Alzheimer’s Disease
and Other Autoimmune Degenerative Conditions: the Mercury Connection. B. Windham (Editor) (snipped from larger paper)
I. Introduction
There
has been a huge increase in the incidence of degenerative neurological
conditions in virtually all Western countries over the last 2 decades(574). The increase in Alzheimer’s and other dementia
has been over 300%. The primary cause
appears to be brain inflammation related to increased exposures to toxic
pollutants and bad dietary habits(445,574,577,598,etc.).
Mercury
is known to be one of the most toxic substances commonly encountered and to be
along with lead the toxic substances adversely
affecting the largest numbers of people (276).
Mercury in the presence of other metals in the oral environment
undergoes galvanic action, causing movement out of amalgam and into the oral
mucosa and saliva(174,183,192,436,199). Mercury in
solid form is not stable due to its negative vapor pressure and oral galvanism
of mixed metals so that it evaporates continuously from amalgam fillings in the mouth, being transferred over a period
of time to the host (49,79,83,85,183,199,335,etc.). The daily total exposure of mercury from
fillings is from 3 to 1000 micrograms per day, with the average exposure for
those with several fillings being above 30 micrograms per day and the average
uptake over 7 ug/day (49,183,199,79,83,85,335, etc.), with the majority of the
rest excreted through the feces and
often being over 40 ug/day (79,335).
Amalgam
fillings are the largest source of mercury in most people with daily exposures
documented to commonly be above government health guidelines (49,79,183,199,506,600,217). This is due to continuous vaporization of
mercury from amalgam in the mouth, along with galvanic currents from mixed
metals in the mouth that deposit the mercury in the gums and oral
cavity(605). Due to the high daily
mercury exposure and excretion into home and business sewers of those with
amalgam, dental amalgam is also the largest source of the high levels of
mercury found in all sewers and sewer sludge, and thus according to government
studies a significant source of mercury in rivers, lakes, bays, fish, and
crops(603). People also get significant
exposure from vaccinations, fish, and dental office vapor(600).
When
amalgam was placed into teeth of monkeys and rats, within one year mercury was
found to have accumulated in the brain, trigeminal ganglia, spinal ganglia,
kidneys, liver, lungs, hormone glands, and lymph glands(20). People also commonly get exposures to mercury and other toxic
metals such as lead, arsenic, nickel, and aluminum from food, water, and other
sources(600,601). All of these are
highly neurotoxic and are documented to cause neurological damage which can result
in chronic neurological conditions over time, as well as ADHD, mood, and
behavioral disorders(600,601,577).
Another
major source of mercury exposure is vaccines such as flu vaccines which have
large amounts of mercury and aluminum, and have been linked to conditions like
depression and dementia(445,598). It has been found
that vaccines contain adjuvants like aluminum plus mercury thimerosal which
overstimulate the immune system and brain, causing high levels of inflammation
over long periods of time. It has been found that those who get at least 5 flu
shots have an increased risk of inflammatory conditions like Alzheimer’s of at
least 500%.
Mercury is one of the most toxic substances
in existence and is known to bioaccumulate
in the body of people and animals that have chronic
exposure(85,600,577). Mercury exposure
is cumulative and comes primarily from 4 main sources: mercury amalgam dental
fillings, food(mainly fish), vaccinations, and
occupational exposure. Whereas mercury exposure from fish is primarily methyl mercury
and mercury from vaccinations is thimerosal(ethyl
mercury), mercury from occupational
exposure and dental fillings is primarily from elemental mercury vapor.
Developmental and neurological conditions occur at lower levels of exposure
from mercury vapor than from inorganic mercury or methyl mercury(606). Mercury in amalgam fillings, because of its low vapor pressure and
galvanic action with other metals in the mouth, has been found to be
continuously vaporized and released into
the body, and has been found to be the
directly correlated to the number of
amalgam surfaces and the largest source of mercury in the majority of people
(49,183,199,209,79,99,600), typically between 60 and 90% of the total. The level of daily exposure of those with
several amalgam fillings commonly exceeds the U.S. EPA health guideline for
daily mercury exposure of
0.1 ug/kg body weight/day, and the oral mercury level commonly
exceeds the mercury MRL of the U.S.ATSDR
of 0.2 ug/ cubic meter of air(217,600).
When amalgam fillings are replaced, levels of mercury in the blood,
urine, and feces typically rise temporarily but decline between 60 to 85%
within 6 to 9 months (79,600.).
II. Cytotoxic, Neurotoxic,
and Immunotoxic Effects of Mercury
Mercury vapor from amalgam readily crosses
cell membranes and binds to the -SH (sulphydryl) groups, resulting in
inactivation of sulfur processes and blocking of enzyme functions such as
cysteine dioxygenase(CDO), sulfite oxidase, and gamma‑glutamyltraspeptidase(GGC)
, producing sulfur metabolites with extreme toxicity that the body is unable to
properly detoxify(33,111,114,194,258,330,331,333), along with a deficiency in
sulfates required for many body functions.
Sulfur is essential in enzymes, hormones, nerve tissue, and red blood
cells. These exist in almost every
enzymatic process in the body. Blocked
or inhibited sulfur oxidation at the cellular level has been found in most with
many of the chronic degenerative diseases, including Parkinson’s, Alzheimer’s,
ALS, MS, lupus, rheumatoid arthritis, MCS,
etc (330,331,33,35,56,194,258), and appears to be a major factor in
these conditions. The deficiency in
conjugation and detoxification of sulfur based toxins in the liver results in
toxic metabolites and progressive nerve damage over time (331). Mercury also blocks the metabolic action of
manganese and the entry of calcium ions into cytoplasm(333). Oxidative stress and reactive oxygen
species(ROS) have also been implicated as major factors in neurological
disorders including stroke, PD, Alzheimer’s, ALS, etc.
(13,56,84,169,207b,424,442,453,462).
Programmed cell death(apoptosis)
is documented to be a major factor in degenerative neurological conditions like
ALS, Alzheimer’s, MS, Parkinson’s, etc.
Some of the factors documented to be involved in apoptosis of neurons
and immune cells include inducement of the inflamatory cytokine Tumor Necrosis
Factor-alpha(TNFa) (126), reactive oxygen species and oxidative
stress(13,43a,56a,296b,495), reduced glutathione levels(56,126a,111a), liver
enzyme effects and inhibition of protein kinase C and cytochrome
P450(43,84,260), nitric oxide and peroxynitrite toxicity (43a,521,524),
excitotoxicity and lipid peroxidation(490,496), excess free cysteine levels
(56d,111a,33,330),excess glutamate toxicity(13b, 416,445,598), excess dopamine
toxicity (56d,13a), beta-amyloid generation(462), increased calcium influx
toxicity (296b,333,416,432,462c,507) and DNA fragmentation(296,42,114,142) and
mitochondrial membrane dysfunction (56de, 416,444d). The mechanisms
by which mercury causes(often synergistically along
with other toxic exposures) all of these conditions and neuronal apoptosis will
be documented.
Chronic neurological conditions such as Alzheimer’s
appear to be primarily caused by chronic or acute brain inflammation. The brain
is very sensitive to inflammation.
Disturbances in metabolic networks: e.g., immuno-inflammatory processes,
insulin-glucose homeostasis, adipokine
synthesis and secretion, intra-cellular signaling cascades, and mitochondrial
respiration have been shown to be major factors in chronic neurological conditions
(592,593,598, etc.). Inflammatory chemicals such as mercury, aluminum, and
other toxic metals as well as other excitotoxins including MSG and aspartame
cause high levels of free radicals, lipid peroxidation, inflammatory cytokines,
and oxidative stress in the brain and cardiovascular systems(13,595-598,etc.)
Mercury and other toxic metals inhibit
astrocyte function in the brain and CNS(119), causing
increased glutamate and calcium related neurotoxicity (119,333,416,496).
Mercury and increased glutamate activate free radical forming processes like
xanthine oxidase which produce oxygen radicals and oxidative neurological damage(142,13).
Nitric oxide related toxicty caused by peroxynitrite formed by the
reaction of NO with superoxide anions, which results in nitration of tyrosine
residues in neurofilaments and manganese Superoxide Dimustase(SOD) has been
found to cause inhibition of the mitochondrial respiratory chain, inhibition of
the glutamate transporter, and glutamate-induced neurotoxicity involved in
ALS(524,521).
These
inflammatory processes damage cell structures including DNA, mitochondria, and
cell membranes. They also activate
microglia cells in the brain, which control brain inflammation and
immunity. Once activated, the microglia
secrete large amounts of neurotoxic substances such as glutamate, an
excitotoxin, which adds to inflammation and stimulates the area of the brain
associated with anxiety(598). Inflammation also
disrupts brain neurotransmitters resulting in reduced levels of serotonin,
dopamine, and norepinephrine. Some of
the main causes of such disturbances that have been documented include vaccines, mercury, aluminum,
other toxic metals, MSG, aspartame, etc. (593,598,600,etc.)
Reduced levels of magnesium and zinc are related to
metabolic syndrome, insulin resistance, and brain inflammation and are
protective against these conditions(595,43). Mercury and cadmium inhibiting magnesium and
zinc levels as well as inhibiting glucose transfer are other mechanisms by
which mercury and toxic metals are factors in metabolic syndrome and insulin
resistance/diabetes (43,198,338,597).
TNFa(tumor necrosis
factor-alpha) is a cytokine that controls a wide range of immune cell response
in mammals, including cell death(apoptosis) in neuronal and immune cells. This process is involved in inflamatory and
degenerative neurological conditions like ALS, MS, Parkinson’s, rheumatoid
arthritis, etc. Cell signaling
mechanisms like sphingolipids are part of the control mechansim for the TNFa
apoptosis mechanism(126a,598). Gluthathione is an amino acid that is a normal cellular
mechanism for controlling apoptosis.
When glutathione is depleted in the brain, reactive oxidative species
increased, and CNS and cell signaling mechinsisms are disrupted by toxic
exposures such as mercury, neuronal cell apoptosis results and neurological
damage. Mercury has been shown to induce
TNFa and deplete glutathione, causing inflamatory effects and cellular apoptosis
in neuronal and immune cells(126b,126c).
Mercury’s biochemical damage at the
cellular level include DNA damage, inhibition of DNA and RNA synthesis
(42,114,142,197,296,392); alteration of
protein structure (33,111,114,194,252,442);
alteration of the transport of calcium(333,43b,254,263,416,462,507);
inhibitation of glucose transport(338,254), and of enzyme function,protein
transport, and other essential nutrient transport (96,198,254,263,264,33,330,331,339,347,441,442); induction of free radical
formation(13a,43b,54,405,424), depletion of cellular gluthathione(necessary for
detoxification processes) (111,126,424), inhibition of glutathione peroxidase
enzyme(13a,442), inhibits glutamate uptake(119,416,445), induces peroxynitrite
and lipid peroxidation damage(521b), causes abnormal migration of neurons in
the cerebral cortex(149), immune system
damage (34,111,194, 226,252,272,316, 325,355); and inducement of inflamatory
cytokines(126,181).
Na(+),K(+)-ATPase is a
transmembrane protein that transports sodium and potassium ions across cell
membranes during an activity cycle that uses the energy released by ATP
hydrolysis. Mercury is documented to
inhibit Na(+),K(+)-ATPase function at very low levels
of exposure(288ab). Studies have found that in Alzheimer’s cases there was a
reduction in serum magnesium and RBC membrane Na(+)-K+
ATPase activity and an elevation in plasma serum digoxin (263). The activity of all serum free-radical
scavenging enzymes, concentration of glutathione, alpha tocopherol, iron
binding capacity, and ceruloplasmin decreased significantly in Alzheimer’s,
while the concentration of serum lipid peroxidation products and nitric oxide
increased. The inhibition of Na+-K+
ATPase can contribute to increase in intracellular calcium and decrease in
magnesium, which can result in 1) defective neurotransmitter transport
mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial
dysfunction, 4) defective golgi body function and protein processing
dysfunction. It is documented in this
paper that mercury is a cause of most of these conditions seen in Alzheimer’s
(13a,111,288,442,521b,43,56,263etc.)
Autoimmunity has also been found to be
a factor in chronic degenerative autoimmune conditions such as ALS, with
genetic susceptibility a major factor in who is affected. One genetic factor in Hg induced
autoimmunity is major histocompatibility complex(MHC)
linked. Both immune cell type Th1 and
Th2 cytokine responses are involved in autoimmunity(425c). One genetic difference found in animals and
humans is cellular retention differences for metals related to the ability to
excrete mercury(426).
For example it has been found that individuals with genetic blood factor
type APOE-4 do not excrete mercury readily and bioaccumulate mercury, resulting
in susceptibility to chronic autoimmune conditions such as Alzheimer’s,
Parkinson’s, etc. as early as age 40(437b), whereas those with type APOE-2
readily excrete mercury and are less susceptible (437,35).
Those with type APOE-3 are intermediate to the other 2 types. The incidence of autoimmune conditions have
increased to the extent this is now one of the leading causes of death among women(450). Also
when a condition has been initiated and exposure levels decline, autoimmune
antibodies also decline in animals or humans(233,234c,60,369,405)
Mercury has been found in autopsy studies
to accumulate in the brain of those with chronic exposures, and levels are
directly proportional to the number of amalgam filling surfaces
(85,577). Mercury has been found to cause memory loss
by inactivating enzymes necessary for brain cell energy production and proper
assembly of the protein tubulin into microtubules(258).
In a recent study, mercury at extremely low levels found commonly in those with
amalgam fillings was found to disrupt membrane structure and linear growth
rates of neurites in most nerve growth cones exposed, causing
tubulin/micortubile structure to disintegrate.
The study also found that mercury also interferes with formation of
tubulin producing neurofibrillary tangles in the brain similar to those
observed in Alzheimers patients(207,462), as well as causing neuronal somata to
fail to sprout. The process was found to
result in low levels of zinc in the brain(158,43). There is evidence that certain redox active
metal ions including copper and mercury are important in exacerbating and
perhaps facilitating Abeta‑mediated oxidative damage and amyloid deposits
in Alzheimer's disease(462,488,590). Mercury has also been shown to induce cell
cytotoxicity and oxidative stress and increases beta‑amyloid secretion
and tau phosphorylation in neuroblastoma
cells resulting in amyloid plaques which is found in Alzheimer’s patients, and
to also cause the formation of the neurofibrilla tangles found in the
Alzheimer’s patient brain(462,258).
Mercury and the induced neurofibrillary tangles also appear to produce a
functional zinc deficiency in the of AD sufferers(242), as well as
causing reduced lithium levels which is another factor in such diseases. Lithium protects brain cells against excess
glutamate induced excitability and calcium influx(280,416,445,56).
These studies clearly implicate mercury as having the ability to cause
neurodegeneration in the brain and CNS, at levels of 20 ppb, which is lower
than that of many with several amalgam fillings or dental occupational exposure(462).
Researchers at Geriatric and Psychiatric Univ. Clinics in Basel,
Switzerland concluded that inorganic mercury appears to be a causative factor
in Alzheimer’s and the Swizz Dental Assoc. recommended avoidance of amalgam use
in those with neurological disorders(462).
Clinical tests of patients with MND,ALS,
Parkinson’s, Alzheimer’s, Lupus(SLE),
rheumatoid arthritis and autism have found that the patients generally
have elevated plasma cysteine to sulphate ratios, with the average being 500% higher
than controls(330,331,56,33d), and in general being poor sulphur
oxidizers. This means that these
patients have insufficient sulfates available to carry out necessary bodily
processes and that cysteine levels build up in the brain and CNS to neurotoxic
levels. Mercury has been shown to
diminish and block sulphur oxidation and thus reducing glutathione levels which
is the part of this process involved in detoxifying and excretion of toxics
like mercury(33). Glutathione is produced through the
sulphur oxidation side of this process. Low levels of available glutathione
have been shown to increase mercury retention and increase toxic effects(111),
while high levels of free cysteine have been demonstrated to make toxicity due
to inorganic mercury more severe(333,194,56,33d). Mercury has also been found to play a part in
inducing intolerance and neuronal problems through blockage of the P-450
enzymatic process(84,33d).
Mercury
also blocks the immune function of magnesium and zinc (198,427,43,38),
whose deficiencies are known to cause significant neurological
effects(461,463,443). The low Zn levels result in deficient CuZnSuperoxide dismustase (CuZnSOD),
which in turn leads to increased levels of superoxide due to toxic metal
exposure(443). Mercury is known to
damage or inhibit SOD activity(33,111). Mercury
induced lipid peroxidation has been found to be a major factor in mercury’s
neurotoxicity, along with leading to decreased levels of glutathione
peroxidation and superoxide dismustase(SOD)(13,254,489,494-496).
Mercury
inhibits sulfur ligands in MT and in the case of intestinal cell membranes
inactivates MT that normally bind cuprous ions(477),
thus allowing buildup of copper to toxic levels in many and malfunction of the
Zn/Cu SOD function. Modern amalgams
commonly used in the U.S. have higher levels of copper than the traditional
silver amalgams and result in much higher exposure levels to mercury and copper(258). This is a factor in higher incidence of
neurodegnerative condidtions like Alzheimer’s. Exposure to mercury results in changes in metalloprotein
compounds that have genetic effects, having both structural and catalytic
effects on gene expression(114,241,296,442,464,477,495). Some of the processes affected by such MT
control of genes include cellular respiration, metabolism, enzymatic processes,
metal-specific homeostasis, and adrenal stress response systems. Significant
physiological changes occur when metal ion concentrations exceed threshold
levels.
Copper
is an essential trace metal which plays a fundamental role in the biochemistry
of the nervous system(489,495,464). Several chronic neurological conditions
involving copper metabolic disorders are well documented like Wilson’s Disease and Menkes Disease. Mutations in the copper/zinc enzyme
superoxide dismustase(SOD) have been shown to be a major factor in the motor
neuron degeneration in conditions like familial ALS and similar effects on
Cu/Zn SOD to be a factor in other conditions such as autism, Alzheimer’s,
Parkinson’s, and non-familial ALS(489,495,464,111). This condition can result in zinc deficient
SOD and oxidative damage involving nitric
oxide, peroxynitrite, and lipid peroxidation(495,496,489), which have been
found to affect glutamate mediated excitability and apoptosis of nerve cells
and effects on mitochondria (416,445,495, 496,119) These effects can be reduced
by zinc supplementation(464,495,517), as well as supplementation with
antioxidants and nitric oxide-suppressing agents and peroxynitrite scavengers
such as Vit C, Vit E, lipoic acid, Coenzyme Q10, carnosine, gingko biloba,
N-acetylcysteine, etc.(444,464,494,495,469). Some of the antioxidants were also
found to have protective effects through increasing catalase and SOD action,
while reducing lipid peroxidations(494a). Ceruloplasmin in plasma can be similarly affected by copper
metabolism disfunction, like SOD function, and is often a factor in
neurodegeneration(489).
There is accumulating
evidence that interactions between beta-amyloid and copper, iron, and zinc are
associated with the pathophysiology of Alzheimer's disease (AD). (590) A
significant dyshomeostasis of copper, iron, and zinc has been detected, and the
mismanagement of these metals induces beta-amyloid precipitation and
neurotoxicity. Chelating agents offer a potential therapeutic solution to the
neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper
and zinc chelating agent clioquinol represents a potential therapeutic route
that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the
accumulation of neocortical beta-amyloid.
There is also evidence that melatonin may have beneficial effects on
reducing metal toxicity(591).
Low
levels of mercury and toxic metals have been found to inhibit dihydroteridine
reductase, which affects the neural system function by inhibiting transmitters through its effect on
phenylalanine, tyrosine and tryptophan transport into neurons
(122,257,289,342,372). This was found
to cause severe impaired amine synthesis and hypokinesis. Tetrahydrobiopterin, which is essential in
production of
neurotransmitters, is significantly decreased in patients with
Alzheimer’s’s, Parkinson’s, MS, and
autism. Such patients have abnormal inhibition of neurotransmitter production.
Some studies have also found persons with
chronic exposure to electromagnetic fields(EMF) to
have higher levels of mercury exposure and excretion(38).
Magnetic fields are known to induce current in metals and would increase the
effects of galvanism. Occupational
exposure to higher levels of EMF have also been found in many studies to result
in much higher risk of chronic degenerative neurological conditions such as ALS(39) and Alzheimer’s Disease(40) Since EMF causes increased mercury exposure
in those with amalgam, and mercury is also known to cause these conditions,
again it is not clear the relative importance of the factors since the studies
were not controlled for mercury levels or number of amalgam fillings. Studies
have also found a correlation between high levels of aluminum exposure and
dementia such as Alzheimer’s(470). It is well
documented that neurological effects of toxics are synergistic. Flu shots have mercury and aluminum which
both are known to accumulate in the brain over time. A study of people who
received flu shots regularly found that if an individual had five consecutive flu shots between 1970
and 1980 (the years studied) his/her chances of getting Alzheimer's Disease is
ten times higher than if they had one or no shots(475).
Many
studies of patients with major neurological or degenerative diseases have found
evidence amalgam fillings may play a major role in development of conditions such as such as Alzheimer’s
(66,67,158,166,204, 207, 221,238,242,244,257,300,303,369,444d,462,35,38d) and
significantly improve after dental amalgam replacement and dental infection
cleanup. Low levels of toxic metals
have been found to inhibit dihydroteridine reductase, which affects the neural
system function by inhibiting brain transmitters through its effect on
phenylalanine, tyrosine and tryptophan transport into neurons(122,257,289,372). This was found to cause severe impaired
amine synthesis and hypokinesis. Tetrahydro-biopterin, which is essential in
production of
neurotransmitters, is significantly decreased in patients with
Alzheimer’s’s, Parkinson’s, and MS. Such patients have abnormal inhibition of
neurotransmitter production.(supplements which inhibit
breach of the blood brain barrier such as bioflavonoids have been found to slow
such neurological damage).
Also
mercury binds with cell membranes interfering with sodium and potassium enzyme
functions, causing excess membrane permeability, especially in terms of the
blood-brain barrier (155,207,311). Less
than 1ppm mercury in the blood stream can impair the blood- brain barrier. Mercury was also found to accumulate in the
mitochondria and interfere with their vital functions, and to inhibit
cytochrome C enzymes which affect energy supply to the brain(43,84,232,35). Persons with the APO-E4 gene form of apolipoprotein E which transports
cholesterol in the blood, are especially
susceptible to this damage(207,221,346,437), while those with APO-E2 which has
extra cysteine and is a better mercury scavenger have less damage. The majority have an intermediate form
APO-E3. This appears to be a factor in susceptibility to Alzheimer’s
disease, Parkinson’s disease and multiple sclerosis(291). Ones susceptibility can be estimated by
testing for this condition.
In some cases replacement of amalgam
fillings has been found to result in cure or significant improvement in Alzheimer’s
patients (204,35,38c).
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