The Rabbit Retina: A Long-Term Model System

             Alzheimer’s disease is a progressive neurodegenerative disorder which is characterized by a profound decline in cognitive function . It is one of a group of disorders called neurofibrillary degenerative diseases which are characterized by the development of tangles of minute fibers called neurofilaments in specific types of neurons in several areas of the brain. With Alzheimer’s disease, this tangle formation is only one of the changes which may ultimately result in the death of large numbers of neurons. Usually beginning in middle to late life, Alzheimer’s disease is the most common type of adult-onset dementia and affects approximately seven percent of all persons over the age of 65 years and upwards to twenty percent of those over the age of 80 years. At the present time, there is little known about the cause of Alzheimer’s disease, no definitive diagnostic tool, no treatment and no satisfactory animal model. This is particularly disturbing when we consider that the average age of our population is steadily increasing. Studies have estimated that the number of people aged 60 years and over doubles-within a generation. With these rapidly changing demographics, it is apparent that Alzheimer’s disease is destined to become one of the major public health problems of the early 21st century. As such, the development of an effective animal model with which to study the cause of this insidious disorder and to evaluate potential pharmacotherapeutic treatments is of great interest to both basic and clinical scientists.           Several scientific studies over the past decade have indicated that injection of small amounts of the metal, aluminum, into the cerebrospinal fluid surrounding the brain of the rabbit produces a condition with some of the characteristics of Alzheimer’s disease. Unfortunately, however, it was not possible to study this model for more than a short period of time following the initial injection because of the appearance of severe neurological deficits which almost always result in death of the animal within 2-3 weeks. This short-term nature of the aluminum model has greatly limited its usefulness as a model for a long-term disorders such as Alzheimer’s disease. In addition, the limited data available from these studies has led many investigators to believe that the aluminum model is not a valid model for the study of Alzheimer’s disease. This is especially unfortunate in light of evidence that gradual ingestion of aluminum into the body from the environment may be somehow linked to a variety of neurofibrillary degenerative disorders including Alzheimer’s disease. Several studies have reported elevated levels of aluminum in those areas of the brain affected by Alzheimer’s disease. Recently, population studies have suggested that those people living in areas where there are high levels of aluminum in the drinking water may have a greater risk of developing Alzheimer’s disease. Aluminum has also been reported to be associated with a range of other neurodegenerative disorders including Parkinsonism-dementia and amyotrophic lateral sclerosis. It is clear, therefore, that development of a long-term animal model would greatly enable studies of these disorders and the role that aluminum may play in their etiology. Our studies to date indicate that the retinal model may indeed provide an appropriate system to study aluminum intoxication in the central nervous system. Injections of aluminum into the vitreous of the eye produces the same changes in the population of retinal ganglion cells as are observed in other regions of the brain following intracistemal delivery of aluminum. However, injection of aluminum into the eye does not produce the neurological deficits that often resulted in the premature death of experimental animals in earlier studies. This has permitted us to examine the neurodegenerative effects of the exposure to low doses of aluminum over the lifetime of the experimental animal, a situation more closely mimicking the gradual exposure to metals and other toxins in the environment. Exposure to aluminum has resulted in dose-dependent and time-dependent degeneration which is characterized by the formation of neurofibrillary tangles and loss of specific retinal neurons called ganglion cells. With longer survival times (6 to 9 months), there is a substantial increase in the number of cells undergoing neurofibrillary degeneration as well as the number of cells that are dying . These observations suggest that a cascade of events is responsible for these neurodegenerative changes. One of the preliminary findings relevant to this patternof degeneration is the observation that corticosteroid treatment administered at the time of the injection of aluminum prevents the formation of neurofibrillary tangles in the injected eye.             A search for the underlying cause of corticosteroid blockage of the formation of tangles in aluminum-treated retinas led to inquiries into the mechanism / s underlying aluminum-induced degeneration. Studies to date indicate that there may be many factors that are playing a role in the etiology of neurofibrillary degenerative diseases such as Alzheimer’s disease. It has been proposed that the disease might arise as the result of a complex interaction between genetic predisposition to the illness, natural aging processes , environmental factors and pathological changes in the immune system. One hypothesis that has been advanced to account for these many causal factors is the oxygen free radical hypothesis. Free radical toxicity has been implicated in a number of disease processes such as inflamation, emphysema and ischemia. Free radicals act by breaking down membranes, inactivation of enzymes and disruption of complex sugars and nucleic acids. One important circuit in this cascade of events is the self-propagating interaction that exists between oxygen free radicals and the excitatory amino acid neurotransmitter, glutamate. Recent studies have indicated that aluminum interacts with both of these compounds. The proposed studies are designed to investigate these interactive relationships in an attempt to identify some of the potential mechanisms through which the neurodegerative effects of aluminum are mediated. Initial phases of this project have concerned themselves with the manner in which the aluminum is presented to the nervous system and the effect on the tissue , including glutamate levels and polyamine levels. Whereas all previous experiments relied on the use of aluminum salts, it was decided that the experiments would have more significance if the aluminum , was presented to the nervous system in the manner that it is normally carried in the circulating blood . The vast majority of aluminum in the human bloodstream is carried by the iron -binding protein transferrin. Treatment of animals with aluminum-transferrin resulted in the appearance of a syndrome identical to that observed in earlier experiments but with much lower levels of elemental aluminum. This indicates that aluminum as it is found in the blood is highly neurotoxic. Treatment of animals with the aluminum-transferrin resulted in increased levels of glutamate , an excitotoxic neurochemical. The exact amount of this increase is currently being determined. No changes were observed in another class of very important compounds known as polyamines . Further studies currently underway are examining variou s aspects of the relationship between aluminum, glutamate and free radical generation.