Kip Sullivan is an attorney from Minneapolis that has recovered from an "incurable" illness after having his amalgam fillings removed. Since then he has been an advocate for making this treatment more readily accepted and available to others suffering from neurological diseases, and has done extensive research which is documented in a memo that he is presenting to several well known Alzheimer's medical researchers in the Minneapolis area. The following are excerpts from the memo, presented here with Kip's permission, without the extensive footnotes, references and tables contained within the memo. Anyone wishing additional information with regard to the content presented here should contact Kip at (612)823-1459.

Robert Terry et al. are the authors of a book which reviews current knowledge about Alzheimer's Disease (AD). The book was recently described as "the best single book on the topic" by the New England Journal of Medicine and as "a most useful reference for practitioners of medicine" by the Journal of the American Medical Association. At page 363 of this book, Terry et al. state: "Taken together, these studies suggest that chronic low level Hg toxicity in AD should be considered as a potential pathogenetic factor in AD." Because amalgam is the dominant source of human exposure to mercury, one may paraphrase this conclusion as follows: "Chronic low level exposure to mercury from amalgam should be considered as a factor in AD."

The scientific evidence supports the following statements:

1. People with amalgams have much more mercury in their bodies, including their brains, than people without amalgams; the extra mercury carried by people with amalgams constitutes half to three-fourths of all mercury found in their bodies;
2. People who die of AD have elevated levels of mercury in their brains; in rat brains and human brain homogenate, mercury blocks a biochemical process that is also blocked in the brains of AD victims; mercury causes emotional and mental symptoms frequently found in AD patients;
3. Twin studies suggest an environmental cause of AD; epidemiological evidence (the temporal and racial distribution of AD) suggests mercury from amalgams plays a role in AD;
4. The hypothesis that mercury causes AD is consistent with other hypotheses about the etiology of AD, namely, that apolipoprotien E status is a strong predictor of AD, that education and estrogen protect against AD, and that trauma to the head may trigger AD;
5. Mercury may be a cause of other diseases of the central nervous system, including amyotrophic lateral sclerosis, multiple sclerosis, and Parkinson's Disease.

Mercury escapes from the amalgam in three ways: (a) corrosion, caused by electrical currents passing through the filling; (b) what one expert calls "direct dry evaporation;" and (c) removal of small pieces of the fillings caused by chewing. The liberated mercury is taken into the body via (a) inhalation, (b) swallowing and (c) absorption into nearby mouth and nasal tissue. People with amalgams have at least twice as much mercury vapor in their mouths, twice as much mercury in their blood, three to six times as much in their urine, at least six times as much in their kidneys, and double the amount of mercury in their brains and other body parts as people without amalgams. Several of these mercury burden studies found a correlation between the number of amalgam surfaces and mercury levels in the brain. One of the latest and most disturbing of these studies found that women with ten or more filled teeth give birth to babies with twice as much mercury in their bodies as mothers with two or fewer filled teeth.

Estimates of amounts of mercury absorbed from amalgams

In 1991 the World Health Organization...... concluded the daily dose of mercury from the environment is 2.6 ug......... If the correct figure for absorption of mercury from amalgam turns out to be 8 ug, then the total mercury absorbed per day from all sources -- the environment plus amalgam -- is 10.6 ug, according to the WHO data. This means amalgam mercury constitutes three-fourths of all mercury absorbed by the body (8 ug is 75% of 10.6 ug). If 10 ug turns out to be the correct figure for mercury taken up from amalgams, then the total absorbed is 12.6, which means about four-fifths of all mercury absorbed comes from amalgams (10 ug is 79% of 12.6 ug).

In a 1995 report prepared for Health Canada (Canada's national health department), Richardson estimated that amalgam mercury constitutes half of the mercury absorbed daily by adult Canadians.

Whether amalgam mercury is the source of 50% of all mercury absorbed, as Richardson's data indicates, or three-fourths, as the WHO data suggests, mercury from amalgams contributes a substantial portion of the mercury absorbed each day, not a "very small" portion as the ADA would have the public believe.

In this last study, the authors discussed three mechanisms by which mercury could cause AD symptoms: reducing the brain's ability to utilize tubulin, a protein used to manufacture microtubules; alteration of cell membranes; and other forms of cell dysfunction caused by the loss of zinc and selenium, a loss "possibly" due to the role zinc and selenium plan in detoxifying mercury. The University of Kentucky researchers have conducted several studies examining the first hypothesis.

Tubulin is a protein found in every cell. In nerve cells, tubulin is an element of microtubules, described by one writer as "neuronal railroad tracks, transporting molecules between the cell body and nerve terminals." The hypothesis that AD brains cannot use tubulin to make microtubules is at least ten years old. The contribution of the University of Kentucky researchers has been to show that mercury may be the cause of this defect. Three studies by these scholars support this hypothesis. The first demonstrated that the tubulin-guanosine-5'-triphosphate (GTP) interaction is greatly reduced in AD brains; the second that EDTA "complexed" with mercury reduces GTP-tubulin interaction in normal human brain homogenates; the third, that the brains of rats exposed to mercury vapor demonstrate the same marked reduction in tubulin-GTP interaction demonstrated in humans in the first study. In the third study (which was done with scholars at the University of Calgary medical school), rats were exposed to mercury vapor at 300 micrograms per cubic meter for four hours a day for periods ranging up to 28 days. The authors noted that 300 micrograms is "a level detectable in mouths of some human subjects with large numbers of amalgam fillings." The authors found that by the fourteenth day the rate of tubulin-GTP binding had been reduced by 75 percent. "The identical neurochemical lesion of similar magnitude is evident in Alzheimer brain homogenates. . .," stated the authors.

Patients with Alzheimer's exhibit changes in personality and social skills. They . . . may become socially uninhibited or lose all initiative and interest in activities. These patients often have delusions, hallucinations, and sleep disorders. They sometimes show grossly inappropriate judgement and sometimes are misdiagnosed as being depressed or psychotic.

Every one of these symptoms are common symptoms of mercury poisoning.

The American Dental Association and its state affiliates cite a 1995 study of 129 elderly nuns as conclusive evidence that amalgams cannot cause AD. But this study lacked a control group, and is therefore useless. The authors divided 129 nuns into five groups depending on how many teeth and how much occlusal amalgam surface they had. The authors referred to these groups as "risk categories," which is to say the authors assumed that an old woman's risk of contracting Alzheimer's-like symptoms is higher if, at the time of the study, she had teeth with amalgams than if she had no teeth. The reader is led to think, in other words, that the edentulous (toothless) nuns were the least likely to get AD because their amalgam load at the time of the study was lower than that of nuns in the other four categories. This is an absurd assumption. No one other than the authors of this study postulates that mercury from amalgams causes AD overnight. If amalgam mercury causes AD in elderly women, it does so over decades, beginning possibly when the women got their first fillings, which for most people occurs when they are children. Having made this untenable assumption, the authors proceeded to measure the mental abilities of the nuns with the Mini-Mental State Examination, a commonly used test of mental function, and other tests, and found no difference in test scores among the five "risk categories." "In fact," note the authors in an attempt to get the reader to think the edentulous group was the control group, "the group with the highest amalgam surface area had the same mean Mini-Mental State Examination score as the edentulous group." Nowhere in this article does the phrase "control group" appear.

What the authors of this study should have done was to measure the lifetime exposure of the nuns to amalgam mercury as well as mercury levels in their brains during autopsy, and see if there is a correlation between lifetime exposure and brain mercury levels, or between either of these variables and performance on cognitive skills tests. In such a study, nuns edentulous by the time of the study may turn out to be the "risk category" with the highest exposure to amalgam mercury. After all, a toothless person has almost certainly suffered from greater tooth decay than someone with teeth, and, therefore, has probably been exposed to more amalgam mercury for a substantial period of time than someone who remains dentate. Because mercury stays in the brain for decades, one could be edentulous for a very long time and still have more brain mercury than someone who is dentate and has a lot of amalgams.

Scholars affiliated with the University of Minnesota and the Minnesota Pollution Control Agency have demonstrated that atmospheric mercury levels rose dramatically during the 1800's. In a 1992 article published in Science, they reported that the rate at which mercury accumulated in seven lakes "increased by a factor of 3 to 4 during the past 140 years." Because the seven lakes are at great distance from industrial sources of mercury and are spread out over a large area encompassing northern Wisconsin and northern and central Minnesota, and because "the deposition rates are relatively uniform" across the seven lakes, the authors concluded that the mercury sources were "regional if not global." Data for six of the seven lakes indicated a substantial increase in deposition rates around 1850 and another increase around 1920. Subsequent research indicates mercury deposition rates may have peaked in the 1970s.

Amalgam is the dentist's stock in trade. Today a typical adult carries ten amalgams weighing a total of about ten grams, of which five grams is mercury. What little research there is on the rate at which mercury escapes amalgam suggests about half a gram of mercury will escape from these ten fillings over the ten-year life of these fillings, and most of this mercury will be absorbed by the bearer of the amalgams. To put a half-gram in context, consider these facts: Half a gram of mercury dropped into a ten-acre lake warrants the promulgation of a fish advisory for the lake in Minnesota; the tennis shoes with mercury in them that were banned by the Minnesota legislature in 1994 contained half a gram of mercury per shoe. (0.5 gram in a 180 lb. body, produces a concentration of 6.168 PPM. Compare this level, to the elements in the "Water of Life". TRC)

Mammals have been evolving on this earth for 70 million years. A permanent tripling or quadrupling of environmental mercury levels over a mere century may well have had some impact on human health even if amalgams had never been invented. If in fact amalgam accounts for at least half of all mercury absorbed today, then we may say with some accuracy that the introduction of amalgam coupled with the increase in atmospheric mercury exposed humanity to at least a six-fold increase in mercury over approximately 100 years. A century is a very short period of time for any organism to develop new defense mechanisms against unprecedented levels of something as toxic as mercury.

Some direct evidence that anti-inflammatory drugs may delay the onset of AD already exists. McGeer et al. reported data suggesting that "the prevalence of Alzheimer disease in patients with rheumatoid arthritis is unexpectedly low and that [the use of] anti-inflammatory therapy might be the explanation." Aisen and Davis cite two other studies that reach the same conclusion.

Haley hypothesizes that the apoE4-AD correlation is due to the inability of apoE4 protein to transport mercury out of the brain. The following statement by David Kennedy, a dentist and researcher on amalgam toxicity, summarizes Haley's theory:

The function of [the apoE] protein is to transport cholesterol out of the brain... The difference between apoE2, E3 and E4 is that E2 has two cysteines, in E3 one cysteine is replaced by an arginine, [and] in E4 both cysteines are replaced by arginine. [Haley] explained that unlike cysteine the arginine does not pick up mercury since it contains no sulfur. Sulfur is called a mercaptan (Latin for mercury capture). Mercury loves sulfur more than other molecules. It will drop whatever it is attached to and bind with sulfur.... E2 people, who are less likely to get AD, have a protein that carries mercury as well as cholesterol out of the brain by binding mercury with sulfur seats.

Haley's explanation of the relationship between apoE status and AD is consistent with a 1988 study of trace element levels in hair and nails of AD patients done at the University of Kentucky by Vance et al. The study found no difference in hair mercury levels of patients with and without AD; it found that AD patients had lower mercury levels in their nails than did the non-AD controls. In his review of the literature on amalgam toxicity, Richardson cited the study by Vance et al. as evidence against the conclusion that amalgams cause AD. If Haley's description of apoE is correct, or if research demonstrates some day that for other reasons some humans are have diminished capacity to scavenge and excrete mercury, we should expect to find that AD victims have the same or lower mercury levels in hair and nails despite having above-average levels in their brains.

If Haley's thesis is correct, the following hypothesis seems quite plausible: because of a reduced capacity to excrete mercury, mercury (from amalgam and nonamalgam sources) builds up more rapidly in the brains of people with the epoE4 gene; rising mercury levels in the brain eventually cause the destruction of microtubules which in turn leads to neuron death; rising mercury levels trigger an inflammatory response that accompanies, and may contribute to, neuron death.

AD afflicts many who do not carry the apoE4 gene. What that signifies is that an intolerable level of mercury can build up in people regardless of their apoE status. This intolerable level may be reached (1) because of exposure to high levels of mercury, (2) because of exposure to other toxins and stressors that reduce the ability to cope with mercury, (3) because of genes other than those controlling apoE status, or (4) some combination of these three conditions.

Evidence supports the claim that estrogen supplements reduce the risk of AD in women. Animal experiments indicate that estrogen stimulates nerve growth, perhaps indirectly by its effect on nerve growth factor. Higher education levels may also protect against AD. Like estrogen, education (or perhaps the habits of mind that higher education encourages) may help the brain maintain or construct neurons. These findings are consistent with the mercury hypothesis. Estrogen and education may protect against AD by minimizing or compensating for the neuronal destruction caused by mercury.

Trauma to the head is occasionally mentioned in the literature as a factor associated with a higher incidence of AD. At least one expert believes head trauma is a risk only for people with the apoE4 gene. A blow to the head may aggravate the toxic effect of mercury in at least two ways: it might stress the body and thereby weaken the body's ability to withstand the presence of mercury; the trauma may fracture fillings and increase the victim's exposure to mercury.

I base the latter explanation on my familiarity with the health history of June Varner, a Little Falls woman who overcame nearly paralyzing confusion by getting her amalgams removed. Her inability to concentrate and make decisions set in after a 1978 car accident. The problem was severe. June stated in a letter to me, "I can remember looking down at my shoelaces months after the accident; I could not remember how to tie them. I knew that I knew how to do it but I could not remember." Other symptoms that appeared after the accident included headaches, vertigo, nausea, extreme fatigue, and memory loss. These symptoms persisted until 1992 when her dentist discovered that several teeth in the upper right side of her mouth with amalgams in them were cracked. The replacement of these amalgams with crowns eliminated the mental confusion and the other symptoms that came with the confusion. June speculates that the blow to her head suffered during her auto accident allowed mercury from her fillings to gain access to her brain.

Golden mentions a study done by Eugene Sobel at the University of Southern California which found "that the onset of Alzheimer's is unusually high in dressmakers and tailors," possibly because sewing machines create large electromagnetic fields (EMFs). EMFs could augment the damage that mercury does to the brain in two ways. They may render the blood-brain barrier more permeable to toxic material, including mercury; they may accelerate the release of mercury from amalgams (see discussion of the role of electricity in releasing amalgam mercury in attachment).

Finally, smoking seems to play a protective role against AD. The reason for this may be that nicotine has the opposite effect on neurotransmitters that mercury has. Whereas mercury inhibits the uptake of, or otherwise reduces the effect of, dopamine, norepinephrine, serotonin and acetycholine, nicotine increases the levels of these neurotransmitters. This may explain why people with amalgams tend to smoke more than people without amalgams.

Monica's symptoms were mild; she would say one word when she meant another, and her memory deteriorated. She overcame these symptoms with a combination of amalgam removal and supplements. Because Monica's mother had AD for many years, Monica has little doubt she has the genes that make her susceptible to AD. Upon her mother's death, Monica and her sister asked the Mayo Clinic to determine the levels of aluminum, nickel and mercury in their mother's brain. The results: aluminum, normal; nickel and mercury, extremely high.

Mary's symptoms were severe, especially for a woman in her thirties which is when Mary's health deteriorated. She suffered from memory loss so severe she could not remember people she had known for years or how to drive to places she had driven to for years. She suffered fits of rage so intense she had to lock herself in the bathroom to avoid hurting her children. She recovered quickly after having her amalgams removed. We can only speculate whether Mary and Monica had the plaques and tangles of fully developed AD.

I am told dozens, perhaps hundreds, of other Americans could tell similar stories. I have the phone numbers of several of them.

The scientific literature on mercury, amalgam and ALS

The first of several reports on ALS-like symptoms triggered by exposure to mercury appeared in 1954. The article described an ALS-like syndrome in a 39-year-old farmer who absorbed organic mercury from a fungicide he used on oats. At least three similar articles have been published since. One described ALS symptoms in 11 Iranians who ingested bread made with wheat treated with a fungicide containing ethyl mercury; another reported ALS symptoms in two men exposed to mercuric oxide and mercury vapor in a factory that manufactured mercuric oxide; the third described a 54-year-old man who developed ALS symptoms three-and-a-half months after he spent two days gathering liquid mercury from old thermometers.

A number of people who have had amalgams removed have recovered from ALS. In a 1994 article, Redhe and Pleva described such a recovery by a 29-year-old Swedish woman. She had been diagnosed with ALS by the neurology department at the University Hospital in Umea, Sweden. This same department pronounced her free of ALS in August 1984, five months after her amalgams were removed. Nine years later the woman was still free of ALS symptoms.

Mercury has also been implicated by studies examining health histories of groups of people diagnosed with ALS. Felmus et al. found that 25 ALS patients were more likely to be exposed to mercury and lead than a control group of sick people with non-ALS diagnoses (although the two groups did not differ in number of amalgams). Sienko et al. sought to explain the sudden appearance of ALS in six residents of Two Rivers, Wisconsin over the 1975-1983 period. They found that the ALS victims suffered more instances of physical trauma, reported more cancer in their families, and had eaten more fish from Lake Michigan than had 12 controls.

Some of the University of Kentucky scholars who examined mercury levels in AD victims were among the authors of a similar study of ALS patients. They found that seven deceased ALS victims had more mercury in their brains than did nine deceased controls who did not have ALS, and that blood cells of 40 living ALS patients contained more mercury than the blood cells taken from 31 living controls. Interestingly, ALS victims had lower levels of selenium in blood serum. Selenium has been shown to "protect experimental animals against the toxcity of heavy metals, such as mercury . . . ."

The Redhe-Pleva article on the Swedish woman who recovered from ALS after amaglam removal is the only such report in the peer-reviewed literature I know of. However, similar but unpublished stories are numerous. I recount one here. Cynthia Hughes is a Nevada woman who recovered from ALS after her amalgams were removed by Dr. Hal Huggins, a Colorado dentist who practiced mercury-free for 23 years until the Colorado Board of Dental Examiners took his license because of his public criticism of amalgam. Cynthia and the neurologist who diagnosed her appeared on a four-part television report entitled "Toxic Teeth" which aired on a Las Vegas TV station in the early 1990s. The reporter stated: "Cynthia could not walk or talk until she had her mercury fillings removed. Even her doctor was amazed by her sudden improvement." At this point the camera showed a doctor sitting at his desk with his name and specialty shown on the screen -- "Dr. Hal Griffith, neurologist." Dr. Griffith stated, Cynthia "had a dramatic . . . complete recovery."

Evidence that mercury is swallowed and absorbed
into mouth tissue: the corrosion studies

It has been known since at least 1878 that amalgams create these electrical currents. It has been known since at least 1881 that amalgams discolor and soften the dentin (the soft material between the enamel and the pulp), and since at least 1953 that one phenomenon causes the other, that is, that the electrical currents in the mouth cause fillings to corrode and release metals that then travel into the dentin causing discoloration. The 1953 study examined 300 freshly extracted teeth containing amalgams and found a "greenish to grayish black discoloration" in the dentin of 85% of the teeth. In this discolored dentin the authors found "relatively large amounts of mercury . . . with smaller amounts of silver, zinc, tin and copper. . . ." The authors recreated this same greenish-black color in the dentin by running electric currents through the amalgam, leading the authors to conclude that the migration of mercury and other materials from the amalgam was precipitated by "intermittent galvanic action arising from within the amalgam filling itself." Other studies have confirmed this finding. By the 1970s it was established that mercury was migrating into the gums, pulp, and, by the 1980s, the jawbone.

Patterson and two other New Zealand researchers reported in 1985 that brushing one's teeth with a soft tooth brush for one minute also stimulates mercury vapor release. Mercury vapor levels rose from an average of 3.1 ng/L of expired air before brushing to 8.2 ng/L after brushing. Even eating musli, a soft cereal, raised mercury vapor levels.

In 1988, Langworth et al. published a study of "intratracheal mercury levels" (that is, mercury levels in the air in the windpipe) of ten subjects (all, apparently, with amalgams). Prior to brushing their teeth, tracheal mercury vapor levels were below the instrumental detection limit of 1 ug/m³ for five subjects and ranged from 1-6 ug/m³ for the other five. After brushing, the average level for all ten subjects rose to 56.4 ug/m³.

The last study of oral mercury vapor levels was published in 1994 by Siblerud et al. They reported that people with amalgams had twice as much mercury vapor in their mouth air as people without amalgams prior to chewing and four times as much after chewing.

The reader should note that the breath levels just reported are averages among the people volunteering for the various studies and therefore do not reveal the high levels of mercury vapor reached in some people's mouths. Dr. Wayne King, a Georgia dentist, in testimony before the FDA Dental Panel in 1991, made this remark indicating that oral mercury vapor levels can reach very high levels in some of his patients: "I have been absolutely horrified to see some of the numbers that I have measured coming out of some of the mouths of my patients; for instance, 200 micrograms per cubic meter in a suicidally depressed patient."

That mercury vapor is released by amalgams is no longer debatable. As one expert who defends amalgams put it at the 1991 National Institute of Dental Research conference, "The question is not if, but how much mercury vapor is released."

Those interested in more information may contact Kip Sullivan at (612)823-1459.

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Mercury Toxicity and Alzheimer’s Disease

by Steven Wm. Fowkes

The body of scientific evidence indicating that mercury toxicity underlies Alzheimer's disease (AD) has grown to the point that it must now be considered a primary mechanism. During the last ten years, scientists have connected mercury toxicity to a variety of enzymatic changes that are seen in AD. Now, for the first time, scientists have shown that mercury exposure alone induces the characteristic morphological (visual) changes (i.e., neurofibrillary tangles) that are associated with AD. This article will present the primary evidence supporting the role of mercury toxicity in AD, and discuss how mercury toxicity may be connected to genetic risk factors, oxidative stress and beta-amyloid plaque formation.

The Politics of Mercury

Mercury is a medically loaded subject. According to orthodox dental associations, the mercury exposure from “silver” (mercury amalgam) dental fillings is not, they repeat, not a significant health hazard. However, there is a massive amount of evidence to the contrary. This evidence has prompted many countries to pass laws, restricting or banning its use and even recommending removal of amalgam fillings.

Despite the strong political influence of the American Dental Association (ADA), grass-roots awareness of mercury amalgam risks is growing in the US. Part of this can be atrributed to the educational efforts of the International Academy of Oral and Medical Toxicology, a professional organization promoting mercury-free medicine and dentistry. As criticism of amalgams has increased, so has the political pressure being applied to bolster public confidence in mainstream dental practices.

Mercury is not just a dental issue. The mercury-based preservative thimerosal is commonly used in vaccines. Although US public health officials state that thimerosal toxicity is minimal compared to the benefits of vaccines, use of vaccines is now tied to autism in children. Whether this is related to mercury toxicity or some kind of immune disruption, or both, is not yet known. However, the mechanisms of mercury toxicity in AD may significantly relate to the spectrum of neurological dysfunction seen in autistic children.

As a consequence of “official” policy on mercury safety, medical regulation has been manipulated for political ends. Dentists have been “disciplined” (a politically correct term for “punished”) for counseling patients about mercury toxicity, or (gasp!) actually removing amalgam dental fillings and replacing them with composite materials (usually plastic/ceramic mixtures). Fortunately, medical dysregulators have not been completely effective in suppressing the mercury-toxicity issue and there are an increasing number of dentists that perform amalgam-removal services. There are areas where amalgam removal is still considered heretical or deviant medical practice, so it may be extremely difficult to get mercury-oriented therapy for anybody with AD, let alone anybody merely concerned about reducing their AD risks. Fortunately, there are also self-care options that individuals can consider.

Exposure vs Detoxification

One of the scientific problems delaying acceptance of the idea that Alzheimer’s disease (AD) relates to mercury toxicity has been a number of studies that show no correlation between amalgam-filling status and AD. Although there is reason to doubt the scientific objectivity of some of these studies due to their sources of funding and their being published in dental journals, blood levels of mercury do correlate with AD (see Figure 1). Mercury blood levels in AD patients were double those of controls [Hock et al., 1998]. In early-onset cases, mercury levels were almost triple.

At autopsy, mercury levels are usually higher in AD brains than control brains. However, in many specific brain locations, the differences do not reach statistical significance [Ehmann et al., 1986; Thompson et al., 1988]. Subcellular organelles (nuclei, microsomes, mitochondria) also have elevated mercury levels in AD, but it only reaches statistical significance in microsomes (cell protein “factories”) [Wenstrup, 1990].

Although mercury accumulation appears to be much more related to AD than mere exposure, neither can adequately account for AD. Some AD patients have substantially lower levels of mercury than people without AD. There must be other factors involved. Two of these are 1) biological detoxification mechanisms thatmitigate the toxicity of mercury, and 2) pathological processes that augment the toxicity of mercury.

If detoxification mechanisms are robust, the brain can coexist with high levels of mercury. If these mechanisms fail, then dramatically lower levels of mercury are enough to precipitate AD. Detoxification mechanisms for mercury are extremely complicated and not yet fully understood. As a consequence, there is currently no clear consensus on the best way to decrease mercury toxicity. Many clinical techniques in current practice increase mercury-related symptoms in the process of removing mercury from the body.

Some possible aggravating factors are 1) fungal infections that can produce the neurotoxin gliotoxin (see illustration), which independently attacks mercury-sensitive brain enzyme systems, and 2) as-yet-uncharacterized bacterial infections in teeth (root-canal or otherwise) that produce highly potent inhibitors of brain enzyme systems. Some of this toxicity may relate to anaerobic degradation of methionine and cysteine into methanethiol and hydrogen sulfide (see illustration). These low-molecular-weight sulfide species can bind to mercury and increase its toxicity and mobility. Other chemical entities are likely to be involved as well.

Mercury Exposure and the Brain

This year, researchers from the University of Calgary have finally shown the transformation of a healthy cultured neuron to an AD-like state by the simple addition of nanomolar mercury [Leong et al, 2001] (see the adjacent sidebar for an explanation of nano and molar). For the first time, a single causal influence has produced the characteristic neurofibrillary tangles that are an accepted diagnostic marker of AD. The researchers even made a time-lapse movie of the process. It will be interesting to see how long political pressures will keep the movie from being shown on public television, the Discovery Channel, or network news.

The concentration of mercury in the average human brain varies from 10^-8 to 10^-6 M [Haley, 2001]. This is roughly ten-fold greater than the nanomolar (>10^-9) solutions that produce neurofibrillary tangles in cell culture. The reason that small increases in mercury precipitate AD morphology (structural changes) is that the mercury increase is comparatively sudden. In vivo, brain mercury accumulation is a gradual process in which detoxification mechanisms have time to adjust. Sudden addition of mercury overwhelms the delicate balance between mercury and protective sulfur compounds. This leads to catastrophic consequences.

Enzymatic Changes

The effects of nanomolar mercury are not limited to visible changes. Other researchers have previously shown that nanomolar mercury causes the same shifts in brain enzyme function that are seen in AD. These include 1) inhibition of GTP-tubulin interactions [Pendergrass et al., 1987; Khatoon et al., 1989], 2) inhibition of glutamine synthetase [Gunnersen and Haley, 1992; Olivieri, 2000], 3) inhibition of creatine kinase, and 4) increased tau phosphorylation and beta-amyloid secretion [Olivieri, 2000]. Each of these will be discussed individually later.

As with neurofibrillary tangles, the level of mercury necessary to affect these enzymatic changes is a small fraction of the amount that is commonly found in human brains that do not exhibit the signs of AD. In fact, at autopsy, some human brains show levels of mercury in excess of micromolar levels (10^-6 M), without any sign of neurofibrillary tangles. In one person with a particular kind of heart disease (see sidebar file), heart-muscle mercury levels were measured at millimolar (10^-3) levels!

How could somebody have almost a tenth of a percent mercury in a critical body tissue and still be alive? It’s obvious that the body has the potential to detoxify very large amounts of mercury. However, mercury toxicity is not just a matter of detoxification. Different chemical forms of mercury have widely differing toxicities. Mercury cloride is very toxic. But mercury selenide is not very toxic at all. This is why mercury researchers often measure selenium at the same time as mercury. Methyl mercury can be even more toxic to the brain than ionic mercury because it easily passes through the blood-brain barrier. Methylthiomercury is even more toxic. So mercury’s toxicity depends on the presence or absence of other substances that can bind with it and potentiate or mitigate its toxicity and/or mobility.

The Importance of Sulfur

Mercury (Hg) and sulfur (S) have a special chemical affinity for each other. This is evidenced not only by mercuric sulfide (HgS) being the primary mercury-containing ore found in the earth’s crust (and exploited for commercial production of mercury), but by the fact that mercury ions (Hg++) readily bind to sulfhydryl (SH, thiol) groups in biological systems. These sulfhydryl groups are chemically active in a variety of biological capacities. For examples, glutathione (GSH) is a primary antioxidant defending cellular membranes from oxidative damage. Alpha-Lipoic acid is an essential component of dehydrogenase complexes that drive the Krebs citric-acid cycle, which generates the primary energy for the cell. A wide variety of proteins and enzymes contain cysteine-to-cysteine links (disulfide bridges), which link sections of protein chains to each other to determine their final 3-D structures. And many enzymes contain cysteine at their active sites, the sulfhydryl group of which participates in the chemical transformation catalyzed by the enzyme. The chemical reactivity of sulfhydryl groups is essential to the healthy functioning of biological systems.

When mercury ions are present, they bind to sulfhydryl groups and destroy their special reactivity. Enzymes with mercury bound at their active sites do not catalyze their normal reactions. Glutathione (GSH) bound to mercury does not function as an antioxidant.

There are always mercury ions present in biological systems. However, if they are dramatically outnumbered by sulfhydryl groups, the “poisoning” effect is minimized and normal metabolic functions proceed to a significant degree. So the ratio of sulfhydryl groups to mercury ions is an important aspect of mercury detoxification. This offers one insight into how some people can tolerate higher levels of mercury than others.

Sulfhydryl Brain Enzymes

Over the last decade, many research teams have focussed on enzyme systems and structural proteins in the brain that are disrupted in AD patients. It turns out that the most seriously impaired systems contain sulfhydryl groups.

One of the most plentiful, and arguably the most important, sulfhydryl compound in the brain is glutathione (GSH). Glutathione has a strong affinity for mercury. In recent experiments, glutathione depletion has been found to be one of the quickest effects of low-level mercury exposure on cultured neurons [Haley, 2001]. Glutathione and vitamin C are the primary water-soluble antioxidants in the brain, and they are absolutely essential to protect neural membranes and protein structures from a wide variety of oxidative stresses. Depletion of glutathione represents a potential mechanism for 1) the observations of oxidative stress in AD, and 2) the catastrophic destabilization of neuron infrastructure that is seen in AD.

Creatine Kinase

Creatine kinase (cree-a-teen kie-naze) is a sulfhydryl enzyme that is highly expressed in the brain and regulates ATP “storage.” During times of ATP surplus, creatine kinase uses ATP to phosphorylate creatine into creatine phosphate (see Figure 2). During times of ATP demand, creatine kinase performs the reverse reaction, using creatine phosphate to rapidly convert ADP back to ATP. So creatine phosphate is like a back-up battery for peak-energy-use periods, and creatine kinase acts like a battery charger when energy is plentiful and an emergency power generator when it is not.

There has been a lot of research into creatine’s important role in muscle tissue, specifically relating to peak strength and stamina. However, creatine plays an equally critical role in the central nervous system, where brain proteins and enzymes tend to beamong the most highly phosphorylated structures in the human body. In the AD brain, creatine kinase is over 95% inhibited. It is also rapidly inhibited by nanomolar mercury exposure, although not quite as quickly as glutathione.

Kinases are enzymes that phosphorylate (attach phosphate groups to) other enzymes and proteins. In the process, they modify the properties of those enzymes and proteins. Phosphate groups are bulky and highly electronegative (see Figure 3), so this can shift the physical structure and alter electrical attractive and repulsive forces at the surfaces of proteins, which can change the conformation (shape) and activity of enzymes. In some cases, phosphorylation increases enzyme activity. In other cases, phosphorylation reduces enzyme activity. This means that increasing or decreasing the overall level of phosphorylation can modulate phosphorylation-sensitive enzyme activities in a concerted manner. This capability seems to be extensively utilized by the human brain in the regulation of cytoskeletal growth and function. The latest research indicates that phosphorylation peaks and troughs on a one-minute cycle, which correlates with a tightening and relaxing of the cytoskeleton. The energy demands of maintaining such a high level of phosphorylation may be a primary contributor to the remarkably high metabolic rate of the brain.

Phosphatases operate oppositely to kinases. While kinases attach phosphate groups, phosphatases remove them. Some phosphatases are known to be seriously inhibited in AD.

There are many dozens of kinases and phosphatases that regulate different aspects of phosphorylation. More are being discovered every year. Some specialize in phosphorylation or dephosphorylation of serine and threonine residues (aliphatic amino acids with exposed hydroxy groups), while others operate on tyrosine residues (an aromatic amino acid with an exposed hydroxy group). Some kinases and phosphorylases are quite specific to particular enzymes or enzyme families, while others can have widespread and overlapping activities. One of the latter, protein kinase C (PKC), is more highly expressed in the human brain than in any other tissue.Like creatine kinase, PKC is also strongly inhibited by mercury ions.

Our understanding of the specifics of feedback control mechanisms involving phosphorylation is still rudimentary. Given 1) the large numbers of proteins and enzymes that are being phosphorylated and dephosphorylated, 2) the large numbers of kinases and phosphatases that are competing against each other, 3) the kinases (or phosphatases) with overlapping activities, and 4) the possibility of inverse enzymatic response to changes in phosphorylation, it may be decades before we have it all figured out.

Paired Helical Fillaments

Neurofibrillary tangles are one of the hallmarks of Alzheimer’s disease (AD). They consist of paired helical fillaments, which are composed of the microtubule-associated protein tau (see next section for discussion of microtubules). The tau in neurofibrillary tangles is different from normal tau; it is heavily over-phosphorylated. This appears to be the result of inhibition of protein phosphatases. Recently, researchers have provided evidence that protein phosphatases PP-1 and PP-2A, and phosphotyrosyl-protein phosphatase (PTP), are significantly inhibited in the AD brain. Furthermore, in vitro, the addition of PP-2A and PP-2B restores tau to normal levels of phosphorylation [Pei et al., 1998]. This inhibition of phosphatase activity is not related to any decrease in the production of PP-1, PP-2A or PTP. In fact, levels appear to be slightly higher in the AD brains than in controls, possibly indicating an unsuccessful attempt to compensate for the phosphatase defect.

Tubulin and the Cytoskeleton

There are numerous protein polymers in neural cells that serve a wide variety of structural functions. Collectively, these protein polymers are referred to as the cytoskeleton, which, among other things, is responsible for creating and maintaining the complicated three-dimensional structures of neurons. Cytoskeletal development controls 1) neuron growth, 2) neural branching, and 3) neural migration patterns, which ultimately determine the “hard wiring” of the brain. The development and maintenance of the cytoskeleton is regulated by changes in phosphorylation.

The cytoskeleton is made up of neurofilaments, microfilaments and microtubules. Neurofillaments and microfillaments are smaller diameter fibers. Neurofillaments (10 nanometers (nm) in diameter) have side arms that allow attachment to other cytoskeletal structures. They seem to specialize in branched structures that may serve a “scaffolding” purpose. Microfillaments (5-12 nm diameter) are extensively used in muscle fibers to “pull” structures together. They also help regulate the conformation of the outer cell membrane in cells that move — which include neurons. And they may regulate cytoplasmic fluidity.

Microtubules (MTs) are of special interest in AD because they are seriously disrupted. In healthy brain, MTs are long, rigid, linear structures with a larger diameter (20 nm) than both neurofillaments and microfillaments. MTs do not branch, although they are often bound by numerous neurofillament linkages to the rest of the cytoskeleton. In cell cultures, MTs are readily disrupted by nanomolar mercury exposure.

Microtubules (MTs) are formed from tubulin proteins, which come in alpha, beta and gamma forms. The role of gamma-tubulin appears to be limited to MT initiation. Once initiated, alpha-tubulin and beta-tubulin are used to elongate the MTs.

The first step in the MT assembly process (see Figure 4) is the formation of a heterodimer, consisting of one alpha-tubulin protein joined to one beta-tubulin protein (hetero means “different”). This dimer requires a molecule of GTP for its assembly. GTP (guanosine triphosphate) is a close chemical cousin of ATP (adenosine triphosphate), which is the primary energy currency of the cell. GTP is produced from ATP, so it is a special form of energy currency that is used to power the building and maintenance of the cytoskeleton.

The alpha-tubulin beta-tubulin dimers then assemble into long chains or protofilaments, also requiring GTP. Thirteen of these protofilaments then bind together to form the “wall” of a MT (see Figure 4). The MT is hollow inside, like a straw.

The beta-tubulin protein contains more than a dozen sulfhydryl groups. Two of these sulfhydryl groups are located near the GTP binding site. When mercury binds to these two sulfhydryl groups, GTP binding is seriously inhibited, which prevents tubulin polymerization. The mercury-mediated disintegration of MT infrastructure causes gross neural dysfunction.

The Neural Highway

Because the tubulin dimers are electrically polarized, they can only join alpha-unit to beta-unit. Alpha-tubulin will not polymerize by itself. Neither will beta-tubulin. It takes both, and they necessarily end up in an alternating (alpha-beta-alpha-beta) sequence.

Because of this electrical polarity, microtubules (MTs) are inherently directional! They start at one place in the cell (usually near the cell nucleus) and grow in a straight line 1) towards the cell periphery, 2) down an axon or dendrite, and/or 3) to a nerve terminus, where neurotransmitters and receptors are located. The directionality of the MT is then exploited by motor proteins (transporters) that bind to the MTs and move in only one direction (i.e., outward or inward). The motor protein kinesin moves outward (towards the positive end of the MT), and will carry vessicles (membrane-bound “sacks” of biological material) from the nucleus to the cell periphery. The motor protein dynein moves inward (towards the negative end of the MT). It carries material from the cell periphery back to the nucleus. Thus, MTs function as two-way highways, on which motor proteins travel to bring their cargo to some kind of cellular destination.

This transport function of MTs is especially critical to the proper functioning of neurons. Unlike the vast majority of cells that tend to be globular, neurons grow long, thin extensions with multiple branchings. If a microtubule (20 nm width) were the size of a highway (approx. 20 feet lane width), the distance between a nucleus and its nerve terminus in a 1 inch long (2.54 cm) dendrite would be almost 5000 miles (8000 km). Imagine contemplating such a trip without roads or motor vehicles. Axons can be an order of magnitude longer than dendrites. Given such immense distances, it is easy to see how the central nervous system is critically dependent on MT infrastructure.

Genetic Risks of ApoE

There is very good evidence that the risks of Alzheimer’s disease (AD) are genetically related (see SDN v3n2p1). Several research teams have demonstrated that variations in apolipoprotein (A-poe-lie-poe-pro-teen) E, a cholesterol-carrying blood protein, are related to age of onset of AD (see Figure 5). The association of ApoE4 with increased risk has become widely accepted. However, until recently, nobody has been able to offer an explanation as to how ApoE variants might actually influence AD pathology. Moreover, individuals with protective ApoE alleles (genes) still get AD. They just get it a few years later in life than people who carry the alleles associated with increased risk. Clearly, ApoE is not a cause of AD. It is merely influencing or modulating a deeper mechanism.

ApoE is also produced in neural cells for housekeeping purposes that have not yet been made clear. It travels from the cell into cerebrospinal fluid, which is then flushed out into the body.

In humans, ApoE comes in three different forms, ApoE2, ApoE3 and ApoE4. ApoE4 is associated with increased risk of early onset Alzheimer’s disease (see Figure 5). ApoE3 is the most common form in humans. The rarest is ApoE2, which seems to offer significant protection from Alzheimer’s disease. Is ApoE connected to mercury?

Dr. Boyd Haley and colleagues think it is. The genetic differences between ApoE alleles involve substitutions between arginine and cysteine at positions 112 and 158 of the proteins. All the other amino acids in the ApoE protein are identical. The protective form (ApoE2) has two cysteines at those positions, the common form (ApoE3) has one cysteine and one arginine, and the increased-risk form (ApoE4) has two arginines. Since cysteine can bind mercury and arginine cannot, the cellular production of ApoE2, and ApoE3 to a lesser extent, can carry mercury from brain neurons into the cerebrospinal fluid and dump it into the body. This explanation easily integrates ApoE genetics into the mercury model. The number of cysteine residues in ApoE correlates perfectly with the observed age of AD onset (Figure 5) and AD risks (Figure 6).

Mercury and Excitotoxicity

Glutamine synthetase (GS, glue-tah-mean sin-theh-taze) is another sulfhydryl enzyme that is seriously inhibited in AD. GS is important for 1) ammonia detoxification in the brain, and 2) termination of the glutamate signal in excitatory synapses [Gunnersen & Haley, 1992]. It converts glutamate (an excitatory neurotransmitter) to glutamine (which is not excitatory) using ammonia and ATP. It is found in large amounts in astrocytes, which surround and protect excitatory neurons.

Activation of excitatory receptors by glutamate (or aspartate) triggers calcium influx into the neuron. This flow of calcium ions across the neural membrane causes a shift in electrical polarity, which triggers nerve electrical firing. The calcium is then pumped back out of the neuron to get ready for the next firing.

Excessive stimulation of excitatory receptors produces a calcium-influx burden in excitatory neurons. This is called excitotoxicity. If calcium can’t be pumped out fast enough and exceeds a threshold level, it triggers apoptosis (cell suicide). So it is very important to be able to modulate excitatory activity to avoid apoptosis (a-poe-toe-sis).

Glutamine synthetase is found in the cerebrospinal fluid of AD patients, but not normal controls [Gunnersen & Haley, 1992; Tunami et al., 1999]. Its function is inhibited by mercury ions, and its production is increased by mercury exposure. Perhaps excitotoxicity is responsible for the loss of neurons in AD.

The central role of mercury in these AD-associated processes suggests that anybody concerned about the possibility of AD should now focus on 1) minimizing environmental mercury exposure, 2) reducing accumulated mercury stores in body tissues, especially the brain, 3) supporting antioxidant defenses, especially those that relate to mercury detoxification, 4) supplementing minerals that mitigate mercury toxicity, especially when deficient, and 5) avoiding metals and unnecessary minerals that may exacerbate mercury toxicity. Although such strategies make sense, none of these options has been systematically evaluated for its efficacy in reducing the toxicity of mercury to brain enzyme systems.

Protective Effects of Melatonin

Melatonin seems to offer significant protection from mercury toxicity. In a neuroblastoma cell culture exposed to mercury (HgCl2), pretreatment with 10^-6 M melatonin 1) protected cells from loss of glutathione (GSH), 2) prevented over-phosphorylation of tau, and 3) attenuated beta-amyloid secretion [Olivieri et al., 2000].

In a clinical study, 9 mg doses of melatonin before bed provided sleeping benefits and prevented further deterioration in 14 Alzheimer’s patients over a period of 22-35 months [Brusco et al., 2000].

Minerals: Toxic and Protective

The mercury sensitivity of brain enzyme systems is modulated by the presence or absence of other ionic species. Magnesium is closely associated with ATP and GTP complexes, and magnesium deficiency increases symptoms of mercury toxicity. It is possible that magnesium supplementation may significantly decrease mercury toxicity in a general manner. It is important to remember that inexpensive supplements based on magnesium oxide or dolomite depend on robust stomach-acid production for their efficient absorption. Well chelated supplements, like magnesium citrate, aspartate, orotate or ascorbate, are bioavailable even in achlorhydric people.

Even though magnesium aspartate is efficiently absorbed, aspartate is an excitatory neurotranmsmitter that may pose a slight excitotoxic risk. Since there are other chelating agents available, it may be best to avoid all aspartate chelates.

There are two minerals, cadmium and zinc, that are chemically related to mercury: cadmium is just above mercury on the periodic table, and zinc is just above cadmium (see Figure 8). The presence of cadmium increases mercury toxicity. Zinc may also increase mercury toxicity. Is it a good idea to avoid zinc supplements in AD? There is some evidence to justify that position.

The ability of relatively low doses of zinc chloride to increase mercury toxicity towards beta-tubulin in brain homogenates is dramatic at the lowest levels of mercury exposure (see Figure 7). Zinc chloride alone, at 10 mcM and 20 mcM, inhibited beta-tubulin’s ability to bind GTP by approximately 18% and 27%, respectively (see black diamonds). At this level, zinc chloride is significantly toxic.

Mercury (white circles) is more than ten times more toxic. GTP binding is about 30% inhibited by 1.25 mcM mercury, which is comparable to zinc at 20 mcM.

At the lowest level of mercury, 0.625 mcM, GTP binding is only 4% inhibited. But when this low level of mercury (4% inhibition) is combined with 10 mcM of zinc (18% inhibition), the GTP binding is 50% inhibited (see gray circles). With 20 mcM of zinc (27% inhibition), GTP binding is 75% inhibited. Although this synergistic effect of zinc on mercury toxicity lessens at higher levels of mercury, it is still observed.

This in vitro (test-tube) experiment deals with adding zinc chloride (ZnCl2) to brain homogenates, which is not the way zinc would be delivered to a living brain. So are these data an artifact of the unnatural circumstances of the experiment? That is certainly possible, and maybe even likely. This is not a clinical finding. Nevertheless, it might be wise to closely monitor cognitive function for adverse changes with any increase in zinc supplementation during AD therapy.

Copper, which often competes with zinc for enzyme sites, also aggravates mercury toxicity to brain enzyme systems.

Conclusion

The brain’s fundamental reliance on microtubules (MTs) and phosphorylation make it more sensitive to mercury than other tissues. The human brain’s greater reliance on neural branching gives it greater intellectual abilities than the brains of other mammal species, but also more sensitivity to mercury toxicity. Mercury-mediated disruption of MTs, phosphorylation and sulfhydryl enzyme systems produces the characteristic enzymatic and morphological changes that are seen in Alzheimer’s disease (AD). The evidence connecting mercury to AD is now robust and well integrated. It is now time to focus our energies on clinical research to learn how to deal with mercury toxicity, to find a cure for AD. There are already a plethora of clinical techniques to accomplish this end. All we need is the will to undertake the process.

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References

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