. "Appendix A: Age-Related Shifts in Neural Circuit Characteristics and Their Impact on Age-Related Cognitive Impairments." The Aging Mind: Opportunities in Cognitive Research. Washington, DC: The National Academies Press, 2000.
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The Aging Mind: Opportunities in Cognitive Research
the hopes of developing a therapy for Parkinson's disease. As early as the 1970s and 1980s, this strategy was demonstrated to be successful with respect to survival of the transplanted neurons, formation of the appropriate connections, and functional recovery of the animal (Bjorklund et al., 1981; Stromberg et al., 1985). Based on a large body of animal literature, the prospects for transplantation in such human neurodegenerative diseases as Parkinson's disease were considered in the 1980s, and there was limited success as a therapeutic intervention (see Lindvall, 1991, for a review).
However, in recent years the success of this strategy has improved, and in fact, there are now clinical trials with relatively long-term evaluation that demonstrate success with respect to the survival of the transplant, a degree of functional recovery, and even demonstrated release of dopamine from the transplanted axons into the newly innervated striaturn (Olanow et al., 1996; Hauser et al., 1999; Piccini et al., 1999). The strategy of transplanting fetal tissue has been modified and improved through the use of genetically modified cells that secrete doparnine into the striaturn, and these cells can be injected directly into the striaturn (Martinez-Serrano et al., 1995; Kordower et al., 1994, 1995). In addition, a gene delivery system employing a viral vector to deliver a growth factor into the septum successfully protected experimentally damaged cholinergic neurons innervating the hippocampus (Blomer et al., 1998).
While these approaches are potentially very promising for certain neurodegenerative disorders such as Parkinson's disease, such transplant approaches will clearly be most successful with a target circuit that has relatively little synaptic specificity in its target region, which is the case with the nigrostriatal doparninergic circuit. For example, such a strategy would seem to have very limited feasibility with respect to replacing complex, highly specific, corticocortical circuits.
Perhaps most relevant to aging are two recent primate studies that have employed gene therapy to reverse naturally occurring age-related compromise in two vulnerable circuits. One study targeted the cholinergic projection emanating from nucleus basalis that is known to be vulnerable in Alzheimer's disease (Smith et al.,1999a), and the other study used a viral vector approach to deliver a growth factor to reverse the natural age-related decline in dopa-mine function in the nigrostriatal projection (Kordower et al., 2000). Smith et al. demonstrated in primates that atrophic cell shrinkage and loss of cholinergic markers in nucleus basalis neurons could be reversed with human NGF (nerve growth factor) therapy. Interestingly, the neurons had not fully degenerated, and in that sense this is not analogous to late-stage Alzheimer's disease. The neurons had shrunk and their gene expression had shifted in a manner that impaired cholinergic function, but they had not degenerated. Both the morphologic and biochemical age-related shifts were reversible with NGF therapy.