Feature

Neural Transplantation

Restoring levels of important brain chemicals may offer a chance to reduce or reverse the symptoms of Alzheimer's Disease.

Craig S. Webster and John C. Dalrymple-Alford

Alzheimer's Disease is characterised by the progressive worsening of memory to the point where the sufferer may no longer recognise their own relatives or remember what they did a few minutes ago. The cost of nursing home care for such individuals is relatively high, and is rising with the increasing proportion of elderly in the population.

How an individual contracts Alzheimer's Disease remains unknown, but it is known to be genetically predisposed and to involve a specific kind of neurological degeneration. A decline in the level of the neurochemical acetylcholine (ACh) in the cortex and hippocampus of the brain, with the demise of specific populations of cholinergic brain cells, is known to be a major contributing factor to the memory impairments in Alzheimer's Disease. As memory impairment in Alzheimer's may be caused by a lack of ACh, restoring this neurochemical to normal levels could be expected to reverse at least the symptoms of the disease.

Some of the cognitive and neurochemical deficits which occur in Alzheimer's Disease are commonly modelled in rats for the purposes of neural transplant research. Very specific lesions which reduce or eliminate the neurochemical ACh from the hippocampus are typically used. The hippocampus is a brain structure which plays a central role in memory function, and a lesion which causes depletion of ACh here will typically result in a severe memory loss -- a cognitive impairment very similar to that in human Alzheimer's. Once lesioned in this way, such memory-impaired rats can be used as subjects for experimental ameliorative regimes currently not feasible in humans.

One of the most promising attempts to restore ACh levels is to re-introduce ACh-rich cells by way of a cell transplant to reverse the functional impairment caused by the lesion. Recently, skin cells have been genetically modified in such a way that they are capable of producing certain neurochemicals, and these cells transplanted into the lesioned host brain act as tiny neurochemical pumps. Such genetically modified cells have been dubbed "dumb" cells, however, as they lack the cellular apparatus necessary to functionally integrate with the host brain and produce neurochemicals when they are needed to suit the varying demands of the surrounding tissue.

The Smart Option

Transplanting live neural cells is the comparatively "smart" option since such cells are capable of responding to neurochemical signals in the surrounding host brain tissue and producing neurochemicals in appropriate amounts and at appropriate times. However, the transplanted cells must be of the right age for this to be successful. Only immature foetal neural cells that are young enough not to have yet formed inter-cellular connections can be used. One of the best ways to introduce these cells into the host brain is in the form of a cell suspension. Young foetal neural cells are remarkably robust, able to survive the suspension transplant process, integrate with the host brain, and ameliorate functional and neurochemical impairments. Taken together these factors make foetal neural transplantation an attractive experimental tool with which to study recovery of function after brain damage.

In recent research in the Psychology Department at the University of Canterbury, profound memory deficits were produced in rat subjects by making selective lesions to a brain structure called the fimbria-fornix to effectively eliminate ACh from the hippocampus. Memory ability was tested using a behavioural task where the animal had to remember what it did a few seconds ago to receive a reward. Before they received their lesions all animals had learned very quickly how to get the reward, but after the lesions they performed purely at chance level, despite extensive practice.

Suspension transplants were then performed with two different types of ACh-rich foetal neural cells. Our results showed that near normal levels of ACh were effectively and dramatically restored in the transplant animals who received tissue from the Medial Basal Forebrain (MBF), but less successfully in rats who received tissue from the Lateral Basal Forebrain (LBF).

We took brain sections of the hippocampus from the different experimental groups, and used acetylcholinesterase (AChE) a marker for the presence of ACh. The degree of ACh reinnervation in the transplant sections can be seen by comparing the appropriate brain sections with a normal section; the complete absence of ACh is obvious in the section after lesion with no transplant. It is from this level of depletion that the transplants began their ACh restoration, with near-normal ACh reinnervation due to the MBF transplant produced. Further brain sections demonstrate the less successful ACh reinnervation due to the LBF transplant.

Just One Catch

Tempering these impressive neurochemical findings are the behavioural results of this experiment: none of the transplant animals performed significantly better than the memory impaired lesion-only animals. That is, although it appears that our transplants were a great success in restoring ACh levels, this restoration did not translate into behavioural recovery even in the MBF group. One reason for this negative result may be the involvement of other neurochemicals. Our fimbria-fornix lesion will have also damaged other neurochemical systems, for example some noradrenaline and serotonin systems, while our transplant restored only ACh. It is as yet unclear, however, what the precise factors are that determine the behavioural success of neural transplants.

The normal rat hippocampus

Hippocampus after lesion showing complete depletion of the neurochemical marker, AChE

Hippocampus with restored levels of AChE after MBF transplant

Both types of tissue used for transplantation in this experiment were ACh-rich, and one, the MBF tissue, restored ACh in the hippocampus to near normal levels. This demonstrates that for a successful reinnervation of brain structure the transplant needs to be more than simply rich in the neurochemical you are trying to restore. There are other factors such as a match between the transplant tissue itself and the area of the brain you are transplanting it into. The MBF tissue normally sends projections to the area of the brain that we transplanted it into, but the LBF tissue does not. This demonstrates an "appropriateness" relationship between the transplant tissue and the site of transplantation in the host brain.

One mechanism controlling this relationship may be trophic factors which are chemicals present in the brain that help keep brain tissue healthy. Foetal neural cells which are transplanted into an "inappropriate" area of the host brain may not respond to local trophic factors and so may not flourish, despite being rich in the neurochemical that is lacking in that area. This may have impeded the integration and growth of our LBF tissue transplants.

On the whole, the critical factors for behaviourally and neurochemically successful transplants are not yet fully understood. There exist many conflicting findings, including ones that conflict with our own. Promising results have been found in Marmoset monkeys using a similar lesion and transplant regime as described here with rats. However, it is clear that good neurochemical restoration does not necessarily mean good behavioural recovery; the results of our experiment add further weight to this conclusion. It is likely that transplants composed of mixtures of different neural tissues will be important in developing techniques to restore cognitive function.

While many years of research lie ahead in the field of neural transplantation before results can be translated into therapies for human neuro-degenerative disorders, the potential usefulness of a fully developed transplantation technology is great, and is likely to extend the benefits of more traditional drug therapies.

John Dalrymple-Alford is a senior lecturer and head of the Psychology Department at the University of Canterbury.
Craig Webster is currently a clinical researcher in the Anaesthetics Department at Auckland's Green Lane Hospital.