The Rabbit Retina: A Model System for Neurofibrillary Disorders

The Rabbit Retina: A Model System for Long-Term Studies of Neurofibrillary Degenerative Disorders          Alzheimer’s disease (AD) i s a progressive neurodegenerative disorder, characterized by a profound decline in cognitive function and accompanied by a variety of pathological changes in the brain including the formation of filamentous tangles, the appearance of amyloid plaques and the large-scale degeneration of nerve cells. The most common type of adult-onset dementia, AD usually begins in middle to late life, and affects approximately 10 % of all person s over the age of 65 years and upwards to 47% of those over 85 years of age. These statistics are disturbing when we consider that the average age of our population is steadily increasing. The consequences of these changing demographics are compounded by the fact that there is little known about the etiology of AD, no definitive diagnostic probe and no available treatment. AD appears destined to become one of the major public health problems of the early 21st century.              Research into the causes and treatment of AD has been severely hampered by the unavailability of animal models with which to perform research. One of the models which has been forwarded as potentially useful for the study of neurofibrillary changes in AD is the aluminum intoxication model. This model was first described as early as 1965 when it was found that one of the pathological landmarks of aluminum intoxication is a neurof ibrillary degeneration with many of the characteristics of AD. One of the major drawbacks of this model was that the aluminum injection s, usually made into the cerebrospinal f luid, resulted in death of the animal within a period of 2-3 weeks, thereby restricting the study to short-term analysis. This limitation combined with the failure to see any of the other pathological landmarks of AD, e.g. paired helical filaments, senile plaques or neuronal cell death, within the 2-3 week time-frame presented by the model, resulted in the aluminum intoxication model falling into disrepute among the vast majority of AD researchers. This is unfortunate in 1 ight of recent evidence which has suggested the existence of a possible link between gradual ingestion of aluminum into the body from the environment and a variety of neurofibrillary degenerative disorders including AD. These include epidemiological studies which appear to demonstrate a positive correlation between high levels of bioavailable aluminum in drinking water supplies and increased incidence of AD, and analytical studies which show elevated aluminum levels in association with neurof ibrillary tangles and amyloid plaques in brain tissue from patients affected by AD. Importantly, these analytical studies have examined brain tissue from seve ral countries as well as a range of geographic locales within North America. Aluminum has a l so been implicated in other disorders including amyotrophic lateral sclerosis (ALS) and ALS-parkinsonism dementia complex (ALS-PDC) which is a disorder found among the populations of Guam, New Guinea and the Kii Peninsula of Japan. The incidence of ALS-PDC has been suggested to be related to deficiencies of calcium and magnesium, and increased levels of aluminum in the soil and drinking water. It is clear , therefore, that development of a long-term animal model for aluminum intoxication might help resolve some of the growing controversy over aluminum’s role in neurofibrillary degenerative disorders such as AD and also help to the investigate the long-term effects of aluminum intoxication itself. It is also clear that if aluminum does play some role in AD, it is likely to occur over a time-frame which can be expressed in terms of months and years, not weeks, thereby adding to the need for a long-term animal model for aluminum intoxication.          Ongoing studies in our laboratory on the structural organization of the retina suggested that this piece of the central nervous system (CNS) might be an excellent model for studying the long-term effects of aluminum intoxication on nervous tissue . Besides being among the best characterized and understood areas of the CNS, the retina is unique in that it is physically isolated from the remainder of the brain and its surrounding cerebrospinal fluid. The retina should, therefore, provide an aluminum intoxication model which is characteristic of central nervous tissue but does not exhibit the major drawback of the other models, i.e. the short-term nature . Preliminary studies in which aluminum was injected into the vitreous of a rabbit eye revea l ed that the gan glion cells of the retina undergo a neurofibrillary degeneration which is ide n tical to that observed in other aluminum intoxication models. Importantly, however, the animals did not demonstrate any of the life-threatening neurological deficits observed in the earlier models. This suggested that the primary effects of the aluminum did remain localized to the retina and that the aluminum itself did not enter the cerebrospinal fluid. Further examination of these animals revealed several new and exciting findings regarding aluminum intoxication. These included evidence that aluminum may be able to travel selectively throughout the nervous system possibly passing from neuron to neuron, that only certain susceptible types of neurons are affected by aluminum and that aluminum intoxication may, in fact, result in large scale death of neurons, not unlike that observed in AD. Several of the injected animals were followed for 6-9 months, clearly demonstrating the potential of this model for long-term studies. Availability of a model system such as the retina will allow us to determine whether long-term aluminum intoxication may result in pathology more characteristic of diseases such as AD, eg. presence of paired he l ical filaments and amyloid protein. The proposed study will examine aluminum intoxication in retinal ganglion cells with regard to its potential use as a long-term model for neurofibrillary degenerative disorders such as AD and to study the potential role that aluminum may play in these disorders. More specifically, the study will: i) examine the development of neurofibrillary degeneration, eg. dose-dependency, long-term effects on neuropathology (type of filament in tangle, possible deposition of amyloid, etc.), neuronal degeneration, reversibility of effects, effects on contralateral eye or at central projection sites of ganglion cells, ii) examine the long-term effects of aluminum intoxication on the neurochemicals used by neurons to corrununicate, iii) study the effects on retina of other aluminum-containing compounds such as aluminosilicates and aluminum maltolate, iv) study the mechanism of how aluminum may travel through the nervous system, and v) study the relationship between this animal model and clinically occurring neurofibrillary degenerative disorders such as AD.              Besides providing us with a potential model for studying AD and helping us to understand the potential link between aluminum and AD, the retinal model will also help us to understand the visual manifestations of AD. It is interesting to note that many of the visual deficits associated with AD have been primarily attributed to degeneration of the retinal ganglion cells. As such, the retinal model of aluminum intoxication also has the potential to provide important new information on the relationship between neurofibrillary degeneration and ganglion cell function as well as on the mechanism of how this degenerative process manifests itself clinically.