Annals of Neurosciences, Volume 13, Issue 1 (January), 2006

ALUMUNIUM MEDIATED OXIDATIVE

STRESS: POSSIBLE RELATIONSHIP TO
COGNITIVE IMPAIRMENT OF
ALZHEIMERS TYPE
Abbas Ali Mahdi, Sandeep Tripathi, Jayanti Neerja, Mahdi Hasan*
Departments of Biochemistry and * Anatomy, King George's Medical University, Lucknow
226003, (UP), India
Corresponding author
Abbas Ali Mahdi
Departments of Biochemistry, King George's Medical University, Lucknow 226003
Abstract
Aluminum (Al) is a trivalent cation that does not undergo redox change and it may cause a
variety of neurological disorders. In this review, we discuss evidence for a significant role of
aluminum in Alzheimer's disease (AD). Al has been implicated as a potential risk factor in AD
and for elderly cognitive impairment by epidemiological studies of drinking water, food,
medicine as well as natural resources. Neurotoxicity from excess brain exposure to aluminum is
documented from both clinical observations and animal experiments. The pathology of
Alzheimer's disease is related to the alteration in neurotransmission, beta amyloid production,
plaques formation and cytoskeletal abnormalities. The exact mechanism of Al toxicity is still
unclear; however accumulating evidences suggested that Al could potentiate oxidative and
inflammatory events leading to tissue damage. In conclusion it is proposed that a combination of
anticholinergic drugs and micronutrients including antioxidants may be more effective than the
individual agents in prevention and treatment of Alzheimer's disease.
Introduction
Aluminum is the most prevalent metal and the third most important abundant element in earth's
crust, only oxygen (49.5%) and silicon (26%) occur more commonly than aluminum (8%). In
biological systems, aluminum is present only in trace amounts. In no case, Al 3+ has been shown to
have a definite biological function and it is poorly absorbed and efficiently eliminated when
absorption does occur; Al is described mainly in bone, liver, testes, kidney, and brain (1). The salts
of aluminum are soluble in water and are, therefore, easily assimilated in to the body and may be
deposited in to the brain and neuronal tissue and accumulate there.
The subject of aluminum toxicity has been controversial for the last around three decades and its
toxicity (depending on amounts) has been known over a hundred years. Epidemiology, autopsy,
therapy and laboratory studies provide rich direct evidence that aluminum is one of the primary risk
factors for the development of Alzheimer's disease and Al is also an indirect factor of AD. Aluminum
is found in our food supply, in the air and soil, and is bound to bauxite in nature. Drinking water has
been identified as a potential route of Aluminum exposure and concomitant neurotoxicity in both
laboratory animals and humans (2).
Al was first recognized as human neurotoxin in 1886, in Prussian army studies of amputees whose
wounds were treated with Al to staunch bleeding (3). The first laboratory animal study linking Al to
brain damage was published in 1973 (4). The Al hypothesis was born in 1965 when Wisniewski,
Terry and Klatzo showed that introduction of Al salt into the brains of rabbits induces the formation of
neurofibrillary tangles that appeared similar to the neurofibrillary tangles of Alzheimer's disease (5
7). Berlyne and co workers (8) reported increased sensitivity to the toxic effect of Al in rats with
impaired renal function and cautioned against the use of Al salts in humans with renal failure.
Aluminum as a possible cytotoxic factor in the mechanism associated with neurofibrillay
degeneration in senile and presenile dementia of Alzheimer type was suggested by Crapper and
associates (9). The hypothesis that this form of Al toxicity might be important in the process
associated with neurofibrillary degeneration in human disease, including senile and presenile
dementia of the Alzheimer type, was investigated by several laboratories (1012).
Aluminum hypothesis and Alzheimer's
disease
Three routes have been proposed by which Al could enter the brain from systematic circulation;
blood brain barrier (BBB), nasal olfactory pathway and cerebrospinal fluid (CSF) (13,14). More rapid
exchange is possible through the BBB, via transferrin (TF) mediated transport of Al (15). Another
important carrier for brain Al influx may be monocarboxylate transporter (MCT), a proton co-
transporter, which is located at both the luminal and abluminal surfaces of the BBB (16). As
mentioned earlier aluminum hypothesis began when Wisniewski, Terry and Klatzol's demonstrated
AD like neurofibrillary pathology by injection of Al salts into the rabbit brain. However, subsequent
work by these investigators showed that the similarities between Al involved tangles and those of AD
were more apparent than real. As reviewed in Wisniewski and Wen (17) Al induced tangles and AD
pathology appeared similar only if the tissue was treated with silver staining and then viewed under
the light microscope. Analysis showed that AD tangles are in effect quite different from the pathology
induced by Al. Aluminum induced tangles differ from those of AD in their distribution at both gross
and ultra structural levels (Table no. 1).
Table 1: Features of tangles associated with aluminum in animal model and AD
Tangle Characteristics Aluminum-Induced AD
Protein composition Neurofilament Tau
Configuration Single, Straight Filaments Paired Helical Filaments
Diameter 10 nM 2024 nM
Building block 2.0 nM Protofilaments .2 nM Protofilaments
Tangle Characteristics Aluminum-Induced AD
Intraneuronal localization Cell body, Proximal Protein of
Dendrites and Axons
Entire Neuron
Regional Localization Forebrain, Spinal Cord Forebrain
Epidemiological studies
Several studies indicate that chronic Al exposure may have long-term detrimental effects. All elderly
persons face Al exposure putting them at potential risk of injury to health and brain function. Only
small proportion of elderly people progress to cognitive impairment or dementia, though this
proportion doubles every five years after a population reaches 65 years of age (18).
Alzheimer's disease is the most common form of adult onset dementia (19). It is fourth leading cause
of death in western countries, preceded only by heart disease, cancer and stroke (20). Currently,
there are estimated two million AD patients in India and 1725 million worldwide (21). Age is by far
the main risk factor for AD. Its prevalence illustrates an exponential risk with age, approximately
doubling each five year period, from 1% incidence at the age 65 years to 1620% at 85 years (18).
Ecological studies have suggested that concentration of aluminum in drinking water of 0.100.20
mg/l may increase the risk of Alzheimer's disease with relative risks ranging from 1.352.6 (4, 22
25). All the epidemiological studies, however, have ignored the greatest source of Al for the ordinary
citizen, viz foods. According to World Health Organization (WHO), the provisional food weekly intake
(PTWI), Al as a contaminant (also as an additive) is 7 mg/kg daily weight for adults, for children the
acceptable daily intake (ADI) is 2 mg.
Aluminum mediated pathological
lesions in brain
Alzheimer's disease is a progressive dementia, characterized clinically by a specific pattern of
memory impairment, followed by cognitive deficits. The confirmed diagnosis of the disease is made
histologically by the presence of numerous amyloid containing senile plaques and neurofibrillary
tangles in Alzheimer's brain, it is possibly correlated to the memory impairment of the patients,
whereas hypophosphorylated tau is the major component of the tangles. Al is a recognized
neurotoxin that is reported to be one of the possible factors responsible for AD and it may be the
source of initial injury. This metal is a known toxin to the nervous system to cause brain cell death,
senile plaques and neurofibrillary tangles (26). It has been reported that Al3+ accumulated in the
human brain at 6 microgram per year of life as well as an autopsy composition of the brain of normal
elderly people aged 75 to 101 with those of younger persons aged 32 to 46 measured a dramatic
increase of bulk aluminum levels (27). Hippocampus aluminum content averaged 28 times higher in
the non-demented elderly than in the younger people and its level in frontal cortex averaged 19
times higher. The brain of these elderly people showed hallmark changes typical of AD, such as
senile plaques and neurofibrillary tangles. The patient with Alzheimer's disease is neurobiologically
characterized by the occurrence of a minimum density of neurofibrillary tangles and neurotics
plaques in the hippocampus and the associated cortex of brain.
Armstrong et al. (28) reported that aluminum enters the individual neurons where it may be involved
in the production of abnormal tau protein leading to the formation of cellular neurofibrillary tangles,
neuropil threads and the processing of amyloid precursor protein resulting in the formation of beta
amyloid deposits and senile plaques. Tau protein is the major component of paired helical filaments
(PHFs), which form a compact filamentous network described as neurofibrillary tangles (NFTs).
Although neurofibrillary tangles are more closely associated with neuronal death than beta amyloid,
the evidence is becoming convincing that beta amyloid is the factor most responsible for starting the
degenerative processes of Alzheimer's disease. Neurofibrillary tangles are bundles of filaments
inside the neuron that abnormally twist around one another. Numerous neurofibrillary tangles are
found in area of the brain associated with memory and learning (hippocampus), fear and aggression
(amygdala), and thinking (cerebral cortex). It is believed that neurofibrillary tangles play a role in the
memory loss and personality changes associated with AD.
The beta amyloid peptide present in the core of senile plaques is a 42 amino acid chain produced by
cleavage of a longer protein known as amyloid precursor protein (APP). It has been reported that
APP is normally found embedded in neural membrane where it may serve to stabilize the contact
points between synapses (29). Furthermore, some aggregates of beta amyloid accumulate
throughout brain tissue also in normal ageing. As it is cleaved and destroyed, more beta amyloid is
formed and accumulates; the damage begins when the beta amyloid becomes concentrated in
senile plaques and an inflammatory reaction with ongoing oxidative stress occurs. Axon of a neuron
uses microtubules to transport substances between the center of neuron and its periphery. The
assembly and structural integrity of microtubules are dependent upon several factors, the most
important of which is a protein called 'Tau'. When Tau is abnormally phosphorylated, it forms the
paired helical filaments known as neurofibrillary tangles. The similarity between aluminum induced
tangles and AD pathology manifests only when the tissue is treated with silver stain and then viewed
under light microscope (17). Detailed analysis showed that AD tangles are in fact; quite different
from the pathology induced by aluminum. Aluminum induced tangles differ from those of AD in their
distribution at both gross and ultra structural levels. While both types of tangles are found in the
cortex and hippocampus, only aluminum induced pathology is also found in the spinal cord. Indeed
with aluminum induced tangles, the spinal cord burden appears to exceed that of the brain itself.
Within single neuron, aluminum induced tangles are found in the perikaryon and the proximal parts
of the dendrites and axon. In contrast, AD tangles are found throughout the axons, including the
terminals (Fig. 1 ).

Fig 1: Amyloid Plaques and Neurofibrillary tangels in Normal and AD brain.
Aluminum mediated oxidative stress in
brain
Aluminum is the trivalent cation that does not undergo redox changes. It has nonetheless been
implicated in a variety of neurological disorders that have been associated with an increase in the
formation of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) and the superoxide
radical (O*-2). These species are generated by electron leakage from enzymes involved in the
mitochondrial electron transport chain, which contain transition metal ions at their active sites (30).
Although the exact mechanism of aluminum toxicity is not known, however, accumulating evidence
suggests that the metal can potentiate oxidative and inflammatory events leading to tissue damage
(31). The brain is particularly sensitive to oxidative stress due to increased level of oxidative damage
and decrease level of antioxidants (32). Furthermore, neurons appear to be particularly vulnerable to
free radicals as the important natural antioxidant glutathione content is low, they have higher
membrane content of polyunsaturated fatty acids and brain requires substantial quantities of oxygen
for metabolism. Moreover, many neurotransmitters are autooxidisable (Dopamine, Noradrenaline)
and they react with oxygen to form superoxide, hydrogen peroxide and reactive quinines as well as
Fe are found through out the brain and important Fe containing proteins in brain includes
cytochromes, ferritin and tyrosine (21).
Mitochondria are one of the sensitive targets of oxidative stress in adult neurons (Wallace 1992).
This may be due to the fact that mitochondrial DNA (mt DNA) does not encode for any repair
enzymes and unlike nuclear DNA, it is not shielded by protective histones. Whereas mtDNA is in
close proximity to the site where free radicals are generated during oxidative phosphorylation (33).
Oxidative damage not only occurs to the proteins comprising the lesions of Alzheimer' disease, i.e.,
neurofibrillary tangles and senile plaques, but also precedes lesion formation in neurons at a risk of
death during the disease. It has been reported that oxidative stress may not be the primary etiology
of the disease, it precede specific cellular and tissue damage that underlies the onset of dementia
(19). The direct evidence supporting increased oxidative stress in AD is an increased brain Fe, Al
and Hg, capable of stimulating free radical generation (3436).
Aluminum is considered one of the contributing factors to oxidative stress, as it generates ROS.
Aluminum has been shown to cause oxidative damage to neurons through Iron (Fe2+) (37). It has
been reported that aluminum stabilize ferrous (Fe2+) ion by reducing its rate of oxidation. Fe2+
promotes the generation of oxidative species, as it actively catalyzes the Fenton reaction (38). The
Fenton reaction leads to formation of OH*, OH- and Fe3+ as aluminum suppress the superoxide
dismutase (SOD) and catalase. Superoxide radical is readily converted to H202, and the breakdown
of H2O2 to H2O and O2 by catalase is slowed down. Excess accumulation of H2O2 further leads to
the production of OH* radicals, which in turn damages various proteins, DNA and membrane lipids
(39,40).
Alteration in cell membrane structure and function in AD has been shown in several studies (41,42)
and aluminum has also been demonstrated to modify biophysical property of the membrane
structure and function. Aluminum is also reported to disturb the resting membrane potential, voltage
activated ionic channels, transmitter's secretions as well as trans membrane potential differences
and these alterations in cell membrane may be either due to direct interaction of aluminum with
membrane proteins or induction of alterations in the lipid matrix (36). Aluminum appears to bind to
the membrane polar heads resulting in injurious consequences for biological transport process and
cellular metabolism (42).
Antioxidants in cognitive dysfunction
There are a number of reports implicating oxidative stress as one of the most important contributing
factor in the development of AD. It has been reported that antioxidant supplements help to block the
process of -amyloid aggregation. According to free radical hypothesis of AD, numerous approaches
for an effective antioxidants neuroprotection have been developed. Many free radical scavengers
have been used in experimental paradigms of neuronal cell death in vitro and vivo. A number of
experimental studies have shown that free radical scavenging substances inhibit the toxic effect of
beta amyloid or superoxide on cell cultures and organs-typic hippocampus culture (43,44). Oxidative
stress is reported to be involved in the early phase of Alzheimer's disease and therapeutic
interventions then may be more useful. Commenges and Coworkers (45) found an inverse
relationship between the intake of flavonoids and the risk of incident dementia of which AD is one
possible cause. Furthermore, it has been reported that Vitamin E supplements may be associated
with a reduced risk for AD (46). Also, Engelhart and coworkers (47) assessed the relationship
between dietary intake of beta carotene, flavonoids , vitamin C and vitamin E and related risk of AD.
Sharma and Gupta (48) suggested that alpha lipoic acid act as potent free radical scavenger and it
helps in preventing cognitive impairment, oxidative stress, dementia, age and age related disorders
such as AD, Parkinson. Large population based prospective COHART study results obtained after a
mean follow up six years indicate that high dietary intake of vitamin C and vitamin E is associated
with a significantly lower risk for AD (49) (Table no.2).
Involvement of Al in the generation of
ROS:-
Table 2: Prevention of AD by antioxidants (Kedar et al; 2002).
ANTIOXIDANTS PATEINTS
WITH
EARLY AD
PATEINTS
WITH
MODERATE TO
ADVANCE AD
Al facilitate iron driven biological oxidation by formation of aluminum superoxide ion (AlO2*) and it act as a prooxidant by both catalyzing the
formation of H2O2 and reducing Fe3+ to Fe2+.
Fe
2+
+ O2 Fe
3+
+ O
2

.
2O
2
+ 2H+ H
2
O
2
+ O
2

2O
2

Al
3+
AlO2*
2+
(2H+) H
2
O
2
+ Al
3+

and Fe
3+
+ A1O2
*2+
Fe
2+
+ O
2

there by facilitating the reaction
Fe
2+
+ H
2
O
2
OH* + OH

+ Fe
3+

Ferric and ferrous forms of iron can also react with superoxide anion and hydrogen peroxide to produce molecular oxygen and hydroxyl radical (OH*)
respectively:
Fe
3+
+ O

2
Fe
2
+ O
2

Fe
2+
+ H
2
O
2
Fe
3+
+ OH* + OH

(Fenton reaction)
Hydroxy radical can be formed from superoxide anion and via Haber Weiss reaction :-
O
*
+ H
2
O
2
O
2
+ OH

+ OH*
ANTIOXIDANTS PATEINTS
WITH
EARLY AD
PATEINTS
WITH
MODERATE TO
ADVANCE AD
Natural beta carotene 30 mg/day 30 mg/day
Vitamin E d- Tocopherol succinate + d-
Tocopherol
400IU/day 600IU/day
Vitamin C (Calcium ascorbate) 2g/day 2g/day
Selenium 250g/day 200g/day
Co enzyme Q10 90mg/day 120mg/day
NADH 10mg/day 20mg/day
N-Acetyl cysteine 250mg/day 1000mg/day
-Lipoic acid 30mg/day 60mg/day
Medical therapy:
Alzheimer's disease is a slowly progressing disease, starting with mild memory problems and ending
with severe brain damage. The course disease takes and how fast changes occur vary from person
to person. On average, AD patients live from 8 to 10 years after they are diagnosed, though the
disease can last for as many as 20 years. Although prescription medications neither stop nor
slowdown the progression of Alzheimer's dementia, Cholinesterase inhibitors such as tacrine,
donepezil, matrifonate and rivestigmine might improve system in people with mild to moderate
cases. Another drug mementine (Namenda) has been approved for treatment of moderate AD.
Acetylcholine inhibitors (such as Tacrine, Donepezil, Metrifonate and Revastigmine) are currently
prescribed after disease has actually developed. This class of drugs increases the amount of
neurotransmitter, acetylcholine at the nerve terminal by decreasing its breakdown by the enzyme
Cholinesterase. Acetylcholenesterase inhibitors have been shown to modestly improve memory and
language and decrease the emotional symptoms of apathy, anxiety, hallucination, inappropriate
behavior, and abnormal movement (51).
Conclusion
Healthy human body has effective barriers, such as skin, lungs and gastrointestinal tract against
aluminum. Aluminum is not a nutrient, in other words the body has no need for this metal and
avoidance has no negative consequence. The harmful forms of aluminum enter our foods as
additives, such as emulsifier, acidifying agent, anticaking agent or coloring, cooking utensils etc.
Packaging and handling food in aluminum containers increases the amount of Al in foods. Natural
sources may be drinking water, vegetables and air. There are a number of ways for minimizing our
exposure to aluminum. Al containing antidepressants can easily be avoided, as can aluminum
utensils and even to play it safe, Al containing antacids. Commercially processed food such as
pancake, wines, frozen dough and rising flours, are source of dietary Al. Their ingestion should be
minimized. Sodium Aluminum phosphate an ingredient in baking powder, pickle and cheese should
also be avoided. Besides minimizing aluminum exposure, taking the recommended dietary
allowance (RDA) of calcium, magnesium, zinc and antioxidants should help to protect against Al
accumulation (52).
Acknowledgement
We acknowledge with thanks the financial assistance from Indian National Science Academy,
New Delhi to MH as Senior Scientist and from Indian Council of Medical Research (ICMR),
New Delhi for Adhoc grant No.59/22/2004/BMS/TRM.
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