Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To evaluate the causative role of environmental aluminum (Al) in the development of neurodegeneration in Kiiamyotrophic lateral sclerosis (ALS), we examined how chronic exposure to a low-Ca/Mg and high-Al diet induced neuronal loss and tau-related neuronal degeneration in experimental animals. Optical microscopic examination showed tau-positive cells, atrophic neurons with darkly stained cytoplasms or swollen perikarya in the cerebrum, hippocampus and the brainstem of mice fed a low-Ca/Mg high-Al diet (Group 3). The neuronal loss was found in the frontal and parietal cortices of the mice and was not due to a classical apoptosis as detected by the terminal de ynucl otidyl transferase-mediated dUTP-digoxigenin nick end-labeling (TUNEL) method. Neuronal degeneration and spheroid formation was also seen in the spinal cord of the Group 3 mice. The Morin fluorescence technique showed Al and Ca deposition in the cortical neurons and vessels in the basal ganglia of these mice. An electron microscopic examination showed intranuclear filamentous structures, intracytoplasmic vacuoles and/or darkly stained cytoplasm in the cortical neurons of Group 3 mice. These findings were seen in mice of the 11-month-experimental period and increased until the 25-month-experimental period. The present findings suggested that chronic exposure to a low-Ca/Mg high Al condition induced an accumulation of hyperphosphorylated tau in the cortical neurons, swelling of the neuronal cytoplasm and loss in the cerebrum and spinal cord of mice. Environmental factors such as a low-Ca/Mg high Al exposure might be one of the risk factors for the development of neuronal degeneration of ALS in the Kii Peninsula.
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PMID:Chronic low-Ca/Mg high-Al diet induces neuronal loss. 1241 56

Recent investigations of scrapie, Creutzfeldt-Jakob disease (CJD), and chronic wasting disease (CWD) clusters in Iceland, Slovakia and Colorado, respectively, have indicated that the soil in these regions is low in copper and higher in manganese, and it has been well-known that patients of ALS or Parkinson's disease were collectively found in the New Guinea and Papua islands, where the subterranean water (drinking water) contains much Al3+ and Mn2+ ions. Above facts suggest that these neurodegenerative diseases are closely related with the function of a metal ion. We have investigated the chemical functions of the metal ions in detail and established the unique mechanism of the oxygen activation by the transition metal ions such as iron and copper, and pointed out the notable difference in the mechanism among iron, aluminum and manganese ions. Based on these results, it has become apparent that the incorporation of Al(III) or Mn(II) in the cells induces the "iron-overload syndrome", which is mainly due to the difference in an oxygen activation mechanism between the iron ion and Al(III) or the Mn(II) ion. This syndrome highly promotes formation of hydrogen peroxide, and hydrogen peroxide thus produced can be a main factor to cause serious damages to DNA and proteins (oxidative stress), yielding a copper(II)- or manganese(II)-peptide complex and its peroxide adduct, which are the serious agents to induce the structural changes from the normal prion protein (PrP(c)) to abnormal disease-causing isoforms, PrP(Sc), or the formation of PrP 27-30 (abnormal cleavage at site 90 of the prion protein). It seems reasonable to consider that the essential origin for the transmissible spongiform encephalopathies (TSEs) should be the incorporation and accumulation of Al(III) and Mn(II) ions in the cells, and the sudden and explosive increase of scrapie and bovine spongiform encephalopathy (BSE) in the last decade may be partially due to "acid rain", because the acid rain makes Al(III) and Mn(II) ions soluble in the subterranean aquifers.
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PMID:Elucidation of endemic neurodegenerative diseases--a commentary. 1457 44

A condition of unbalanced minerals was found in soil and drinking water from three amyotrophic lateral sclerosis (ALS) foci on Guam, in the Kii Peninsula and in West New Guinea with a low concentration of calcium and magnesium coupled with a high concentration of aluminum and manganese. The current epidemiological studies in the Western Pacific including the Kii Peninsula of Japan, have suggested that environmental factors contribute to the pathogenetic process of ALS and parkinsonism-dementia (PD). Six Kii cases with ALS showed higher Ca and lower Mg contents in the central nervous system (CNS) tissues than those of neurologically normal controls. We subsequently designed an animal study to experimentally ascertain the mineral or metal deposition in CNS tissues under various dietary regimens using rats. The experimental results suggest that unbalanced minerals and/or metals lead to the accumulation not only of Ca, but also Mn, and Al, and diminution of Mg and Zn in CNS tissues of rats and humans on these dietary regimens, with implication for long-term neuronal degeneration and accumulating CNS deficit.
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PMID:[Calcium and the degenerative neurological diseases]. 1557 66

The hypothesis that neurotoxins may play a role in neurodegenerative disorders remains an elusive one, given that epidemiologic studies often provide conflicting results. Although these conflicting results may result from methodological differences within and between studies, the complexity of chemical disruption of the central nervous system cannot be ignored in attempts to evaluate this hypothesis in different neurodegenerative disorders. Spencer provides a detailed review of the complex processes involved in defining the neurotoxic potential of naturally occurring and synthetic agents. Even concepts such as exposure and dose, as often reported in studies attempting to evaluate the risk imparted by a potential compound, can be deceptive. For example, although dose reflects "that amount of chemical transferred to the exposed subject", factors such as time and concentration in the organism, the ability to access the central nervous system, and how a compound reaches the central nervous system (routes of administration) or secondarily affects other organ systems leading to central nervous system disruption are clearly important to the concept of neurotoxic risk in neurodegenerative disorders. These factors would appear to explain the observed disagreements between studies using animal or neuronal models of neurotoxicity and population-based studies in humans. The importance of these factors and how a potential neurotoxin is investigated are clearly seen in the data on AD and aluminum. In contrast, the impact of MTPT on the central nervous system is more direct and compelling. Added complexity in the study of neurotoxins in human neurodegeneration is derived from data showing that agents may have additive, potentiating, synergistic, or antagonistic effects. Therefore, data from studies evaluating EMF risks could be readily confounded by the presence or absence of heavy metals (eg, arc welding). Other factors that may conceal neurotoxic causes for a given disorder focus on additional features such as genetic predispositions, physiologic changes that occur in aging, and even nutritional status that can support or hinder the affect of a given agent on the central nervous system. Finally, many studies that investigate exposure risk do not readily incorporate the five criteria proposed by Schaumburg for establishing causation. For example, if we apply Schaumburg's first criterion, epidemiologic studies often determines the presence of an agent through history, yet they cannot readily confirm exposure based on environmental or clinical chemical analyses to fulfill this criterion for causation. Additional limitations in research design along with the populations and methods that are sued to study neurotoxins in human neurodegenerative disorders often fail to meet other criteria such as linking the severity and onset with duration and exposure level. Therefore, although studies of agents such as MTPT provide compelling models of neurotoxins and neurodegeneration in humans, disorders such as ALS, PD, and particularly AD will require additional effort if research is to determine the contribution (presence or absence) of neurotoxins to these neurologic disorders.
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PMID:Neurodegenerative memory disorders: a potential role of environmental toxins. 1575 94

The parkinsonism-dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) were the fatal neurological diseases, showing very high incidence during 1950-1970 and dramatic decrease after 1970 on Guam. Through the research, the present author insisted that; (1) NFTs in Guam ALS patients are merely a background feature widely dispersed in the population, (2) Guam ALS and PDC are basically different diseases, and (3) Guam ALS occurs initially as classic ALS. As pathogeneses of the diseases, intake of low calcium (Ca) and magnesium (Mg) and high aluminum water and of some plant excitatory neurotoxin has been speculated. To elucidate the pathogenesis, the author performed an experiment exposing rats to low Ca and/or Mg intake for two generations, so as to follow the actual way of human living on the island, since several generations live continuously in the same environment. The study indicates that continuous low Mg intake for two generations induces exclusive loss of dopaminergic neurons in in rats, and may support the Mg hypothesis in the pathogenesis of PDC of Guam.
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PMID:The nature of the parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam and magnesium deficiency. 1588 23

Aluminum is environmentally abundant, but not an essential element. Aluminum has been associated with several neurodegenerative diseases, such as dialysis encephalopathy, amyotrophic lateral sclerosis and Parkinsonism dementia in the Kii peninsula and Guam, and in particular, Alzheimer's disease. Although this association remains controversial, there is increasing evidence which suggests the implication of metal homeostasis in the pathogenesis of Alzheimer's disease. Aluminum, zinc, copper, and iron cause the conformational changes of Alzheimer's amyloid-beta protein. Al causes the accumulation of tau protein and amyloid-beta protein in experimental animals. Aluminum induces neuronal apoptosis in vivo as well as in vitro. Furthermore, a relationship between aluminum and the iron-homeostasis or calcium-homeostasis has been suggested. Based on these findings, the characteristics of aluminum neurotoxicity are reviewed, and the potential link between aluminum and neurodegenerative diseases is reconsidered.
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PMID:Effects of aluminum on the nervous system and its possible link with neurodegenerative diseases. 1630 86

Parkinsonism-dementia complex (PDC) and amyotrophic lateral sclerosis (ALS) are fatal neurological diseases. The incidence on Guam was very high between 1950 and 1965 but decreased dramatically after 1965. It is thought that drinking water containing low levels of calcium (Ca) and magnesium (Mg), and high levels of aluminum and of a plant excitatory neurotoxin are involved in the pathogenesis of these diseases. The present experiment was performed in rats that were exposed to low Ca and/or Mg intake over two generations, thus simulating the conditions of human life on Guam, where several generations live continuously in the same environment. Significant loss of dopaminergic neurons was identified exclusively in the substantia nigra in 1-year-old rats that had been exposed continuously to low Mg intake (one-fifth of the normal level) over generations. The present study suggests that low Mg intake over generations may be involved in the pathogenesis of substantia nigra degeneration in humans.
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PMID:Magnesium deficiency over generations in rats with special references to the pathogenesis of the Parkinsonism-dementia complex and amyotrophic lateral sclerosis of Guam. 1670 44

It is now 25 years since the publication of our original paper investigating the association aluminum with Alzheimer's disease. This publication reported on the results of scanning electron microscopy coupled x-ray spectrometry microprobe elemental studies of both neurofibrillary tangle-bearing and tangle-free neurons in the hippocampus of cases of Alzheimer's disease and controls. Peaks related to the presence of aluminum were consistently detected within the tangle-bearing neurons. This paper supported the association of aluminum and Alzheimer's disease on the cellular level of resolution and caused considerable interest and discussion. Subsequent work demonstrated prominent evidence of aluminum accumulation in the tangle-bearing neurons of cases of amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam. This latter observation has now been replicated using five different forms of microanalysis. Finally, using laser microprobe mass analysis, we demonstrated that the abnormally high aluminum-related signal which we originally detected was actually located within the neurofibrillary tangle, itself, and was accompanied by excess concentrations of iron. Although it is unlikely that aluminum represents an etiologic cause of Alzheimer's disease, we believe that this highly reactive element, known to cross-link hyperphosphorylated proteins, may play an active role in the pathogenesis of critical neuropathologic lesion in Alzheimer's disease and other related disorders.
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PMID:Aluminum and Alzheimer's disease, a personal perspective after 25 years. 1700 65

Gulf War illness (GWI) affects a significant percentage of veterans of the 1991 conflict, but its origin remains unknown. Associated with some cases of GWI are increased incidences of amyotrophic lateral sclerosis and other neurological disorders. Whereas many environmental factors have been linked to GWI, the role of the anthrax vaccine has come under increasing scrutiny. Among the vaccine's potentially toxic components are the adjuvants aluminum hydroxide and squalene. To examine whether these compounds might contribute to neuronal deficits associated with GWI, an animal model for examining the potential neurological impact of aluminum hydroxide, squalene, or aluminum hydroxide combined with squalene was developed. Young, male colony CD-1 mice were injected with the adjuvants at doses equivalent to those given to US military service personnel. All mice were subjected to a battery of motor and cognitive-behavioral tests over a 6-mo period postinjections. Following sacrifice, central nervous system tissues were examined using immunohistochemistry for evidence of inflammation and cell death. Behavioral testing showed motor deficits in the aluminum treatment group that expressed as a progressive decrease in strength measured by the wire-mesh hang test (final deficit at 24 wk; about 50%). Significant cognitive deficits in water-maze learning were observed in the combined aluminum and squalene group (4.3 errors per trial) compared with the controls (0.2 errors per trial) after 20 wk. Apoptotic neurons were identified in aluminum-injected animals that showed significantly increased activated caspase-3 labeling in lumbar spinal cord (255%) and primary motor cortex (192%) compared with the controls. Aluminum-treated groups also showed significant motor neuron loss (35%) and increased numbers of astrocytes (350%) in the lumbar spinal cord. The findings suggest a possible role for the aluminum adjuvant in some neurological features associated with GWI and possibly an additional role for the combination of adjuvants.
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PMID:Aluminum adjuvant linked to Gulf War illness induces motor neuron death in mice. 1711 26

Aluminum (Al), a known neurotoxin, has been implicated in Alzheimer's Disease (AD), Amyotrophic Lateral Sclerosis (ALS), Parkinsonism Dementia Complex, etc., and it causes extensive damage to the nervous system, including the impairment of learning and memory. However, to date, the mechanism of Al neurotoxicity has not been fully elucidated. Neuronal apoptosis has become a focus of interest, as it has been reported to play a key role in the impairment of learning and memory processes (Thompson, Science 267:1456, 1995). The Bcl-2 gene acts as an important effector for inhibiting apoptosis. In the present study we observe neuronal apoptosis in association with learning and memory impairment, as well as regional brain alterations in Bcl-2 expression in rats chronically exposed to Al. The chronic Al-intoxicated model was established by i.p. injection of AlCl3 in adult Sprague Dawley rats for 3 successive days, with one-day intervals, for 60 days. After exposure, the step-down test was performed to examine the behavioral reaction of the rats. Neuronal apoptosis and Bcl-2 protein expression in different regions of rat brain were then assessed by an immunohistochemical method. In the step-down test, the latency of Al-exposed rats was significantly lower than that of controls. Also, the number of performance errors in 5 minutes of exposure was significantly higher than that of controls. Neuronal apoptosis was extensive in the brain of Al-exposed groups, and the expressions of Bcl-2 protein in frontal cortex, cerebellum and hippocampus of Al-exposed rats was stronger. In conclusion, chronic Al-exposure in rats is associated with neuronal apoptosis in brain, and impaired learning and memory. Augmented Bcl-2 protein expression may be a stimulated compensatory mechanism.
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PMID:The relationship between Bcl-gene expression and learning and memory impairment in chronic aluminum-exposed rats. 1796 40


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