|Year : 2020 | Volume
| Issue : 2 | Page : 107-111
The role of trace elements in Alzheimer's disease
Sujeetha Purushothaman1, Aashika Ragavi2, Preethi Basavaraju3, Puthamohan Vinayaga Moorthi4, Arumugam Vijaya Anand5
1 Department of Human Genetics and Molecular Biology, Medical Genetics and Epigenetics Laboratory, Bharathiar University, Coimbatore, Tamil Nadu, India
2 Student, Medical Genetics and Epigenetics Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
3 Research Scholar, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
4 Assistant Professor, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
5 Professor, Medical Genetics and Epigenetics Laboratory, Department of Human Genetics and Molecular Biology, Bharathiar University, Coimbatore, Tamil Nadu, India
|Date of Submission||27-Apr-2020|
|Date of Acceptance||09-Oct-2020|
|Date of Web Publication||14-Jan-2021|
Mrs. Sujeetha Purushothaman
Department of Human Genetics and Molecular Biology, Medical Genetics and Epigenetics Laboratory, Bharathiar University, Coimbatore, Tamil Nadu
Source of Support: None, Conflict of Interest: None
Alzheimer's disease is a degenerative brain disease and the most common cause of dementia. The characteristic symptoms of dementia are difficulties with memory, language, problem solving, and other cognitive skills which affects a person's ability to perform everyday activities. Trace elements have found to play a major role in the Alzheimer's disease. Nowadays, the association of trace elements in the pathogenesis of Alzheimer's disease is more considered, and trace elements such as aluminum (Al), iron (Fe), copper (Cu), and zinc (Zn) imbalances in the amyloid beta peptides have been seen in the Alzheimer's disease This review focuses on the accumulation of trace elements aluminum (Al), copper (Cu), iron (Fe), and zinc (Zn) in the pathogenesis of Alzheimer's disease.
Keywords: Accumulation, Alzheimer's disease, amyloid beta peptides, trace elements
|How to cite this article:|
Purushothaman S, Ragavi A, Basavaraju P, Moorthi PV, Anand AV. The role of trace elements in Alzheimer's disease. Arch Ment Health 2020;21:107-11
|How to cite this URL:|
Purushothaman S, Ragavi A, Basavaraju P, Moorthi PV, Anand AV. The role of trace elements in Alzheimer's disease. Arch Ment Health [serial online] 2020 [cited 2021 Feb 25];21:107-11. Available from: https://www.amhonline.org/text.asp?2020/21/2/107/306860
| Methods of Inquiry|| |
The literature search was performed based on the topics addressing the role of trace metals in Alzheimer's disease in the databases PubMed and Google Scholar, and some literature was searched through Google. The search terms (concept) included the following topics: (1) Alzheimer's disease, (2) metals, and (3) role of metals in Alzheimer's disease. The search language was English. There was no specific time limit.
| Introduction|| |
Dementia is decline in the memory and other cognitive abilities. Alzheimer's disease the most common form of dementia and an irreversible neurodegenerative disorder accounting to 80% of dementia cases. Age is the most important factor in the role of Alzheimer disease. The report “Dementia India” published by Alzheimer's and Related Disorders Society of India has reported that about 4.1 million in India are suffering from it and India hosts its second place. Maharashtra and Uttar Pradesh alone are expected to house more than 500,000 patients by 2026. India has an ever growing elderly population, out of which 1.6 million are suffering from Alzheimer's. This number is only expected to triple by 2050 (Times of India, September 21, 2017). The estimates of rate at which new disease develops can only be measured accurately in prospective incidence studies. According to the World Alzheimer Report 2015, an estimated 46.8 million people worldwide were living with dementia, and these numbers will double every 20 years. The estimated incidence of dementia in 2015 was 9.9 million new cases every year, which means one new, case every 3.2s. Worldwide, nearly 44 million people have Alzheimer's or a related dementia (Alzheimer's disease International). Alzheimer's disease has become the most important economic problem in which it requires a better management and therapies to decrease the burden of the disease. Despite the role of genetics, epidemiology, and risk factor, there is no cure for Alzheimer's disease. Pathologically, it is characterized by the presence of amyloid plaques and neurofibrillary tangles by inhibiting the neuronal activity and the loss of synaptic density. The brain regions that are involved in the accumulation of the plaques and neurofibrillary tangles are the regions of entorhinal cortex, hippocampus, basal forebrain, and amygdale which are meant for learning, memory, and emotional behavior.
Many hypotheses in the pathology of Alzheimer's disease have been formulated in which it involves genetic factors, lack of membrane metabolism, and trace elements neurotoxicity. Metals are necessary elements that our bodies require to carry out the process of living. The consuming of metals is also through food, which can typically clear through the kidneys. However, large amounts of metal cannot be cleared, and those metals can be deposited in the brain. Nowadays, the trace elements and its association in the pathogenesis of Alzheimer's disease is more considered, and it is seen that many trace elements such as aluminum, iron, copper, and zinc imbalances in the amyloid beta peptides has been seen in the Alzheimer's disease. This review focus on the trace elements accumulation leading to the aggregation of amyloid beta peptides in the brain regions which induces the pathology of Alzheimer's disease.
| Metal Homeostasis in Alzheimer's Disease|| |
Metal ions play essential roles in the brain, and there is solid evidence pointing to their homeostatic dysfunction across different neurodegenerative diseases. This includes the first row transition metals, iron, copper, and zinc, and also calcium, whose homeostasis is important for neuronal function and during aging. The most specialized organ the brain which it requires metal ions for performing certain cellular process and it is highly concentrated with more transition metals such as iron, zinc, and copper these take part in the neuronal activity within the synapses Zinc II also regulates the mechanism of other metalloproteinase in which their by make an control over the metal-ion homeostasis. If any fluctuations is seen in the absorption of metals or changes in the balances of ions results in the disease condition which includes Alzheimer's disease. Many studies have shown that copper, zinc, and iron as well as nonphysiological aluminum is involved in Alzheimer's disease. They are suggested to have two distinct roles in the pathophysiology of Alzheimer's disease: Amyloid beta peptide aggregation and production of reactive oxygen species (ROS) induced by amyloid beta peptide.
The aggregation of amyloid beta peptide is mediated by interaction with metals, in particular zinc, copper, and iron. Amyloid beta peptides also catalyses the reduction of Cu2+ and Fe3+ which in the absence of sufficient antioxidant mechanisms, could lead to the production of toxic ROS that may contribute to the pathogenesis of Alzheimer's disease.
| Aluminum|| |
Aluminum is cation that does not undergo redox reactions and plays an important role in much neurological disease by increased ROS formation these accumulating induce the potential oxidative and inflammatory events leading to tissue events. The suspected role of aluminum in the Alzheimer's disease by the intra-cerebral injections to the rabbits with aluminum in which the rabbits show the neurofibrillary tangles., In amyloids, the concentration of Aluminum III is seen in high concentrations, the studies reported that the Aluminum III facilitates the amyloid beta peptide aggregation, but the concentration of Aluminum III is above the significant levels but when exposed to lower concentrations, it does not show any amyloid beta aggregation.
By using the paramagnetic resonance spectroscopy studied the frontal cortex tissue samples of Alzheimer's showed elevated levels of ferrous salts the free radicals when compared to the controlled subjects. Similarly, the investigations of Zhou et al. reported that the rate of lipid per oxidation in the temporal cortex region was more than the controlled subjects and also the level superoxide dimutase was significantly decreased in the regions of frontal and temporal cortex of Alzheimer's than controls. A direct link between the aluminum and Alzheimer's diseases not yet established, but it is clearer that aluminum induces the ROS and inflammation resulting in the disease process.
| Iron|| |
Iron the most copious metals found in the body. Of the total body, two-third is iron which is present in the blood as hemoglobin and myoglobin followed by their regulatory proteins ferritin and transferrin more over it plays a major role in the brain such that it maintains the levels of dopamine and gamma-amino butyric acid ergic neurotransmissions. An elevated level of ferrous iron leads to the neuronal degeneration by the ROS to see this effect Marcus et al. in their investigation reported that the increased amyloid beta levels by elevated iron in the environment by ROS.
Lovell et al. studied the mouse model which lacks IRP2 in this more HFE gene mutations was seen such that it increased the onset of Alzheimer's disease and also an iron dyshomeostasis was induced by the factors and result in the neurogenerative diseases. HFE mutations characterize a risk factor or genetic modifier for Alzheimer's disease. This HFE protein is seen in the astrocytes in the patients of Alzheimer's disease and created an iron imbalances and disturbs the iron metabolism is a primary risk factor for oxidative stress and neurodegeneration in Alzheimer's disease.
The brain of Alzheimer's disease humans is characterized by the accumulation of iron within senile plaques (ca. 1 mM) and neurofibrillary tangles and also by the lowered expression of transferring receptor. As a consequence, these brains are subject to the high levels of oxidative stress.
Iron may also promote amyloid beta deposition and may affect the enzymatic processing of the amyloid precursor protein most likely, iron-induced oxidative damage acting on mitochondria contributes to the cellular death mechanism that results from an attenuation of respiratory chain activity. The significant reduction in transferrin levels, observed in Parkinson's disease and Alzheimer's disease, may act as a contributory factor to increase iron concentrations.
| Copper|| |
In all the living systems, copper plays an preliminary role and act as an active center in oxidase and oxygenase activities electron transfer by limiting the oxygen radicals, it plays an important role in the many disease such as copper metabolism disease and neurodegenerative diseases. The excessive intracellular makes copper to become more toxic and leads to the production of ROS.
Various types of oxidative damage have been noted in Alzheimer's disease, including glycation, protein oxidation, lipid peroxidation, and nucleic acid oxidation. An Aβ-amyloid-42-centred model that amyloid peptide induces and antioxidants inhibit protein oxidation, lipid peroxidation, ROS production, and many other markers of oxidative stress. Besides the production of ROS, a role for copper, in neurodegeneration emerges from the direct binding at specific sites in the involved proteins. Only SOD1 is a cupro-enzyme, but the amyloid precursor protein and its amyloid beta peptides fragments possess sequence motifs that offer specific binding sites to copper II ions.
According to the animal studies (APP-knockout mice), amyloid precursor protein seems to play some role in copper and iron homeostasis. One of the possible functions of amyloid precursor protein is copper transport from the extracellular to intracellular space. The expression of amyloid precursor protein is an modular in the neuronal copper homeostasis and the knockout mice show elevated copper levels. This increase in copper level increases the level of membrane bound amyloid precursor protein and thus inhibits the amyloid beta peptide secretion. Amyloid beta peptide critical for Alzheimer's disease is found as a major species within the senile plaques in the brain. The studies on the intact plaques strongly suggest that amyloid beta peptide is a metalloprotein species in vivo.
In contrast to increased extracellular copper levels, intracellular copper levels appear to be reduced in Alzheimer's disease brain compared to controls. Moreover, the activity of several cuproenzymes is diminished in Alzheimer's disease, including copper/zinc superoxide and cytochrome oxidase. In addition, interactions of copper with Tau peptide have been assumed to induce the development of neurofibrillary tangles, one of the hallmarks of Alzheimer's disease.
| Zinc|| |
Zinc is the second most copious trace elements seen in the body after iron. The highest concentrations of zinc are found in the brain. In the brain, chelatable, i.e., removable by chelating agents, zinc highly occurs in the hippocampus, amygdala, and in the cortex. Beyond this, zinc is tightly bound by many intracellular enzymes. Zinc, in its ionic form, can also exert important modulatory effects on neurotransmission and synaptic function, as well as regulate many signaling pathways.
The potential role of zinc in the pathology of Alzheimer's disease was emphasized by the finding of zinc enrichment within Alzheimer's disease plaques and a zinc increase in the neuropil of Alzheimer's disease patients compared to controls. Zinc has a crucial role in amyloid beta peptides aggregation, which is the most well-established contribution that zinc may have in Alzheimer's disease pathogenesis. Aggregation of amyloid beta peptides into protease-resistant deposits can be rapidly induced in the presence of zinc ions under physiological conditions in vitro.
The precise mechanism of the protective effect of zinc against amyloid beta peptides toxicity is unclear; nevertheless, the possible mechanism may include competing with Cu (or iron) for amyloid beta peptides binding. Binding of zinc to amyloid beta changes its conformation to the extent that copper ions cannot reach its metal binding sites. Preventing copper from interacting with amyloid beta may prevent the copper-amyloid beta peptides induced formation of hydrogen peroxide and free radicals. Recently, it has been shown that zinc can also accelerate the aggregation of a Tau peptide; the major protein subunit of neurofibrillary tangles, under reducing condition. Zinc inhibited the formation of intramolecular disulphide bonds but promoted intermolecular bonds between key cysteine residues.
| Conclusion|| |
From this review, it is clear that the changes in the essential metals trigger the initiation of enzymes which contribute a major role in the pathology of Alzheimer's disease. Moreover, the brain require these metals at higher concentration to carry out the important functions properly but, when these metals get altered in their mechanism the metal ion homeostasis is disrupted severely causes the abnormal levels of copper II, Zinc II, and iron III leading to the Alzheimer's disease. Consequently, the brain has a poor capacity to cope with the oxidative stress generated by the redox active copper II and iron III ions accumulated in amyloid beta aggregates.
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