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Results from the Boyd Haley Laboratory relating to toxic effects of mercury to excerabation of the medical condition classified as Alzeimer's Disease
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Published: 13 years ago

Results from the Boyd Haley Laboratory relating to toxic effects of mercury to excerabation of the medical condition classified as Alzeimer's Disease

Results from the Boyd Haley Laboratory relating to toxic effects of mercury to excerabation of the medical condition classified as Alzeimer's Disease

Research regarding Alzheimer's disease (AD) in our laboratory has been directed towards detecting aberrancy in the nucleotide binding proteins of AD post-mortem brain versus age matched control brain samples. Basic to all of our findings is the following observation. Two very important brain nucleotide binding proteins, tubulin and creatine kinase (CK), show greatly diminished nucleotide binding ability and they are abnormally partitioned into the membrane fraction of AD brain tissue (1,2). What tubulin and CK have in common is that both have a very reactive sulfhydryl in their active sites that, if modified, inhibits their biological activity (14, 15). Mercury has a very high affinity for sulfhydryls and has been proven to be a potent inhibitor of both of these proteins biological activity.

After our laboratory demonstrated that tubulin had diminished biological activity in AD brain, and only AD brain, we searched for possible toxicants that might mimic this biological problem. Our finding was simple and straight-forward. After testing numerous heavy metals we observed that only mercury-II cation (Hg2+) could mimic this effect in homogenates of normal brain at concentrations that might be expected to be found under toxic conditions (3,4). The observation was that Hg2+ at 1-5 micromolar levels could selectively and totally abolish the binding activity of tubulin without any noticeable effect on other proteins. This gave a nucleotide binding profile that was identical to that observed in AD brain (4,5,6). Further, recent results in our laboratory have shown that the addition of Hg2+ to control brain homogenates not only caused the decrease in nucleotide interaction but could also cause the abnormal partitioning of tubulin into the particulate fraction as observed in AD brain (7). This was especially effected in the presence of other metals (see below).

The next set of experiments was to determine if mercury vapor, the form that escapes from dental amalgams, could mimic the effect in rats exposed to such vapor for various periods of time (5). Rats are different from humans in that their cells can synthesize vitamin C whereas humans have to ingest vitamin C. Vitamin C is thought to be somewhat protective against heavy metal toxicity and other oxidative stresses. However, we observed that the tubulin in the brains of rats exposed to mercury vapor lost between 41 and 75 percent of the nucleotide binding capability demonstrating a Hg2+ induced similarity to the aberrancy observed in AD brain (5). Consistent with this was a recent report by Dr. Michael Aschner of Wake Forrest University at the 1998 Spring IAOMT meeting. He stated that Western blot analysis of brains of rats exposed to mercury vapor (as above) showed elevated levels of an enzyme called glutamine synthetase (GS) when compared to non-treated controls. This is consistent with a report published from our laboratory in 1992 where we predicted that the elevation of GS in the cerebrospinal fluid of AD patients had potential as a diagnostic marker for AD (12). This potential value of GS as a diagnostic aid for AD was recently confirmed by German scientists (16). We feel that, while mercury has effects on tubulin, CK and GS and that these proteins are proven to be aberrant in AD, this still does not conclusively prove that mercury exposure causes AD. However, it definitely proves that chronic, daily exposure to mercury would exacerbate the clinical conditions of Alzheimer's disease by the ability of low doses of mercury to inhibit enzymes known to be inhibited in AD brain.

We were interested in the genetic research regarding AD and followed this work to see if it correlated to our results. That is, does susceptibility to heavy metal toxicity have any relationship to AD? When we read the correlation of APO-E4 to age of onset of AD we were intrigued enough to look at the primary structure of this protein and its alleles, APO-E2 and APO-E3. In general, the story is this. Individual with APO-E2 or combinations of APO-E2 and E3 are much less likely to get AD than are individuals who have inherited APO-E4 genes. Also, APO-E2 appears to be more protective than APO-E3 against AD. What is the basic structural difference between these three alleles? Simply, the protective APO-E2 has two sulfhydryls (cysteines) which can bind mercury or other heavy metals that APO-E4 lacks. For example, in APO-E3, one of these cysteines is replaced by an arginine and in APO-E4, both of the cysteines are replaced by arginine. Therefore, lack of protection against AD follows loss of sulfhydryls from APO-E proteins (6). What does APO-E protein do. It is involved in cholesterol transport and all three forms work reasonably well at this. However, APO-E is classified as a "housekeeping protein". That is, in contrast to tubulin and CK which are meant to stay inside of cells where they are synthesized, APO-E is meant to leave the cell carrying out unwanted material for the body to dispose of. In the brain, APO-E protein leaves brain cells and goes into the cerebrospinal fluid (CSF) and then crosses the blood brain barrier into the blood plasma. It is cleared from the blood by processes that dispose of the unwanted material that it is carrying. It is our hypothesis that while APO-E2 or E3 are leaving the brain cells and traversing the CSF they likely bind any heavy metal or other sulfhydryl reactive toxin that may have made it into the central nervous system (6). APO-E4 could not do this and therefore loses the protective parameters that APO-E2 and E3 have. It is interesting to note that the second highest level of APO-E protein is in the CSF that bathes and protects the brain cells.

There was considerable debate concerning whether or not mercury reaches levels in the brain that could be considered toxic. The determination of the levels of mercury toxicity that could cause neurological disease has been done using animals, such as rats, under tightly controlled laboratory conditions where the diet is carefully monitored to exclude other toxicants. However, humans do not live under such restricted conditions and heavy metal imbalances in AD brains have been reported numerous times. For example, lead (Pb) toxicity is not that uncommon in the inter-city environment or for those exposed to leaded gasoline fumes for many years. The latest research in our laboratory has shown that one can add various metals to human brain homogenates to levels that do not affect nucleotide binding to tubulin yet the very presence of these metal potentiate the toxicity of mercury. That is, the presence of Zn2+ and Cd2+, at non-toxic levels, decrease the amount of Hg2+ required for 50% inhibition of tubulin or creatine kinase viability. When we compare the toxicity of Hg2+ in brain homogenates as described above (refs. 3 & 4) the addition of 0, 10 and 20 micromolar Zn2+ increases the inhibition of GTP binding to tubulin from 4% to 50% and 76%, respectively (7,13). In other words, mercury is much more toxic in the presence of other metals that compete with mercury for the binding sites on protective biomolecules (e.g., APO-E2 & E3, glutathione, metallo-thionine, ect.). This observation probably explains some observations on the toxicity of solutions in which dental Amalgams have been soaked. The most recent publication in this area seems to put an end to the argument as to whether or not mercury from dental Amalgams pose a threat to the exacerbation of AD. Olivieri et al. demonstrated that exposure of neuroblastoma cells to 36 X 10-9 molar Hg2+ caused an increased secretion of ß-amyloid protein 4 to 6 hours later and increased phosphorylation of the microtubulin protein Tau (17). Both of these biochemical changes are uniquely observed in AD brain tissues and ß-amyloid protein makes up the 'amyloid plaques' that are the hallmark diagnostic marker for AD on brain pathology. A very strong component of AD researchers believe that amyloid protein is the cause of AD. Therefore, mercury exposure at nanomolar levels causes neuroblastoma cells to produce a protein that is believed to be involved directly in AD. However, this data supports the initial contention from the Haley laboratory that mercury first inhibits enzymes like tubulin, creatine kinase and glutamine synthetase and dramatically affects metabolism. After these inhibitions occur the cell responds to the cytotoxicity by producing and secreting amyloid protein which forms the amyloid plaques observed on brain pathology and used to substantiate the AD diagnosis. To the point, amyloid plaques are the result of AD, not the cause. The cause is exposure to environmental toxicants like mercury.

Wataha et al. (8) reported that extracts of the Amalgam material (trade name, Dispersalloy) "was severely cytotoxic when Zn release was greatest, but less toxic between 48 and 72 hours as Zn release decreased". Zn is an essential metal needed for health and many times recommended by physicians to be taken in supplemental form. It is my opinion that the increased toxicity was not caused by direct Zn toxic effects. Rather, enhanced toxicity was due to the Zn potentiated toxicity of mercury caused by Zn2+ occupying biomolecule chelation sites resulting in a higher concentration of free Hg2+ capable of inhibiting the activity of critical nucleotide binding proteins such as tubulin and CK. This raises the question if mercury is released from Amalgams under similar conditions. Chew et al. (9) tested the "long term dissolution of mercury from a non-mercury-releasing amlagam (trade name Composil)". Their results demonstrated "that the overall mean release of mercury was 43.5 +/-3.2 micrograms/cm2/24hr, and the amount of mercury released remained fairly constant during the duration of the experiment (2 years)". In my opinion, this is not an insignificant amount of mercury exposure if one considers the number of years a 70 year old individual living today may have been exposed. In the Haley laboratory we soaked Amalgam fillings in distilled water and then tested the resulting solution for toxicity. The results were obvious, the water was now extremely toxic and when added to brain homogenates dramatically inhibited the viability of tubulin and creatine kinase, exactly as observed when we added mercury cation. The bottom line is that mercury toxicity is enhanced by the presence of other heavy metals and both are released from dental amalgams. Additionally, when one considers the toxicity of a certain body level of mercury it is somewhat meaningless unless the body level of other heavy metals is also considered.

Many recent literature and popular press reports state that the presence of periodontal disease raises the risk factor or exacerbates the condition of several other seemingly unrelated diseases such as stroke, low birth weight babies, cardiovascular disease (See October 1996 issue of Periodontology). The anerobic bacteria of periodontal disease produce hydrogen sulfide (H2S) and methyl thiol (CH3SH) from cysteine and methionine, respectively. This accounts for the "bad breath" many individuals have. However, in a mouth that produces H2S, CH3SH (from periodontal disease) and Hgo (from Amalgam fillings) the very likely production of their reaction products, HgS (mercury sulfide), CH3S-Hg-Cl (methyl thiol mercury chloride) and CH3S-Hg-S-CH3 (Dimethylthiol mercury) has to occur. This is simple, un-refutable chemistry whose presence is supported by easily observable amalgam tattoos. These tattoos are purple gum tissue surrounding certain teeth where the gum and tooth meet and caused by HgS as determined by mercury analysis of such tissue. HgS is one of the most stable forms of mercury compounds and is the mineral form of mercury, called cinnabar, from which mercury is mined from the earth). All of these compounds are classified as extremely toxic and the latter compound, dimethylthiol mercury is very hydrophobic and it solubility similar to dimethyl mercury. Dimethyl mercury was the compound that was recently in the press where only a small amount spilled on the latex gloves of a Dartmouth University professor caused severe medical problems and finally death. Logic implys that anyone with periodonatal disease, anaerobic bacterial infected teeth and mercury containing fillings would be exposed daily to these very toxic compounds. In the Haley laboratory we synthesized the two methylthiol-mercury compounds and tested them. They are extremely cytotoxic at 1 micromolar or less levels and are potent, irreversible inhibitors of a number of important mammalian enzymes, including tubulin and CK.

To determine if toxic teeth could have an effect on the enzymes/proteins of human brain we have done the following study. Several very toxic teeth were incubated for 1 hour in distilled water. Aliquots of these solutions were then added to control human brain homogenates and the resulting samples tested for enzyme viability. The result showed that several of the solutions, but not all, in which toxic teeth had been incubated inhibited the viability of the same enzymes that are found to be inhibited in AD brain. Therefore, depending on the type of anerobic bacterial infection in avital teeth it is possible to have a toxicant production that would exacerbate the condition classified as AD.

In summary, the data on the effects of mercury on the nucleotide binding properties and the abnormal partitioning of two very important brain nucleotide binding proteins first suggested that mercury must be considered as a contributor to the condition classified as AD. This is strongly supported by the recent finds that nanomolar levels of mercury causes neuroblastoma cells to secrete ß-amyloid protein and increase phosphorylation of the microtubulin associated protein Tau, both major biochemical observations related to AD. Consideration of mercury as an exacerbating factor is especially relevant when mercury is present in combination with other heavy metals such as zinc (Zn) cadium (Cd) and lead (Pb). Bluntly, the determination of safe body levels of mercury by using animal data where the animals have not been exposed to other heavy metals is no longer justifiable. Mercury is much more toxic to individuals with other heavy metal exposures. As I have been sent numerous lab reports on levels of elements in the hair and other tissues of suspected mercury toxic patients I have noticed that many have exceedingly high Pb, Cd, Cu, Zn, etc. levels. It is my opinion that one of the major questions left to be answered concerning the toxic effects of mercury is "does the combination of mercury with different heavy metals lead to different clinical observations of toxicity?" There can be little doubt that the elevated levels of other heavy metals increases the toxicity of mercury. Further, the reaction of oral mercury from amalgams and the reaction of this mercury with toxic thiols produced by periodontal disease bacteria very likely enhances the toxicity of the mercury being released. This makes any claim regarding the determination of safe levels of mercury as obtained under controlled conditions (e.g. in a system where other heavy metals are excluded) very suspect when discussing toxic mercury effects in the uncontrolled environment that humans are exposed to.

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