Molecular Understanding of Aluminum Bioinorganic Chemistry in

Chapter 16

Molecular Understanding of Aluminum Bioinorganic Chemistry in Relevance to the Pathology of Alzheimer's Disease 1

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S. Anitha , P. Shanmugavelu, Valeswara-Rao Gazula , S. K. Shankar , Rani B. Menon , R. V. Rao , Jagannatha K. S. Rao *, and Luigi Zecca 4

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Downloaded by UNIV OF PITTSBURGH on May 4, 2015 | http://pubs.acs.org Publication Date: June 3, 2002 | doi: 10.1021/bk-2002-0822.ch016

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Department of Biochemistry and Nutrition, Central Food Technological Research Institute, Mysore-570013, India Analytical Control Section, Chemical Engineering and Technology Group, BARC, Mumbai-400085, India Department of Neurology, Yale University School of Medicine, New Haven, C T 06520 Department of Neuropathology, National Institute of Mental Health and Neurosciences, Bangalore-560029, India Department of Molecular Neurobiology, IATB, CNR, Milan, Italy

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Aluminum (Al) is a suspected etiological factor in neurological disorders like Alzheimer's, Parkinson's, Huntington's diseases etc. The understanding of Al neurobiochemistry was hampered due to A l speciation chemistry and differential sensitivity animal models for Al toxicity. Experimental and circumstantial evidence provided a great deal of information on the complex inorganic biochemistry of Al in relevance to pathological events observed in Alzheimer's brains. In this contribution, the speciation chemistry of Al in relevance to neurobiology, role of A l , in modulating trace elemental homeostasis in human brains, Al-induced changes in animal brains mimicking Alzheimer's human brains, and its interaction with D N A are discussed.

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© 2002 American Chemical Society

In Group 13 Chemistry; Shapiro, P., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2002.

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Introduction Alzheimer's Disease ( A D ) is a neurodegenerative disorder characterized by progressive impairments o f memory and cognition. It typically occurs in later stages o f life and is associated with a multiplicity o f structural, chemical and functional abnormalities involving brain regions concerned with cognition and memory. A l i o s Alzheimer first reported this form of dementia in 1907 when he described a disease of the cerebral cortex in a 51 year old woman suffering from an inexorably progressive disorder o f dementia. Although other forms of dementia had been well characterized at the time o f Alzheimer's clinical report, his patient was clinically and pathologically unusual because o f her relatively young age and the presence o f the then newly-described intracellular inclusions which have subsequently come to be known as neurofibrillary tangles ( N F T ) . In recognition o f this unique combination of clinical and pathological features, the term "Alzheimer's Disease" subsequently came into common usage. Today, Alzheimer's disease is considered to be one o f the forthcoming scourges of the 21st century. Epidemiological studies suggest that the dementia presently occurs in up to 10% o f individuals over the age o f 65. It has been estimated that there are between 2.5 and 3 million patients suffering from Alzheimer's disease in the U S A and 0.6 m i l l i o n in the U K . These figures have been projected to increase by 20% over the next 20 years as the proportion o f the elderly in the population increases. The cost o f caring for such individuals is well over 80 billion dollars annually and is increasing rapidly. A D is characterized by initial memory loss followed by progressive loss of neurons, leading to dementia and loss o f all nervous function, and eventually death. The neuropathologic characteristics include cortical and subcortical atrophy, formation o f intraneuronal neurofibrillary tangles ( N F T ) , deposition o f Α β peptide in neuritic plaques, formation o f neuropil threads, loss o f synaptic function, oxidative stress, and apoptosis leading to neuronal loss. These events are observed mostly in the hippocampal and cortical regions o f A D brains. Aluminum has never been demonstrated to have definite biological function, suggesting that the ion possesses properties which are incompatible with fundamental life processes. In the last few years, many scientific studies have brought to light the potential toxicity o f A l to humans. It is usually excluded from normal biochemical and metabolic processes because o f low solubility o f its chemical forms, namely silicates, phosphates and oxides, which



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render the A l physiologically unavailable. L i v i n g organisms are carefully and effectively protected from A l aggression by different ways and one o f the studies suggests that naturally occurring silicon species might play a sort of planetarian antidote effect to the ecotoxic potency o f natural A l . Most of the understanding o f A l toxicity in humans was established as a result o f studies o f disorders experienced by dialysis patients when the dialysis fluid contained A l at above 0.5 micromoles/1. In such patients, A l accumulated in various tissues including kidney, liver, bone, and heart (1,2), giving rise to pathological conditions. The pathological conditions include i) dialysis encephalopathy that can lead to dementia and death and ii) dialysis osteomalacic osteodystrophy in which there is defective mineralization o f pre-bone collagen accompanied by bone pain and spontaneous fracture. A l accumulation in the heart is also a contributory factor in the cardiac hypertrophy often observed in hemodialysis patients. In fact, the element might be implicated in the pathogenesis o f Alzheimer's disease. The potential role o f A l in the pathogenesis o f human neurodegenerative disorders remains controversial. Recent studies in experimental animals as well as circumstantial evidence, strongly provided clue that A l might be one o f the factors causing neuronal cell death in devastating disorders like Alzheimer's disease, Parkinson's disease, Huntington's disease, Guam and amyotrophic lateral sclerosis. N o defined mechanism has been proposed for the cell death in the A D brain. A l is the only trivalent metal ion in the periodic table that appears capable o f inducing progressive encephalopathy leading to neurological disorders (3). Normally, A l is prevented from entering the central nervous system ( C N S ) by the blood-brain barrier. Under pathological conditions, however an increased amount of A l has been found in the brain tissue and cerebrospinal fluid (4). The perturbing mechanism is not clearly known, but may be related to blood-brain barrier breakdown as a result o f vascular damage (ischemia and/or inflammation) and by the iron transport pathway. In order to understand the possible role o f A l in such disorders, it is important to understand the complex hydrolysis chemistry o f A l under various biological conditions (5). This chapter mainly deals with A l speciation chemistry in biological systems, its role in modulating trace-element homeostasis in the human brains, aluminum maltolate induced changes in aged rabbit brain that mimic Alzheimer's in the human brains, its modulation in D N A conformation, and the possible hypothetical mechanism for neuronal cell death induced by A l .


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Aluminum Bio-inorganic Chemistry


Aluminum Loading in Humans Although A l is ubiquitous, its bioavailability is limited due to its insoluble nature. Because of the insoluble nature of aluminum compounds, naturally occurring surface and subsoil water is extremely low in A l content and biosystems have little exposure to soluble aluminum. This has played a major role in maintaining low A l burden in animals and most plants. Under certain pathological conditions, an increased amount of A l has been found in biological systems. Its wide use in day-to-day life, however, is increasing A l intake on the part of man through several routes. One of the possible major sources of human aluminum consumption is through food, drinking water, beverages and A l - containing drugs. Aluminum sulfate is used extensively as a flocculation agent to remove organic substances. It is estimated that the dietary intake of aluminum may vary from 3 to 30 mg/day, but a reasonable average dietary intake is probably about 5 mg/day. A l is naturally present in tealeaves. Tea plants have been found with as much as 0.3% A l in older leaves and about 0.01% in younger ones. Typical tea infusions contain 50 times as much as A l as do infusions from coffee. Levels of A l in brewed tea are commonly in the range of 2-6 mg/1 (6). Other possible sources of AI are food additives, containers, cookware, utensils and food wrappings. Dietary intake o f A l from food is small compared with the amounts consumed through the use of A l containing antacids that may provide 50-1000 mg/day o f A l . In order to investigate the potential toxicity of A l in the pathogenesis of neurological disorders, it is not only essential to establish its role in neurodegenerative disorder, but also modes of transport into the human body and its distribution pattern in various parts of the brain.

Potential Biological Carriers of Aluminum Aluminum may gain access to the human body through the gastrointestinal tract, lung tissue and nose. It is generally accepted that about 1% of the intake enters the body, with the remaining excreted by the renal system. The following four factors have been clearly shown to modulate A l absorption: (a) amount of A l ingested, (b) solubility o f A l



232 compounds, (c) integrity of the tight junctions of the small intestine, and (d) the uremic state. The definite mechanism by which A l is transported into body parts is not clearly understood. It was initially thought that inorganic phosphate (1.1 m M ) , citrate (0.1 m M ) , transferrin (50 μ Μ ) and lactate (0.9 m M ) present in plasma were the possible carriers o f A l . The binding o f A l with citrate in aqueous medium has been extensively studied (7). Though the stability constant o f aluminum-citrate complex is high, experiments demonstrated that lipid bilayer permeation by the neutral aluminum-citrate complex is remarkably slow (8). This could possibly suggest that A l enhancement in brain is not due to the involvement o f neutral aluminum-complexes. A l b u m i n is present in the plasma at a concentration o f 40 g/1. It is a weak A l binder at physiological p H and is unable to effectively compete with other stronger carriers. The glycoprotein transferrin is recognized as the major plasma iron transport protein. It is only 30% saturated with iron and regarded as a potential carrier o f A l under physiological conditions, without interference with the sites occupied by iron (9). The stability constant o f transferrin with A l is less than that o f iron by half. Transferrin-mediated brain uptake o f A l is confirmed by the postmortem study of the brains of patients with chronic renal failure (10). A high proportion of A l is bound to transferrin in the blood plasma. This might suggest that A l absorption is interlinked with the pathway of iron's absorption. The uptake o f A l appears to be determined largely by the distribution o f transferrin receptors, which occur in greatest densities in regions o f the brain that are selectively vulnerable to Alzheimer's disease. Further studies provided evidence that A l distribution in the brain in various disorders reflects the regional distribution o f transferrin receptors, suggesting that transferrin and transferrin receptors on endothelia are involved. Thus it is possible that A l may use the system o f uptake and transport o f iron involving transferrin and its receptor-mediated endocytosis. The A l transport across the yeast cells in the presence o f citrate and E D T A using A 1 N M R has been studied by our group ( / / ) . The results showed that A l , as a nitrate salt, could enter the cells within 15 minutes, and that, over a period o f 4 hrs, an equilibrium sets in between outside and inside the cell. A l u m i n u m - citrate does not favor A l transport into the cells above p H 5.0 and E D T A could bring out all A l that entered the cells within 30 min. 27


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The role of Aluminum in Metal Homeostasis in Human AD Brain Trace element homeostasis plays a crucial role in the normal functioning of the human brain. The distribution of trace elements is not homogenous in different regions of the brains, and their concentration varies significantly (12). In biological systems there is an interdependency among the concentrations of certain elements for homeostasis of trace elements. Direct correlation with respect to the changes in the concentration of trace elements in some regions of the brain was observed. A recent study (13) showed a marked difference in trace level metal concentration in different regions of A D brains compared to control brains. The total metal concentration also showed a marked difference in A D brain. Frontal cortex and hippocampus of normal brain contain about 258 μΜ/g and 269 μΜ/g respectively. In A D brain it has elevated significantly. Frontal cortex regions of A D brain showed an elevated level of about 1423 μΜ/g and hippocampal regions showed a still higher level of about 1903 μΜ/g. The rise in the total metal concentration in A D brain is mainly due the elevation of A l and Fe. A l alone is present to the extent of 50-65% in A D brain over other elements as shown in Figure 1. The comparative study indicated that the concentration o f A l and Fe have increased by several fold in both the hippocampal and frontal cortex regions of A D brain compared to normal brain, while Na, Κ and Ρ have been significantly reduced. Co-localization of A l and Fe at high levels in A D brain perhaps confirms the concept of the same A l transport route as that of Fe. The increased level of A l drastically decreased Κ and Na levels thereby affecting the homeostasis, as the binding of A l with the channel forming proteins could interfere with gating mechanisms. The trivalent ions ( A l , Fe) replaced divalent (Mg, Ca, Cu, Zn) and monovalent (Na, K ) ions in severe A D brains as shown in Table I. The data indicated that, during the progression of A D , the percentage of singly charged ions decreased by 2500fold, while the percentage of triply charged ions increased by 10-fold.

Table I. Percentage elemental charge distribution in normal and Alzheimer's brain Hippocampus Frontal Cortex Charge Moderate Severe Moderate Severe Control Control AD AD AD AD 1+ 0.01 0.02 19.5 80 17.6 86.6 2+ 0.09 9.4 50.4 7.1 34.7 0.1 99.9 3+ 45.8 10.6 32 99.9 6.3 1+, 2+ and 3+ charge includes ions o f ( N a , K ) , ( C u , Z n , M g , Ca) and ( A l , F e ) respectively.



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Figure. 1 Comparison of relative mole% of trace elements in control and AD human brain in (a) Frontal cortex (b) hippocampus. (Reproduced with permission from reference 13. Copyright 1999)


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Aluminum Speciation Chemistry and Neurotoxicity


Aluminum Toxicity Studies The toxic effects of A l are very diverse and have been extensively investigated both invivo and invitro. For proof o f the hypothesis that A l may be a significant risk factor for Alzheimer's disease, approximately fifty different neurotoxic effects of A l have been demonstrated (14). They include aluminum's action on the cell nucleus, effect on enzymes metabolic processes, interference with cytoskeletal mechanisms, effect on membranes and effect on neurotransmission. A number of groups (Savory et al, ( U S A ) , Zatta et al, (Italy) and Rao et al, (India)) have studied the effects of different inorganic salts of A l in causing neurodegeneration. A l l these studies have clearly shown that most o f the inorganic A l salts can cause only localized effects at the site of injection. Generally, A l is prevented from entering the C N S through the blood brain barrier; under pathological conditions, however, an increased amount of A l has been found (4). In order to investigate any possible role of A l in such disorders, it is important to understand the complex hydrolysis chemistry of A l as a function of p H (5). The speciation chemistry of A l is especially important in the experimental design of research investigations into A l toxicity. A l speciation in the stock solutions must be evaluated, since it hydrolyzes readily and at p H 7.0 there is a strong tendency for the precipitation of A l ( O H ) which makes the preparation of A l stock solutions difficult. Aluminum is a strongly hydrolyzing element, and is generally insoluble at neutral p H . Its solubility is enhanced under acidic or alkaline conditions, and in the presence o f complexing agents. In aqueous solution at pH

Molecular Understanding of Aluminum Bioinorganic Chemistry in

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