a bridging graft (Eagle et al, 1995) or grafting acetylcholine-producing cells to the hippocampus (Dickinson-Anson et al, 1998).…”

Chronic treatments with cholinoceptor drugs influence spatial learning in rats

“…Studies using transplants of cholinergic cells following lesions of the basal forebrain cholinergic nuclei, ageing or prolonged alcohol administration in animals provide further support for an important role of the cholinergic system in learning and memory function (see Dunnett 1990 for review). However, with the possible exception of THA (Summers etal.…”

Behavioral effects of GM1 ganglioside treatment and intrahippocampal septal grafts in rats with fimbria-fornix lesions

“…An abundant literature exists showing that intrahippocampal grafts rich in cholinergic neurons induce recovery from cholinergic and cognitive deficits associated with fimbria-fornix lesions (Cassel et al 1991;Dunnett 1990;Tarricone et al 1991). However, a few experiments found satisfactory graft-induced cholinergic reinnervation of the hippocampus, but no attenuation of the lesion-induced alterations of cognitive capabilities (Cassel et al 1990a;Dalrymple-Alford 1994;Dunnett et al 1989;Low et al 1982).…”

“…Based on an experimental paradigm of Alzheimer's disease in the rat (i.e., lesions of the septohippocampal pathways), several studies have demonstrated that transplanted fetal ventral forebrain cells, a region rich in developing cholinergic neurons, might reduce or compensate for some of the memory impairments associated with lesions disrupting the septohippocampal interface (Cassel et al 1991;Dunnett 1990;Dunnett et al 1989;Gage et al 1984;Low et al 1982). Such transplants were also found to restore metabolic (Kelly et al 1985) and neurochemical markers altered by the lesion (Björklund et al 1983;Cassel et al 1993;Emerich et al 1992;Kaseda et al 1989) and to establish electrophysiologically and morphologically normal synapses with neurons of the host brain (Clarke et al 1990;Segal et al 1985).…”