Reports on the neurotoxic properties of Aluminum (Al++), as well as those of many other heavy metals, date as far back as the end of the nineteenth century. In 1965, Al was found to induce the formation of neurofibrillary tangles (NFT) in animal brains. These NFT’s were similar to those found in brains of patients suffering from Alzheimer’s Disease (AD). Vast research thus, was targeted at defining the possible etiologic role of Al in AD. However, several findings, among them the fact that Al++ induced NFT’s are structurally different than those found in AD, have contributed to reducing the importance placed on Al++ as an etiologic factor of AD. The Al++ theory, however, still remains a theory, and further research needs to be done before it can be disproved.
In 1970, Alfrey and collaborators described a disease called dialysis encephalopathy (DE). This degenerative disease was seen in renal failure patients who had been undergoing dialysis. Studies following this initial report have implicated Al++ intoxication as a probable cause for the development of the disease. The purpose of this paper will be to describe the possible mechanisms by which Al may in fact act as a contributory factor the in induction of neural degeneration that may lead to DE.
The neurological problems associated with chronic renal failure and its consequent treatment, namely hemodialysis, can be either acute or chronic. When acute, the patient develops a set of symptoms collectively referred to as dialysis disequilibrium syndrome (DDS). This syndrome presents with a transient loss or alteration of the sense of equilibrium due to disturbances to the vestibular system. This disturbance is seen due to sudden changes in the osmotic pressure of the cerebrospinal fluid which occur during dialysis. Chronic neurological problems that may arise following chronic renal failure and dialysis treatment, on the other hand, can be classified as dialysis dementia’s, or more generally, dialysis encephalopathies. Symptoms associated with the latter disease include disturbances in communication, cognition, and movement. Dysarthria, stuttering and impaired language formation are among the communicative impairments; while disorientation and deficient short term memory are the common cognitive deficiencies. Finally, myoclonus, tremor, and facial grimacing are common movement deficits. The duration of the dialysis treatment before the onset of symptoms has been reported to vary from 6 months to over 7 years (3). However, it must be realized that not all dialysis patients develop neurological problems or deficiencies.
One of the many dangers with patients with chronic renal failure is the development of hyperphosphatemia (and its concomitant hypocalcemia) as a result of the system’s inability to eliminate phosphate. The rapidly rising serum phosphate levels in these patients are not effectively and promptly removed via the dialysis treatment. Therefore, substances that reduce phosphate absorption and decrease its concentration in blood need to be administered to patients with chronic renal failure. These substances are called phosphate binders.
The most effective phosphate binder is aluminum hydroxide. This substance successfully reduces serum phosphate levels via two mechanisms. First, aluminum hydroxide is able to form coordination compounds with phosphate ions, and thus "trap and mask" phosphate ions in the blood. Second, aluminum ions form aluminum phosphate precipitates in the gut. These precipitates are insoluble and thus, can not be absorbed. The latter effectively reduces the amount of incoming phosphate into the system and helps prevent a rapid increase in serum phosphate levels.
Post mortem examination of neural tissue from DE patients has shown high Al++ concentrations within the brains studied. It should be remembered that the main portion of excretion of Al++ are the kidneys. Thus, in patients with renal failure, Al++ concentrations are prone to increase, specially if Al++ compounds are administered for phosphate binding purposes. Another complication is that Al++, when in serum, binds very tightly to serum proteins, many of which are too large to be filtered by normal dialysis procedures. In order to overcome the latter problem, low molecular weight Al++chelating agents such as deferroxamine are used after administration of aluminum hydroxide. However, high Al++ levels still appear to remain within the patient’s system. It has been proposed that the high aluminum concentration remaining within dialysis patients eventually might lead to neurological damage.
Several researchers have made valuable contributions with regard to the possible mechanisms by which Al++ intoxication can lead to irreversible neurological damage. Injection of aluminum chloride solutions at different concentrations (ranging from 10 uM to 200 uM) into the brains of rats has been found to induce the formation of neurofibrillary tangles at the sites of injection (7). NFT’s appear to be non-functional disordered double helical aggregates of the protein tubulin, compared to normal neural filaments which are single ordered helical aggregates of tubulin. Normal neurofilaments, however, are necessary for appropriate cellular and axonal transport, among other functions. The presence of NFT’s, thus, mainly impairs the neuron’s ability to mobilize intracellular components, such as vesicles containing neurotransmitters or neuroactive compounds.
Microscopic studies of neurons affected by Al++ injection, have shown that Al++-poisoned neurons have an increased number of lysosomes, each with an increased concentration of Al++ (8). Thus, it has been suggested that Al++ intoxication may play a role in induction of neuronal autolysis.
In addition, Al++ has been shown to be an inhibitor of the enzyme dehydropteridine reductase (DHPR), an enzyme necessary for the synthesis of norepinephrine, epinephrine, dopamine and tyrosine. Also, choline acetyl transferase, the enzyme needed for synthesis of acetylcholine, is inhibited by aluminum. Inhibition of the synthesis of these neurotransmitters would therefore impair neurotransmitter related events necessary for appropriate nervous function, and could thus be implicated as one of the probable causes of the multiple neurological deficiencies seen on DES.
Another mechanism by which aluminum promotes neuronal degeneration is by competitively decreasing the intracellular concentration of calcium, an ion whose concentration is already low due to the hyperphosphatemia condition of patients undergoing dialysis. Reduction of the intracellular Ca++ concentration has many deleterious effects upon neurons, and cells in general. Low intra- and extracellular Ca++ reduces the cell’s membrane potential and, and lowers the neuronal threshold for firing. In addition, Ca++ dependent calmodulin activation is impaired due to low Ca++ concentrations (4). It should be remembered, as well, that Al++ competes with Ca++ for calmodulin binding. Al++-calmodulin complexes are non-functional, and thus block All intracellular activation pathways dependent on calmodulin. The former effects of Al++ would result on a decrease in the relative concentration of activated second messengers within the neurons, as well as neuronal hyperactivity.
Aluminum has also been shown to be a potent inhibitor of hexokinase, an enzyme necessary for glucose metabolism (4). Inactivation of this enzyme, thus, depletes neurons from glucose and may facilitate their progressive degeneration.
Finally, high Al++ concentrations have been shown to increase transmembrane diffusion across the blood brain barrier (BBB), as well as selectively change saturable transport systems without disrupting the integrity of the membrane (8). Alterations in the access to the brain of nutrients, toxins, heavy metals, drugs, etc., could certainly be the initial basis for the several disrupting effects of Al++ upon the nervous system. These alterations would lead to increasing concentrations of neurotoxic substances within the CNS, further promoting neuronal damage and degeneration by mechanisms other than just those associated with Al++.
The former discussion represents a brief attempt at describing several of the probable mechanisms by which high Al++ concentrations found in dialysis patients could lead to DE. It is very possible that disruption of the BBB leads to intrinsic damage of the membrane itself as well as increasingly higher Al++ concentrations within the central nervous system. Increased Al++ within neurons could then lead to neuronal damage via some of the different mechanisms discussed above. The presence of the disease, as well as the time of onset, appears to be dependent on continuous exposure to high aluminum concentrations, and reduced ability to effectively clear Al++ from the body via dialysis treatment.
Even though DE is still seen, its incidence has been markedly reduced. Factors that have aided in reducing the probability of these patients developing chronic neurological symptoms have included the use of lower concentrations of IV aluminum hydroxide, as well as dialysis fluids which are known to be devoid of aluminum. In addition, reduced Al++ intake with avoidance of citrate salts, which are known to increase the absorption of Al++ in the gut, have proven to be helpful. Finally, treatment of dialysis patients with deferroxamine, a chelating agent that facilitates the removal and excretion of Al++ and iron, has proven to be very useful.
Aluminum toxicity has not been proven to be the main etiologic factor in the development of DE. However, the results presented in this paper strongly suggest the direct implication of this metal in the production of the degenerative neurological symptoms see with this disease.
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