Aluminium exposure induces Alzheimer's disease-like histopathological alterations in mouse brain (original) (raw)
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Multifaceted effects of aluminium in neurodegenerative diseases: A review
Biomedicine & Pharmacotherapy, 2016
Aluminium (Al) is the most common metal and widely distributed in our environment. Al was first isolated as an element in 1827, and its use began only after 1886. Al is widely used for industrial applications and consumer products. Apart from these it is also used in cooking utensils and in pharmacological agents, including antacids and antiperspirants from which the element usually enters into the human body. Evidence for the neurotoxicity of Al is described in various studies, but still the exact mechanism of Al toxicity is not known. However, the evidence suggests that the Al can potentiate oxidative stress and inflammatory events and finally leads to cell death. Al is considered as a well-established neurotoxin and have a link between the exposure and development of neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS), Alzheimer's disease (AD), dementia, Gulf war syndrome and Parkinsonism. Here, we review the detailed possible pathogenesis of Al neurotoxicity. This review summarizes Al induced events likewise oxidative stress, cell mediated toxicity, apoptosis, inflammatory events in the brain, glutamate toxicity, effects on calcium homeostasis, gene expression and Al induced Neurofibrillary tangle (NFT) formation. Apart from these we also discussed animal models that are commonly used for Al induced neurotoxicity and neurodegeneration studies. These models help to find out a better way to treat and prevent the progression in Al induced neurodegenerative diseases.
Aluminium in Alzheimer’s disease: are we still at a crossroad
Experientia, 2005
Aluminium, an environmentally abundant non-redox trivalent cation has long been implicated in the pathogenesis of Alzheimer’s disease (AD). However, the definite mechanism of aluminium toxicity in AD is not known. Evidence suggests that trace metal homeostasis plays a crucial role in the normal functioning of the brain, and any disturbance in it can exacerbate events associated with AD. The present paper reviews the scientific literature linking aluminium with AD. The focus is on aluminium levels in brain, region-specific and subcellular distribution, its relation to neurofibrillary tangles, amyloid beta, and other metals. A detailed mechanism of the role of aluminium in oxidative stress and cell death is highlighted. The importance of complex speciation chemistry of aluminium in relation to biology has been emphasized. The debatable role of aluminium in AD and the cross-talk between aluminium and genetic susceptibility are also discussed. Finally, it is concluded based on extensive literature that the neurotoxic effects of aluminium are beyond any doubt, and aluminium as a factor in AD cannot be discarded. However, whether aluminium is a sole factor in AD and whether it is a factor in all AD cases still needs to be understood.
Aluminium and Alzheimer’s Disease: A Suspicious Link
Aluminium (Al) has long been implicated in the etiology of the neurodegenerative diseases like Alzheimer's disease (AD). Although abundant studies substantiated its potential role in inducing neurotoxic effects, yet this subject has been a controversy of profound importance. This article summarizes the various ways in which Al induces oxidative stress, eventually leading to cell death. It also gives a brief account of manifold epidemiological studies that relate the abundant occurrence of Al in soil and water and the prevalence of AD. Al carriers, their role in AD, Al in neurofibrillary tangles, biochemical reactions altered by Al influx in mitochondria have been briefly discussed.
Molecular toxicity of aluminium in relation to neurodegeneration
The Indian journal of medical research, 2008
Exposure to high levels of aluminium (Al) leads to neurofibrillary degeneration and that Al concentration is increased in degenerating neurons in Alzheimer's disease (AD). Nevertheless, the role of Al in AD remains controversial and there is little proof directly interlinking Al to AD. The major problem in understanding Al toxicity is the complex Al speciation chemistry in biological systems. A new dimension is provided to show that Al-maltolate treated aged rabbits can be used as a suitable animal model for understanding the pathology in AD. The intracisternal injection of Al-maltolate into aged New Zealand white rabbits results in pathology that mimics several of the neuropathological, biochemical and behavioural changes as observed in AD. The neurodegenerative effects include the formation of intraneuronal neurofilamentous aggregates that are tau positive, oxidative stress and apoptosis. The present review discusses the role of Al and use of Al-treated aged rabbit as a suitab...
Aluminium and Neuro-degeneration: Mechanism of Pathogenesis and Possible Strategies for Mitigation
One of the most abundant metal in our environment is aluminium (Al). Occupational exposure of humans to Al takes place during its extractions, processing and fabrications of articles of daily use. Al in drinking water and as well as its use in packaging & storage of food is also a potential source of exposure. Acute exposure of higher concentration or chronic exposure of low concentration of Al leads to its aggregation in various parts of the body, resulting in system toxicity. Brain is highly susceptible to Al accumulation toxicity. In humans, exposure of Al is a risk factor for the starting of Alzheimer Disease. The adverse effect of Al exposure on nervous system results in memory loss, balance problems and impairment of coordination. High level of Al in brain increases lipid peroxidation and oxidative stress and reduces antioxidant enzymes level. It also causes aggregation of amyloid beta proteins and formation of Neurofibrillary Tangles (NFTs) of tau proteins which finally leads to death of neuronal cell and neurotoxicity. Metabolism and excretion of heavy metals including Al is very difficult and its leads to accumulation. The chelation therapy has been proposed where the organic molecules like EDTA, Chlorogenic acid and GSH binds with the heavy metals and facilitates for their excretion from body. However, non-specific binding of these chelators is another major safety concern. Medicinal plants and their phytochemicals with multiple mechanism of action have been proposed as a very good alternative for ameliorating heavy metal induced toxicity. In addition to mild chelating activities, the phytochemicals have antioxidant, anti-inflammatory, cytokine modulatory and other specific actions for proving holistic neuro-protection on heavy metal exposure.
Hippocampus, 2009
It is well established that aluminum (Al) is a neurotoxic agent that induces the production of free radicals in brain. Accumulation of free radicals may cause degenerative events of aging such as Alzheimer's disease. On the other hand, melatonin (Mel) is a known antioxidant, which can directly act as free radical scavenger, or indirectly by inducing the expression of some genes linked to the antioxidant defense. In this study, AβPP female transgenic (Tg2576) (Tg) and wild-type mice (5 months of age) were fed with Al lactate supplemented in the diet (1 mg Al/g diet). Simultaneously, animals received oral Mel (10 mg/kg) dissolved in tap water until the end of the study at 11 months of age. Four treatment groups were included for both Tg and wild-type mice: control, Al only, Mel only, and Al+Mel. At the end of the period of treatment, hippocampus was removed and processed to examine the following oxidative stress markers: reduced glutathione (GSH), oxidized glutathione (GSSG), superoxide dismutase (SOD), glutathione reductase (GR), glutathione peroxidase (GPx), catalase (CAT), and thiobarbituric acid reactive substances (TBARS). Moreover, the gene expression of Cu-ZnSOD, GR, and CAT was evaluated by real-time RT-PCR. Aluminum concentration in hippocampus was also determined. The biochemical changes observed in this tissue suggest that Al acts as a pro-oxidant agent. Melatonin exerts an antioxidant action by increasing the mRNA levels of the antioxidant enzymes SOD, CAT, and GR evaluated in presence of Al and Mel, with independence of the animal model. © 2009 Wiley-Liss, Inc.
Journal of Inorganic Biochemistry, 2001
Aluminium (Al) is a neurotoxicant and appears as a possible etiological factor in Alzheimer's disease and other neurological disorders. The mechanisms of Al neurotoxicity are presently unclear but evidence has emerged suggesting that Al accumulation in the brain can alter neuronal signal transduction pathways associated with glutamate receptors. In cerebellar neurons in culture, long term-exposure to Al added 'in vitro' impaired the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activation of NO synthase and NO-induced activation of the cGMP generating enzyme, guanylate cyclase. Prenatal exposure to Al also affected strongly the function of the glutamate-NO-cGMP pathway. In cultured neurons from rats prenatally exposed to Al, we found reduced content of NO synthase and of guanylate cyclase, and a dramatic decrease in the ability of glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP pathway was also strongly impaired in cerebellum of rats chronically treated with Al, as assessed by in vivo brain microdialysis in freely moving rats. These findings suggest that the impairment of the Glu-NO-cGMP pathway in the brain may be responsible for some of the neurological alterations induced by Al.
Aluminum and Alzheimer's disease: a new look
Journal of Alzheimer's disease : JAD, 2006
Despite the circumstantial and sometimes equivocal support, the hypothetic involvement of aluminum (Al) in the etiology and pathogenesis of Alzheimer's disease (AD) has subsisted in neuroscience. There are very few other examples of scientific hypotheses on the pathogenesis of a disease that have been revisited so many times, once a new method that would allow a test of Al's accumulations in the brain of AD patients or a comparison between Al-induced and AD neuropathological signs has become available. Although objects of methodological controversies for scientists and oversimplification for lay spectators, several lines of evidence have strongly supported the involvement of Al as a secondary aggravating factor or risk factor in the pathogenesis of AD. We review evidence on the similarities and dissimilarities between Al-induced neurofibrillary degeneration and paired helical filaments from AD, the accumulation of Al in neurofibrillary tangles and senile plaques from AD, the...
Effects of Aluminium on β-Amyloid (1–42) and Secretases (APP-Cleaving Enzymes) in Rat Brain
Neurochemical Research, 2014
Chronic administration of aluminium has been proposed as an environmental factor that may affect some pathological changes related to neurotoxicity and Alzheimer's disease (AD). The abnormal generation and deposition of b-amyloid (Ab) in senile plaques are hallmark features in the brains of AD patients. Furthermore, Ab is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (a-secretase, or b-secretase) and c-secretase. In the present study, we investigated the modulation of Ab deposition and neurotoxicity in aluminium-maltolate-treated (0, 15, 30, 45 mmol/kg body weight via intraperitoneal injection) in experimental rats. We measured Ab1-40 and Ab1-42 in the cortex and hippocampus in rat brains using ELISA. Subtypes of a-secretase, b-secretase, and c-secretase, including ADAM9, ADAM10, ADAM17 (TACE), BACE1, presenilin 1 (PS1) and nicastrin (NCT), were determined using western blotting analyses. These results indicated that aluminium-maltolate induced an AD-like behavioural deficit in rats at 30 and 45 mmol/kg body weight. Moreover, the Ab1-42 content increased significantly, both in the cortex and hippocampus, although no changes were observed in Ab1-40. Furthermore, ADAM9, ADAM10, and ADAM17 decreased significantly; in contrast, BACE1, PS1, and NCT showed significant increase. Taken together, these results suggest that the changes in secretases may correlate to the abnormal deposition of Ab by aluminium in rat brains.
Neurotoxicology, 2016
Aluminum (Al) is a very common component of the earth's mineral composition. It is not essential element for life and is a constituent of rather inert minerals. Therefore, it has often been regarded as not presenting a significant health hazard. As a result, aluminum-containing agents been used in the preparation of many foodstuffs processing steps and also in elimination of particulate organic matter from water. More recently, the reduced pH of bodies of water resulting from acid rain has led to mobilization of aluminum-containing minerals into a more soluble form, and these have thus entered residential drinking water resources. By this means, the body burden of aluminum in humans has increased. Epidemiological and experimental findings indicate that aluminum is not as harmless as was previously thought, and that aluminum may contribute to the inception and advancement of Alzheimer's disease. Epidemiological data is reinforced by indications that aluminum exposure can resu...