Alzheimer�s Disease and Other Neurodegenerative Conditions : the Mercury & Toxic Metal Connection . B. Windham (Editor)

I. Introduction and Mercury Exposure

Early signs of ALZ (21,52,108) (tingling in fingers or toes, slow, shuffling gait, cramping in arms or legs, trouble with tongue, facial muscles, swallowing, worsening mood/social skills, spatial memory loss, changes in eating and grooming habits, difficulty in depth perception, loss of smell)

There has been a huge increase in the incidence of degenerative neurological conditions in virtually all Western countries over the last 2 decades (574,580,594). Neurodegenerative Conditions are increasing due to increased inflammation from vaccinations and excitotoxicity (445d). Much of the damage occurs during brain development which occurs in pregnancy or the first 2 years after birth. Increased glutamate outside neuron cells is a factor in such, triggering excitotoxicity and death of neuron cells.

Alzheimer�s disease is the leading cause of dementia in the elderly. The increase in Alzheimer�s and other dementia has been over 300%. The primary causes appear to be brain inflammation related to increased exposures to toxic pollutants, vaccines, and bad dietary habits, as well as mitochondrial dysfunction, oxidative stress and depletion of neurotransmitters such as acetylcholine (445,574,577,580,594,598,158, etc.). Inflammation caused by vaccines or other sources can trigger microglial priming which causes microglia and macrophages to secrete high levels of inflammatory cytokines which damage neurons(445d)]; Riboflavin or Thiamin deficiency can be a factor in ALS, etc. & is beneficial (445d): (R5P& B1 ). Luteolin is the most effective compound for brain stimulation or repair(445d). Zinc can stimulate microglia so should be used carefully . A neuroinflammatory response involving polarized microglial activity, enhanced astrocyte reactivity and elevated pro-inflammatory cytokine and chemokine load has long been implicated in AD (6), and studies suggest this facilitates neurodegeneration. Neuroinflammation is also involved with oxidative stress. Reactive oxidative species (ROS) toxicity remains an undisputed cause and link between Alzheimer's disease (AD) and Type-2 Diabetes Mellitus (T2DM). Patients with both AD and T2DM have damaged, oxidized DNA, RNA, protein and lipid products that can be used as possible disease progression markers(6c). Many studies have shown exposure to toxic substances such as toxic metals, pesticides, etc. cause neuroinflammation and likely collectively are factors in neurological conditions such as Alz . Disease. These factors appear to be factors in formation of advanced glycation end products (AGEs) and senile plaques of beta-amyloid peptides, hyper-phosphorylation of Tau, and neurofibrillary tangles-as seen in Alzheimers patients. AGEs also result from high glycemic foods and high temperature cooking.

Alzheimer�s disease (AD) is the most common form of dementia, an incurable and progressive neurodegenerative disease, leading to far-reaching memory loss, cognitive decline and eventually death(1). There are two major forms of the AD disease: early onset (familial) and late onset (sporadic). Early-onset one is rare, accounting for less than 5% of all AD cases. Mutations in three genes, mainly amyloid precursor protein (21q21.3), presenilin-1 (14q24.3) and presenilin-2 (1q42.13), have been identified to be involved in the development of this form. Late-onset AD (LOAD) is common among individuals over 65 years of age. Although heritability of LOAD is high (79%), its etiology is considered to be polygenic and multifactorial. The apolipoprotein E ε4 allele (19q13.2) is the major known genetic risk factor for this form of AD. The E4/E4 genotype does not determine the occurrence of LOAD, but is a factor that increases susceptibility to this disease and lowers the age of disease onset. Moreover, a large number of genes have been suggested to be implicated in risk of late-onset Alzheimer�s, e.g., clusterin (8p21), complement receptor 1 (1q32), phosphatidylinositol binding clathrin assembly protein (11q14.2), myc box-dependent-interacting protein 1 (2q14.3), ATP binding cassette transporter 7 (19p13.3), membrane-spanning 4-domains, subfamily A (11q12.2), ephrin type-A receptor 1 (7q34), CD33 antigen (19q13.3), CD2 associated protein (6p12.3), sortilin-related receptor 1 (11q24.1), GRB2 associated-binding protein 2 (11q13.4�13.5), insulin-degrading enzyme (10q24), death-associated protein kinase 1 (DAPK1) or gene encoding ubiquilin-1 (UBQLN1) [ 51 , 52 ]. The list of genes associated with AD is still growing. For instance, in the recent study, Lee et al. revealed that single-nucleotide polymorphisms in six genes, including 3-hydroxybutyrate dehydrogenase, type 1 ( BDH1 ), ST6 beta-galactosamide alpha-2,6-sialyltranferase 1 ( ST6GAL1 ), RAB20, member RAS oncogene family ( RAB20 ), PDS5 cohesin associated factor B (PDS5B ), adenosine deaminase, RNA-specific, B2 ( ADARB2 ), and SplA/ryanodine receptor domain and SOCS box containing 1 ( SPSB1 ), were directly or indirectly related to conversion of mild cognitive impairment to AD [ 53 ].

Neuropathological lesions characteristic of AD include neurofibrillary tangles (composed of hyperphosphorylated and aggregated tau protein) accumulated in the neuronal cytosol(1) as well as the extracellular plaque deposits of the β-amyloid peptide (Aβ), with their frequency correlating with declining cognitive measures [ 54 ]. Proteolytic cleavage of amyloid precursor polypeptide chain by secretases (mainly β- and γ-secretase) produces Aβ40 and Aβ42 peptides, which consist of 40 and 42 amino acids, respectively. The latter one, due to its hydrophobicity, is characterized by a greater tendency to form fibrils and is believed to be the main factor responsible for the formation of amyloid deposits [ 55 ]. However, Nagababu et al. suggested that the enhanced toxic effect observed for Aβ42 could be attributed to a greater toxicity of the 1�42 aggregates than the 1�40 ones of a comparable size distribution and not to the formation of larger fibrils [ 56 ]. According to Ott et al. [ 54 ] pre-aggregated Aβ42 peptide induces hyperphosphorylation and pathological structural changes of tau protein and thereby directly links the �amyloid hypothesis� to tau pathology observed in AD [ 54 ]. Although the pathogenesis of AD has not been fully understood yet, many studies have demonstrated that ROS and oxidative stress are implicated in disease progression. Aβ peptide was found to enhance the neuronal vulnerability to oxidative stress and cause an impairment of electron transport chain, whereas oxidative stress was shown to induce accumulation of Aβ peptide which subsequently promotes ROS production [ 16 , 22 , 57 ]. Bartzokis et al. in turn [ 58 ] suggested that myelin breakdown in vulnerable late-myelinating regions released oligodendrocyte- and myelin-associated iron that promoted the development of the toxic amyloid oligomers and plaques. There is also the �amyloid cascade-inflammatory hypothesis� which assumes that AD probably results from the inflammatory response induced by extracellular β-amyloid protein deposits, which subsequently become enhanced by aggregates of tau protein [ 59 ]. Moreover, recent research has suggested that AD might be a prion-like disease [ 60 , 61 ].

Many studies have found that r epeated exposure to pesticides has also been found to increase Alzheimer's Disease and dementia risk (9 ,3,4 ). A comprehensive review concluded that pesticides have synergistic risk effects increased by multiple toxic exposures; so, risk measurement in lab doesn�t translate to real life experience that has multiple toxic exposures(3a). in another study performances over the follow-up period demonstrated that exposed subjects had the worst decreases in performance, and the risk of having a two-point lower score on the Mini-Mental State Examination was 2.15 in pesticide exposed subjects. Two other studies looked at type of pesticide exposure. In the first (4a), organochlorine pesticides predicted the development of cognitive impairment, and elders with high vs. low concentrations of organochlorine pesticides had about 3 times higher risks. In the 2 ^nd (4b), investigators found that an increased risk of dementia was associated with occupational exposure to pesticides, and when they restricted the outcome to AD, the risk increased. Occupational exposure to organophosphate pesticides was shown to significantly increase the risk of developing AD later in life. The study suggests an epigenetic mechanism of harm.

Previous studies suggest that environmental exposures, such as heavy metals, trace

elements, radiation and pesticides , were possibly associated with the disease. Past

epidemiological studies also showed self-reported or occupational pesticide exposures

concur with an elevated number of ALS incidents. In a new study (8), the analysis found

that the patients diagnosed with ALS were 1.25 times more likely to have estimated

exposure to pesticides and herbicides including 2,4-D, glyphosate , carbaryl,

and chlorpyrifos , indicating exposures to these chemicals as a potential risk factor

for ALS. Additionally, the study narrowed down about two dozen herbicides

insecticides and fungicides that seemed to be associated with a higher incidence of

ALS and neurological damage seen in neurological diseases. To list a few: 2,4-D

glyphosate, MCPB, Terbacil , carbaryl, Chlorpyrifos, Permethrin, Paraqquat .

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 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.). Mercury vapor is lipid soluble and volatile so crosses the blood brain barrier; as does methyl mercury, which results by the bodies conversion from mercury vapor or inorganic mercury (589,33,606). 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 (49,183,199,79,83,85,335,603, etc.), with the majority of the rest excreted through the feces and often being over 30 ug/day (79,335,603). Mercury exposure from dental amalgam involves all 3 forms of mercury, with most initial exposure as vapor, some of which is converted to inorganic mercury-with some of this converted to methyl mercury by bacteria in the intestines (589,33,606). Both mercury vapor and methyl mercury readily cross the blood-brain barrier and cause damage to brain cells. The average amount of mercury in the feces of a group with amalgams was over 10 times that of controls (79,603). A 2009 study found that inorganic mercury levels in people have been increasing rapidly in recent years(543b). It used data from the U.S. Centers for Disease Control and Prevention�s National Health Nutrition Examination Survey (NHANES) finding that while inorganic mercury was detected in the blood of 2 percent of women aged 18 to 49 in the 1999-2000 NHANES survey, that level rose to 30 percent of women by 2005-2006. Surveys in all states using hair tests have found dangerous levels of mercury in an average of 22 % of the population, with over 30% in some states like Florida and New York(543c). A large U.S. Centers for Disease Control epidemiological study, NHANES III, found that those with more amalgam fillings (more mercury exposure) have significantly higher levels of chronic health conditions(543a).

Amalgam fillings are the largest source of mercury in most people with daily exposures documented to commonly be above government health guidelines (49,79,183,199,437b,506,594,33,607,217). 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 (33).

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 (33,601). 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 (594,33,601,577).

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, Parkinsons , ALS, and dementia (445,585,598). 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.

There is evidence of a link between the aluminum hydroxide in vaccines, and symptoms associated with Alzheimers , Parkinson's, and ALS (585,7). It has been found that those who get at least 5 flu shots have an increased risk of inflammatory conditions like Alzheimers of at least 500%. Research has shown (1) very small amounts of Al are needed to produce neurotoxicity and this criterion is satisfied through dietary Al intake, (2) Al sequesters different transport mechanisms to actively traverse brain barriers, (3) incremental acquisition of small amounts of Al over a lifetime favors its selective accumulation in brain tissues, and (4) experimental evidence has repeatedly demonstrated that chronic Al intoxication reproduces neuropathological hallmarks of AD. The hypothesis that Al significantly contributes to AD is built upon very solid experimental evidence. (7) Aluminum has been shown to cause encephalopathy, anemia, and bone disease in dialyzed patients. Aluminum also causes metabolic impairment and iron (Fe) alterations which could be a factor in neurological conditions such as dementia and Alz . Disease. (7b)

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 (85,33,577,594). 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. However, bacteria, yeasts, and Vitamin B12 methylate inorganic mercury to methyl mercury in the mouth and intestines (607,505) and mercury inhibits functional methylation in the body, a necessary process (504). Developmental and neurological conditions occur at lower levels of exposure from mercury vapor than from inorganic mercury or methyl mercury( 606), but all are extremely toxic and some mercury vapor is converted in the body to methyl mercury(489). 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 (49,183,199,209,79,99,33), 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 (217,33). 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 (79,33.). Susceptibility is a major factor in neurological and immune system damage from toxics such as mercury (490,33, www.myflcv.com/suscept.html ). Superoxide dismustase (SOD) is a major and vital factor in the methylation process that produces glutathione( GSH), the body systems master protector from toxic damage, SOD1 gene is neuroprotective but the mutated form SOD1-G93A is not protective, resulting in lower glutathione levels(490). Because of this, the mutated gene form is associated with familial AD as well as being a factor in AD and other conditions by reduced glutathione availability. Mercury vapor and methyl mercury cause significant damage to SOD1-G93 cells but not SOD1 cells(490c). Resveratrol was found to counteract this damage/effect. Apolipoprotein APOE4, one of the 3 blood allele types of APOE, has been found to result in inability to detoxify cells and the body and is a major susceptibility factor in AD and other neurological conditions (113). APOE2 allele people have less susceptibility to toxic effects. APOE3 allele people have more susceptibility than for type 2. People are exposed to a large number of toxic metals and toxins. Interactions among components of a mixture may change toxicokinetics and toxicodynamics , resulting in additive or synergistic neurological effects( 18). Mercury, lead, arsenic, and cadmium induce Fe, Cu, and Zn dyshomeiostatis which can result in AD, PD, etc.(18c)

Glutathione is produced by methylation that�s responsible for brain neurotransmitter production, immune function, and detoxification. DNA methylation and other epigenetic factors are important in the pathogenesis of late-onset Alzheimer's disease (LOAD). Methylenetetrahydrofolate reductase ( MTHFR ) gene mutations occur in most elderly patients with memory loss (36). MTHFR is critical for production of S-adenosyl-l-methionine (SAMe), the principal methyl donor. A common mutation (1364T/T) of the cystathionine-γ-lyase ( CTH ) gene affects the enzyme that converts cystathionine to cysteine in the transsulfuration pathway causing plasma elevation of total homocysteine ( tHcy ) or hyperhomocysteinemia -a strong and independent risk factor for cognitive loss and AD. Other causes of hyperhomocysteinemia include aging, nutritional factors, and deficiencies of B vitamins.

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(34,110,115,194,258,330,331,333), 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 (330,331,34,35,56,194, 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 and nitrosative stress (ONS) contributes to the pathogenesis of most brain maladies, and the magnitude of ONS is related to the ability of cellular antioxidants to neutralize the accumulating reactive oxygen and nitrogen species (ROS/RNS). SOD2 and GSH are critical for the cellular antioxidant defense. Variable changes of the expression or activities of one or more of the mitochondrial antioxidant systems have been documented in the brains derived from human patients and/or in animal models of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebral ischemia, toxic brain cell damage associated with overexposure to mercury or excitotoxins, or hepatic encephalopathy(490c). 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). A population-based cross-sectional study in Taiwan found those with amalgam fillings had a higher risk of Alzheimer�s than those without amalgam; also studies had shown mercury from amalgam crosses the blood-brain barrier and cause oxidative and apoptotic damage seen in AD, PD, etc. (589).

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 inflammatory cytokine Tumor Necrosis Factor-alpha( TNFa ) (126), reactive oxygen species and oxidative stress(13,43a,56a,296b,495), reduced glutathione levels(56,126a,110a), 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(490,496,593), excess free cysteine levels (56d,110a,34,330), excess glutamate toxicity(13b, 416,445,593,598), excess dopamine toxicity (56d,13a), beta-amyloid generation(462), increased calcium influx toxicity (296b,333,416,432,462c,507) and DNA fragmentation(296,42,115,142) and mitochondrial membrane dysfunction (56defg,416,444d).

mechanisms by which mercury causes all of these conditions and neuronal apoptosis are documented in this review (often synergistically along with other toxic exposures).

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 (592,593,598,56g). 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(13,585,593,595-598) Acetylcholine depletion has been found to be a major factor in Alzheimer�s , and aluminum has been found to inhibit choline transport and reduce neuronal choline acetyltransferase, which can lead to acetylcholine deficiency (580).

The brain has elaborate protective mechanisms for regulating neurotransmitters such as glutamate, which is the most abundant of all neurotransmitters. When these protective regulatory mechanisms are damaged or affected, chronic neurological conditions such as Alzheimer�s can result (593). Mercury and other toxic metals inhibit astrocyte function in the brain and CNS (119), causing increased glutamate and calcium related neurotoxicity (119,333,416,496,593). 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(524,521,56g).

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( 593,598). 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. (585,593,598,33,etc.)

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 mitochondrial membrane dysfunction (56bc, 416). Mitochondrial DNA mutations or dysfunction is fairly common, found in at least 1 in every 200 people( 275), and toxicity effects affect this population more than those with less susceptibility to mitochondrial dysfunction. Mercury depletes GSH and damages cellular mitochrondria , which along with the increased lipid peroxidation in protein and DNA oxidation in the brain appears to be major factors in conditions such as autism, Parkinson�s disease, Alzheimer�s , etc. (34,56,416,442,56g). Some prevention and repair of such damage to mitochondria has been documented using pyroquinoline quinine( PQQ) (56g).

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 (42,115,142,197,296,392); alteration of protein structure (34,110,115,194,252,442); 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 (96,198,254,263,264,34,330,331,339,347, 441,442); induction of free radical formation(13a,43b,54,405,424), depletion of cellular gluthathione (necessary for detoxification processes) (110,126,424), 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 (34,110,194, 226,252,272,316,325,355); and inducement of inflammatory cytokines(126,181). Homocysteine has been found to facilitate and increase mercury toxicity (19c).

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,110,288,442,521b,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). Dozens of studies have documented that exposure to inorganic mercury causes memory loss and memory problems (435,33). 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( 207,462,594), 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( 462,488,590,594). 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 experience has also found that DMSO has some ability to repair tubulin damage( 594).

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(330,331,56,34d), 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 (34). 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 (110), while high levels of free cysteine have been demonstrated to make toxicity due to inorganic mercury more severe( 333,194,56,34d). 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( 34,110). 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 Alzheimers . Exposure to mercury results in changes in metalloproteincompounds that have genetic effects, having both structural and catalytic effects on gene expression(115,241,296,442,464,477,495). 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, Alzheimers , Parkinsons , and non-familial ALS( 489,495,464,110). 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, turmeric, etc.(444,464,494,495,469,497). Some of the antioxidants were also found to have protective effects through increasing catalase and SOD action, while reducing lipid peroxidation (494a). Curcumin as an antioxidant, anti-inflammatory and lipophilic action improves the cognitive functions in patients with AD (497). A growing body of evidence indicates that oxidative stress, free radicals, beta amyloid, cerebral deregulation caused by bio-metal toxicity and abnormal inflammatory reactions contribute to the key event in Alzheimer's disease pathology. Due to various effects of curcumin, such as decreased Beta-amyloid plaques, delayed degradation of neurons, metal-chelation, anti-inflammatory, antioxidant and decreased microglia formation, the overall memory in patients with AD has improved. Ceruloplasmin in plasma can be similarly affected by copper metabolism disfunction, like SOD function, and is often a factor in neurodegeneration (489). Lipoic acid, L-Carnitine, & acetlyl -L- Carnitine have been found to have protective effects against cerebral ischemic-reperfusion, excitotoxic amino acid(glutamate) brain injury, mitochondrial dysfunction, diabetic neuropathy(445c)

Nanoparticles are widely present in the air of workplace environments and affect immune functions, causing different immune responses. A workplace study (18) showed a statistically significant increased level of the pro-inflammatory cytokine TNF-α in serum in both industry exposed groups compared with office workers, as well as a higher level of TNF-α in workers from the woodworking company compared with the metalworking employees. We found an elevated level of IL-6 in the exposed groups as well as an elevated level of IL-8 in the nasal lavage in woodworking employees after work. Thus it is seen that workplace exposures to air nanoparticles can cause increased inflammatory cytokines and inflammatory conditions, which can damage the neurological and immune systems and be a factor in AD & PD.

Studies showed that metals can induce A-beta aggregation and toxicity and are concentrated in Alzheimer's brain. 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 agents clioquinol and desferroxamine represent 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 and curcumin may have beneficial effects on reducing metal toxicity( 591,497). Turmeric/curcumin has been found to reduce some of the toxic and inflammatory effects of toxic metals (497,498).

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, 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) or Wi-fi 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 Alzheimers 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 Alzheimers (470,580 ), and concluded based on extensive literature that the neurotoxic effects of aluminium are beyond any doubt, and aluminium as a factor in some AD cannot be discarded (470b). 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 Alzheimers (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 Alzheimers , Parkinsons , 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 (207,221,346,437,580), 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 Alzheimers disease, Parkinsons disease and multiple sclerosis (291). One�s susceptibility can be estimated by testing for this condition.

A major systematic review of all medical studies found on the connection of mercury exposure and Alzheimer�s Disease was recently carried out by MDs and PhDs. (435) Studies were screened according to a pre-defined protocol. The author�s noted that mercury is one of the most toxic substances known to humans and in addition to being widespread in the environment has also been used extensively in vaccinations and dental amalgam. Studies were screened according to a pre-defined protocol. Most of the studies testing memory in individuals exposed to inorganic mercury (IM), found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients. � In vitro models showed that IM reproduces all pathological changes seen in AD, and in animal models IM produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that IM may promote neurodegenerative disorders via disruption of redox regulation.� IM appears to play a role as a co-factor in the development of AD. It appears to also increase the pathological influence of other metals through adverse effects on the blood brain barrier. �Our mechanistic model describes potential causal pathways. It concludes: As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as quickly as possible.

Earlier research on the biochemical abnormalities of the Alzheimer�s Diseased (AD) brain showed that mercury, and only mercury, at very low levels induced the same biochemical abnormalities when added to normal human brain homogenates or in the brains of rats exposed to mercury vapor. (435) "Since the brain is more vulnerable to oxidative stress than any other organ, it is not surprising that mercury, which promotes oxidative stress, is an important risk factor for brain disorders." Low levels of inorganic mercury were able to cause AD- typical nerve cell deteriorations in vitro and in animal experiments. Other metals like zinc, aluminum, copper, cadmium, manganese, iron, and chrome are not able to elicit all of these deteriorations in low levels, yet they aggravate the toxic effects of mercury (Hg) (435b). Amalgam consists of approx. 50 % of elementary mercury which becomes a gas at room temperature and is constantly being vaporized and absorbed by the organism. Mercury levels in brain tissues are 2 to10- foldhigher in individuals with dental amalgam (435b). The increased AD risk through APO E4 might be caused by its reduced ability to bind heavy metals.

III. Insulin resistance as a factor in Alzheimer�s

Higher insulin and glucose levels in the blood and deficiency of glucose in brain cells that need it has been found to lead to neurological problems such as Alzheimer�s (580,581). Those with either type I or type II diabetes have been found to be more likely to have other chronic conditions including heart disease, strokes, kidney disease, Alzheimer�s, eye conditions and blindness (580,581). Diabetes also impacts memory by increasing the risk blood vessels will become obstructed, restricting blood flow to the brain. High blood glucose levels also impact cognition through formation of sugar-related toxins called advanced glycation end products (AGEs). AGEs have been found to be a factor in aging, diabetes, and Alzheimer�s. Glycotoxins are formed when sugars interact with proteins and lipids, damaging the structure of proteins and membranes, rendering them less able to carry out their many vital processes. (581). Studies have shown that AGEs are a key factor in cross-linking of harmful beta-amyloid plaques in the brain that are implicated in Alzheimer�s. As previously documented mercury and aluminum exposure increase insulin resistance and amalgam replacement and detoxification reduce insulin resistance.

Inflammation induced by vaccine adjuvants like aluminum and mercury or by excitotoxins like MSG has been found to play a significant role in insulin resistance (type-2 diabetes) and in high levels of LDL cholesterol (597,598,585,593). Reduced levels of magnesium and zinc are related to metabolic syndrome, insulin resistance, and brain inflammation, and these are protective against these conditions (599,43). Mercury and cadmium by 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). Mercury inhibits production of insulin and is a factor in diabetes and hypoglycemia, with significant reductions in insulin need after replacement of amalgam fillings and normalizing of blood sugar (35,502). Iron overload and toxic metal effect on gluten have also been found to be a cause of insulin resistance/type 2 diabetes (10,582) of autism/ADHD/ Alz .

IV. Other causes/factors of Alzheimer�s (108,52,41,43)

chronic inflammation, oxidative stress, mitochondrial dysfunction, toxins(108,41,33), fluoride(41), poor diet (41,52,108,109), high meat and dairy consumption (109), [diabetes (41,108)-eat to prevent], [poor sleep pattern leads to loss of brain plasticity (108)-shut off TV, computers, smartphones at least an hour before bedtime, warm bath-consider epsum salt bath; go to bed at same time each night, if problem with waking up during night, try a small snack of nuts or plain yogurt before bed; early morning sun and exercise(99,108)-see insomnia]; artificial sweeteners/ Aspartame/ etc. contain methanol which converts for formaldehyde(99c); [ lyme disease (33,108), In some studies, 13% of those with AD had Creutzfeldt-Jacob spongiform encephalitis(109c). 20 to 40% of US dairy herds were infected with Bovine tuberculosis- a risk factor in human tuberculosis, etc. (100c)] [HSV-1 (108)-treat(lysine, oil of oregano, olive leaf extract, garlic, grapefruit seed extract, zinc, vit C]; [ Metabolic Cognitive Syndrome (low insulin and insulin receptors in brain)(type II diabetes and hypoglycemia related): treat to prevent these conditions-avoid high glycemic foods, add coconut oil or MCT oils, 108a]; [low acetylcholine levels(test and detox environmental toxins)- Acacia extract, skullcap extract, EGCG, Chrysin(108)]; [Resveratrol(prevents acetylation of tau proteins, protects DNA, protects telomeres,108)-red grapes or boiled peanuts]; [lions mane mushrooms(produce nerve growth factor(NGF) ( Amyloban or lions mane supplements)- prevention or treatment of Alz , 108];[peppermint tea, curcumin, Gingko biloba, 108]; alcohol or tobacco(109f); [(mercury (33,108,113,94), divalent copper from plumbing or supplements (112,108), aluminum(33,108); toxic metals cause inflammation, oxidative stress and mitochondrial insufficiency (33,52,105,108,115) and glutamate toxicity, and inflammatory cytokines which are seen as factors in ALZ(33,108,115), www.myflcv.com/Alzhg.html ) , TNFa promotes amyloid-beta buildup(LE, 2-03,52,108) (33) -weight training and detox (suppress TNFa . IGF-1 reduces A-beta buildup (13,33,108)];-test and cleanups & detox, Pectasol (42), milk thistle(108), chlorella or chlorophyll or sulphoraphane (108), for aluminum(lithium,108), IV chelation where needed(33,89,108)], [pesticides & air toxics such as magnetite(108); those living close to heavy traffic have higher dementia risk,108(WHO says air pollution is greatest environmental health threat-causing millions of deaths); reduce air pollution, HEPA air purifier in home & office, HEPA filter on vacuum(108)]; Turmeric Forte with coconut oil (41,108), L-carnitine (2 gm/ day), music therapy, maple syrup extract(108); [AGEs- Excess glucose causes inflammation resulting in advanced glycation end-products (AGEs) and significant adverse health effects such as high blood sugar, insulin resistance, diabetes, cardiovascular disease, kidney disease, and is a factor in dementia/ Alzheimer�s(52b). Highly processed foods and high temp cooking and dry heat cooking (frying, grilling, roasting) or browning of food also produce AGEs. Benfotiamine and carnosine counteract AGEs(52b) and improve such conditions(52b). High blood sugar and formaldehyde (from digestive processes & pollution sources) destroy cell structure by cross-linking proteins(52b,108 ).� Formaldehyde is a factor in dementia, diabetes, depression, aging damage, DNA damage(52b). Carnosine protects against formaldehyde damage and cross-linking]. Eating soy regularly was found to increase dementia risk, while fermented soy products such as tempe decreased dementia risk (116). �In some studies, 13% of those with AD had Creutzfeldt-Jacob spongiform encephalitis(109c). 20 to 40% of US dairy herds were infected with Bovine tuberculosis- a risk factor in human tuberculosis, etc. (109c)

V. Treatment of Alzheimer�s ( see ICT Protocol)

In some cases, replacement of amalgam fillings and/or toxic metals chelation has been found to result in significant improvement in Alzheimer�s patients (204,35,38c). Alzheimer�s patients commonly are found to be deficient in omega 3 fatty acids, vit C, B12, SAMe, vit K, etc. and clinical experience has found supplementing these to be beneficial in some cases (580). A study demonstrated protective effects of methylcobalamin , a vitamin B12 analog, against glutamate-induced neurotoxicity (2,503), and similarly for iron in those who are iron deficient. Supplements with clinical experience indicating benefit in many Alzheimer�s/dementia cases include pantothenic acid(B5), vit B12, vit B1, vit B6, Vit E, Ginkgo Biloba, Vit C, Acetyl-L- Carnatine , CoQ10, EFAs(DHA/EPA), N-Acetyl-Cysteine(NAC), SAMe, folate, inositol, melatonin, carnosine (580). Two treatments shown to be significantly beneficial in the majority of Alzheimer�s patients using the supplement are Huperzine A and Kami- Umtan -To (KUT) (580). Lithium supplements (lithium carbonate and lithium oratate ) have been found to be effective in protecting neurons and brain function from oxidative and excitotoxic effects. A recent study demonstrated that combined treatment with lithium and valproic acid elicits synergistic neuroprotective effects against glutamate excitotoxicity in cultured brain neurons (280).

Those with vegetarian and fish diets had lower AD incidence (109). Melatonin is protective. Virgin coconut oil increases glutathione levels and is neuroprotective (108,111); high homocysteine (see HHCY) (treatment: avoid red meat and dairy(109,111), regular exercise, folate, NAC(52), SAMe, Taurine, TMG, vit B12, Bit B2, Bit B6, Zinc, CDP choline, Creatine(111b) DHEA, curcumin(41) : Super-Bio Curcumin(52,4.5*), Terry Naturally Curamin Extra Strength(4.5*), (B complex vit) ALA, NAC, quercetin , (Coconut oil, berberine, 99);

Natural Antiparasitic treatments : Essential Oils ( oregano, galbanum, nutmeg, sandalwood ,tagetes , combinations)

Vitamin C homeostasis is essential to Brain Health

Vit C is a nutrient of great importance for proper functioning of nervous system and its main role in the brain is its participation

in the antioxidant defense. Apart from this role, it is involved in numerous non-oxidant processes like biosynthesis of collagen, carnitine, tyrosine and peptide hormones as well as of myelin. It plays the crucial role in neurotransmission and neuronal maturation and functions. For instance, its ability to alleviate seizure severity as well as reduction of seizure-induced damage have been proved. Two basic barriers limit the entry of Vit C (being a hydrophilic molecule) into the central nervous system: the blood-brain barrier and the blood-cerebrospinal fluid barrier (CSF). Considering the whole body, ascorbic acid uptake is mainly conditioned by two sodium-dependent transporters from the SLC23 family, the sodium-dependent Vit C transporter type 1 (SVCT1) and type 2 (SVCT2). These possess similar structure and amino acid sequence, but have different tissue distribution. SVCT1 is found predominantly in apical brush-border membranes of intestinal and renal tubular cells, whereas SVCT2 occurs in most tissue cells . SVCT2 is especially important for the transport of Vit C in the brain�it mediates the transport of ascorbate from plasma across choroid plexus to the cerebrospinal fluid and across the neuronal cell plasma membrane to neuronal cytosol . Although dehydroascorbic acid (DHA) enters the central nervous system more rapidly than the ascorbate, the latter one readily penetrates CNS after oral administration. DHA is taken up by the omnipresent glucose transporters (GLUT), which have affinity to this form of Vit C . GLUT1 and GLUT3 are mainly responsible for DHA uptake in the CNS . Transport of DHA by GLUT transporter is bidirectional�each molecule of DHA formed inside the cells by oxidation of the ascorbate could be effluxed and lost. This phenomenon is prevented by efficient cellular mechanisms of DHA reduction and recycling in ascorbate. Neurons can take up ascorbic acid using both described ways , whereas astrocytes acquire Vit C utilizing only GLUT transporters.

It is well known that the main function of intracellular ascorbic acid in the brain is the antioxidant defense of the cells. However, vitamin C in the central nervous system (CNS) has also many non-antioxidant functions�it plays a role of an enzymatic co-factor participating in biosynthesis of such substances as collagen, carnitine, tyrosine and peptide hormones. It has also been indicated that myelin formation in Schwann cells could be stimulated by ascorbic acid [ 7 , 29 ].

The brain is an organ particularly exposed to oxidative stress and free radicals� activity, which is associated with high levels of unsaturated fatty acids and high cell metabolism rate [ 16 ]. Ascorbic acid, being an antioxidant, acts directly by scavenging reactive oxygen and nitrogen species produced during normal cell metabolism [ 30 , 31 ]. In vivo studies demonstrated that the ascorbate had the ability to inactivate superoxide radicals�the major byproduct of fast metabolism of mitochondrial neurons [ 32 ]. Moreover, the ascorbate is a key factor in the recycling of other antioxidants, e.g., alpha-tocopherol (Vitamin E). Alpha-tocopherol, found in all biological membranes, is involved in preventing lipid peroxidation by removing peroxyl radicals. During this process α-tocopherol is oxidized to the α-tocopheroxyl radical, which can result in a very harmful effect. The ascorbate could reduce the tocopheroxyl radical back to tocopherol and then its oxidized form is recycled by enzymatic systems with using NADH or NADPH [ 33 ]. Regarding these facts, vitamin C is considered to be an important neuroprotective agent.

One non-antioxidant function of vitamin C is its participation in CNS signal transduction through neurotransmitters [ 16 ]. Vit C is suggested to influence this process via modulating of binding of neurotransmitters to receptors as well as regulating their release [ 34 , 35 , 36 , 37 ]. In addition, ascorbic acid acts as a co-factor in the synthesis of neurotransmitters, particularly of catecholamines�dopamine and norepinephrine [ 26 , 38 ]. Seitz et al. [ 39 ] suggested that the modulating effect of the ascorbate could be divided into short- and long-term ones. The short-term effect refers to ascorbate role as a substrate for dopamine-β-hydroxylase. Vit C supplies electrons for this enzyme catalyzing the formation of norepinephrine from dopamine. Moreover, it may exert neuroprotective influence against ROS and quinones generated by dopamine metabolism [ 16 ]. On the other hand, the long-term effect could be connected with increased expression of the tyrosine hydroxylase gene, probably via a mechanism that entails the increase of intracellular cAMP [ 39 ]. It has been stated that the function of ascorbic acid as a neuromodulator of neural transmission may be also associated with amino acidic residues reduction [ 40 ] or scavenging of ROS generated in response to neurotransmitter receptor activation [ 34 , 41 ]. Moreover, some have studies showed that ascorbic acid modulates the activity of some receptors such as glutamate as well as γ-aminobutyric acid (GABA) ones [ 22 , 40 , 42 , 43 , 44 ]. Vit C has been shown to prevent excitotoxic damage caused by excessive extracellular glutamate leading to hyperpolarization of the N -methyl- d -aspartate (NMDA) receptor and therefore to neuronal damage [ 45 ]. Vit C inhibits the binding of glutamate to the NMDA receptor, thus demonstrating a direct effect in preventing excessive nerve stimulation exerted by the glutamate [ 26 ]. The effect of ascorbic acid on GABA receptors can be explained by a decrease in the energy barrier for GABA activation induced by this agent. Ascorbic acid could bind to or modify one or more sites capable of allosterically modulating single-channel properties. In addition, it is possible that ascorbic acid acts through supporting the conversion from the last GABA-bound closed state to the open state. Alternatively, ascorbic acid could induce the transition of channels towards additional open states in which the receptor adopts lower energy conformations with higher open probabilities [ 40 , 44 ].

There have also been reports concerning the effect of Vit C on cognitive processes such as learning, memory and locomotion, although the exact mechanism of this impact is still being investigated [ 26 ]. However, animal studies have shown a clear association between the ascorbate and the cholinergic and dopaminergic systems, they also suggested that the ascorbate can act as a dopamine receptor antagonist. This was also confirmed by Tolbert et al. [ 46 ], who showed that the ascorbate inhibits the binding of specific dopamine D1 and D2 receptor agonists.

Another non-antioxidant function of Vit C includes modulation of neuronal metabolism by changing the preference for lactate over glucose as an energy substrate to sustain synaptic activity. During ascorbic acid metabolic switch, this vitamin is released from glial cells and is taken up by neurons where it restraints glucose transport and its utilization. This allows lactate uptake and its usage as the primary energy source in neurons [ 47 ]. It was observed that intracellular ascorbic acid inhibited neuronal glucose usage via a mechanism involving GLUT3 [ 48 ].

Vit C is involved in collagen synthesis, which also occurs in the brain [ 26 ]. There is no doubt that collagen is needed for blood vessels and neural sheath formation. It is well recognized that vitamin C takes part in the final step of the formation of mature triple helix collagen. In this stage, ascorbic acid acts as an electron donor in the hydroxylation of procollagen propyl and lysyl residues [ 16 ]. The role of Vit C in collagen synthesis in the brain was confirmed by Sotiriou et al. [ 49 ]. According to these authors in mice deficient in SVCT2 ascorbate transporter, the concentration of ascorbate in the brain was below detection level. The animals died due to capillary hemorrhage in the penetrating vessels of the brain. Ascorbate-dependent collagen synthesis is also linked to the formation of the myelin sheath that surrounds many nerve fibers [ 26 ]. In vitro studies showed that ascorbate, added to a mixed culture of rat Schwann cells and dorsal root ganglion neurons, promoted myelin formation and differentiation of Schwann cells during formation of the basal lamina of the myelin sheath [ 7 , 29 ].

Vit C is important for proper nervous system function and its abnormal concentration in nervous tissue is thought to be accompanied with neurological disorders. The fact that Vit C can neutralize superoxide radicals, which are generated in large amount during neurodegenerative processes, seems to support its role in neurodegeneration. Moreover, plasma and cellular Vit C levels decline steadily with age and neurodegenerative diseases are often associated with aging. An association of Vit C release with motor activity in central nervous system regions, glutamate-uptake-dependent release of Vit C, its possible role in modulation of N -methyl- d -aspartate receptor activity as well as ability to prevent peroxynitrite anion formation constitute further evidence pointing to the role of Vit C in neurodegenerative processes.

The role of Vit C in AD disease was studied in APP/PSEN1 mice carrying human AD mutations in the amyloid precursor protein (APP) and presenilin (PSEN1) genes (transgenic mouse model of Alzheimer�s disease) with partial ablation of vitamin C transport in the brain [ 9 , 62 , 63 ].

Warner et al. [ 9 ] demonstrated that decreased brain Vit C level in the 6-month-old SVCT2+/− APP/PSEN1 mice (obtained by crossing APP/PSEN1 bigenic mice with SVCT2+/− heterozygous knockout mice, which have the lower number of the sodium-dependent Vit C transporter) was associated with enhanced oxidative stress in brain, increased mortality, a shorter latency to seizure onset after kainic acid administration (10 mg/kg i.p.), and more ictal events following treatment with pentylenetetrazol (50 mg/kg i.p.). Furthermore, the authors reported that Vit C deficiency alone in SVCT2+/− mice increased the severity of kainic acid- and pentylenetetrazol-induced seizures [ 62 ]. According to another study even moderate intracellular Vit C deficiency displayed an important role in accelerating amyloid aggregation and brain oxidative stress formation, particularly during early stages of disease development. In 6-month-old SVCT2+/− APP/PSEN1 mice increased brain cortex oxidative stress (enhanced malondialdehyde, protein carbonyls, F2-isoprostanes) and decreased level of total glutathione as compared to wild-type controls were observed. Moreover, SVCT2+/− mice had elevated levels of both soluble and insoluble Aβ1-42 and a higher Aβ1-42/Aβ1-40 ratio. In 14-month old mice there were more amyloid-β plaque deposits in both hippocampus and cortex of SVCT2+/−APP/PSEN1+ mice as compared to APP/PSEN+ mice with normal brain Vit C level, whereas oxidative stress levels were similar between groups [ 62 ]. Ward et al. [ 63 ], in turn, showed that severe Vit C deficiency in Gulo−/− mice (lacking l -gulono-1,4-lactone oxidase ( Gulo ) responsible for the last step in Vit C synthesis) resulted in decreased blood glucose levels, oxidative damage to lipids and proteins in the cortex, and reduction in dopamine and serotonin metabolites in both the cortex and striatum. Moreover, Gulo−/− mice displayed a significant decrease in voluntary locomotor activity, reduced physical strength and elevated sucrose preference. All the above-mentioned behaviors were restored to control levels after treatment with Vit C (250 mg/kg, i.p.). The role of Vit C in preventing the brain against oxidative stress damage seems to be also proved by the recent study performed by Sarkar et al. [ 64 ]. The researchers share a view that cerebral ischemia-reperfusion-induced oxidative stress may initiate the pathogenic cascade leading eventually to neuronal loss, especially in hippocampus, with amyloid accumulation, tau protein pathology and irreversible Alzheimer�s dementia. Being the prime source of ROS generation, neuronal mitochondria are the most susceptible to damage caused by oxidative stress. The study proved it that l -ascorbic acid loaded polylactide nanocapsules exerted a protective effect on brain mitochondria against cerebral ischemia-reperfusion-induced oxidative injury [ 64 ]. Kennard and Harrison, in turn, evaluated the effects of a single intravenous dose of Vit C on spatial memory (using the modified Y-maze test) in APP/PSEN1 mice. The study was performed on APP/PSEN1 and wild-type (WT) mice of three age spans (3, 9 or 20 months). It was shown that APP/PSEN1 mice displayed no behavioral impairment as compared to WT controls, but memory impairment along with aging was observed in both groups. Vit C treatment (125 mg/kg, i.v.) improved performance in 9-month old APP/PSEN1 and WT mice, but improvements in short-term spatial memory did not result from changes in the neuropathological features of AD or monoamine signaling, as acute Vit C administration did not alter monoamine levels in the nucleus accumbens [ 65 ]. Cognitive-enhancing effects of acute intraperitoneal (i.p.) Vit C treatment in APP/PSEN1 mice (12- and 24-month-old) were investigated by Harrison et al. Vit C treatment (125 mg/kg i.p.) improved Y-maze alternation rates and swim accuracy in the water maze in both APP/PSEN1 and wild-type mice; but like in the previous study had no significant effect on the age-associated increase in Aβ deposits and oxidative stress, and did not also affect acetylcholinesterase (AChE) activity either, which was significantly reduced in APP/PSEN1 mice [ 66 ]. Murakami et al. [ 67 ] in turn reported that 6-month-treatment with Vit C resulted in reduced Aβ oligomer formation without affecting plaque formation, a significant decrease in brain oxidative damage and Aβ42/Aβ40 ratio as well as behavioral decline in an AD mouse model. Furthermore, this restored the declined synaptophysin and reduced the phosphorylation of tau protein at Ser396.

Besides the presented roles, Vit C has also been suggested to prevent neurodegenerative changes and cognitive decline by protecting blood�brain barrier (BBB) integrity [ 68 ].

Kook et al., in the study performed on KO-Tg mice (generating by crossing 5 familial Alzheimer�s disease mutation (5XFAD) mice with mice lacking Gulo ), found that oral Vit C supplementation (3.3 g/L of drinking water) reduced amyloid plaque burden in the cortex and hippocampus by ameliorating BBB disruption (via preventing tight junction structural changes) and morphological changes in the mitochondria [ 69 ]. This seems to be confirmed by other studies that proved that Vit C might affect levels of proteins responsible for the tightness of BBB, like tight junction-specific integral membrane proteins (occludin and claudin-5) as well as matrix metalloproteinase 9 (MMP-9). Allahtavakoli et al. demonstrated that in a rat stroke model Vit C administration (500 mg/kg; 5 h after stroke) significantly reduced BBB permeability by reducing serum levels of matrix metalloproteinase 9 [ 70 ]. Song et al. reported that Vit C (100 mg/kg i.p.) protected cerebral ischemia-induced BBB disruption by preserving the expression of claudin 5 [ 71 ], whereas Lin et al. observed that Vit C (500 mg/kg i.p.) prevented compression-induced BBB disruption and sensory deficit by upregulating the expression of both occludin and claudin-5 [ 72 ].

In the available literature, there were only few studies investigating the role of Vit C in AD disease in human and the existing ones have yielded equivocal results.

Some studies have shown significantly lower plasma/serum Vit C level in AD patients as compared to healthy individuals, whereas others have found no difference [ 73 , 74 ]. However, meta-analysis performed by Lopes da Silva et al. proved significantly lower plasma levels of Vit C in AD patients [ 75 ]. It seems that the above discrepancies may result from the fact that not plasma but rather intracellular Vit C may be associated with AD.

Generally, studies involving human participants are limited to assessing the effect of Vit C supplementation administrated with other antioxidants on AD course.

Arlt et al. [ 76 ] found that 1-month and 1-year co-supplementation of Vit C (1000 mg/day) with vitamin E (400 IU/day) increased their concentrations not only in plasma but also in cerebrospinal fluid (which reflects the Vit C status of the brain), while cerebrospinal fluid lipid oxidation was significantly reduced only after 1 year. However, vitamins� supplementation did not have a significant effect on the course of AD [ 76 ]. These findings were aslo confirmed by the randomized clinical trial of Galasko et al. [ 77 ], which showed that treatment of AD patients for 16 weeks with vitamin E (800 IU/day) plus Vit C (500 mg/day) plus α-lipoic acid (900 mg/day) did not influence cerebrospinal fluid levels of Aβ42, tau and p181tau (widely accepted biomarkers related to amyloid or tau pathology), but decreased F2-isoprostane level (a validated biomarker of oxidative stress). Moreover, is should be emphasized that the above treatment increased risk of faster cognitive decline. This seems to be consistent with results of the recent study which revealed it that Vit C was a potent antioxidant within the AD brain, but it was not able to ameliorate other factors linked to AD pathogenesis as it was proved to be a poor metal chelator and did not inhibit Aβ42 fibrillation [ 78 ]. In the study considering an association between nutrient patterns and three brain AD-biomarkers, namely Aβ load, glucose metabolism and gray matter volumes (a marker of brain atrophy) in AD-vulnerable regions, it was found that the higher intake of carotenoids, vitamin A, vitamin C and dietary fibers was positively associated only with glucose metabolism [ 79 ].

On the other hand(1), a randomized control trial involving 276 elderly participants demonstrated that 16-week-co-supplementation of vitamin E and C with β-carotene significantly improved cognitive function (particularly with higher doses of β-carotene). Furthermore, the authors suggested that such a treatment markedly reduced plasma Aβ levels and elevated plasma estradiol levels [ 80 ]. Vit C and E co-supplementation for more than 3 years was also shown to be associated with a reduced prevalence and incidence of AD [ 81 ]. Moreover, an adequate Vit C plasma level seems to be associated with less progression in carotid intima-media thickness (C-IMT)�the greater C-IMT is suggested to be a risk factor in predicting cognitive decline in the general population, in the elderly population and in patients with Alzheimer�s disease. Polidori et al. showed significant decrease (with a linear slope) in Vit C level among old individuals with no or very mild cognitive impairment from the first to the fourth C-IMT quartile [ 82 ].

(8) Pesticides applied to crops and amyotrophic lateral sclerosis risk in the U.S ; Angeline Andrew , Jie Zhou , et al; NeuroToxicology , Volume 87 , December 2021, Pages 128-135

(9) Repeated Exposure to Pesticides Increases Alzheimer's Disease Risk, K. M. Hayden , Neurology. 2010;74:1524 -1530

(10) Confirmed Adverse Health Effects of Glutens

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(89) � American College for Advancement in Medicine (ACAM) -training courses in chelation, integrative medicine, functional medicine & location assistance for chelation or functional medicine doctors, online at https://www.acam.org

�or call 1-800-532-3688.

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(543) U.S. Centers for Disease Control, National Center for Health Statistics, NHANES III

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(b) Laks , Dan R. Assessment of chronic mercury exposure within the U.S. population,

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(593) Vaccines, Depression and Neurodegeneration After Age 50, By Russell L. Blaylock, www.flcv.com/vaxinfla.html ; &(b) Immunoexcitotoxicity , R L Blaylock, Alt Ther Health Med, 2008, 14:46-53; & (c) Beat Depression and Anxiety with Diet/Nutrition, Blaylock Report, Dec 2010.

(594) Heavy Metal and Chemical Toxicity, Dietrich Klinghardt , MD, Ph.D. www.neuraltherapy.com/chemtox.htm ; & Mercury Toxicity and Systemic Elimination Agents, D. Klinghardt & J Mercola ( DO), J of Nutritional and Environmental Medicine, 2001, 11:53-62; & Amalgam Detox , Klinghardt Academy of Neurobiology, 2008

(595) High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation. Magnes Res. 2006 Dec;19(4):237-43. Rayssiguier Y, Gueux E, et al; & (b) Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort. Am J Clin Nutr . 2006 Nov;84(5):1062-9 Bo S, Durazzo M, Pagano G. et al; & (c) Hypomagnesemia, oxidative stress, inflammation, and metabolic syndrome. Diabetes Metab Res Rev. 2006 Nov-Dec;22(6):471-6. Guerrero-Romero F, Rodr�guez-Mor�n

(596) Effects of antidiabetic and antihyperlipidemic agents on C-reactive protein. Mayo Clin Proc. 2008 Mar;83(3):333-42, Dandona P; & Role of advanced glycation end products in hypertension and atherosclerosis: therapeutic implications. Cell Biochem Biophys . 2007;49(1):48-63, Vasdev S, Gill V, Singal P.

(597) Effects of mercuric chloride on glucose transport in 3T3-L1 adipocytes. Toxicol In Vitro. 2005 Mar;19(2):207-14. Barnes DM, Kircher EA; & Effects of inorganic HgCl2 on adipogenesis. Toxicol Sci. 2003 Oct;75(2):368-77. Epub 2003 Jul 25, Barnes DM, Hanlon PR, Kircher EA; & (b) Heavy metal-induced inhibition of active transport in the rat small intestine in vitro. Interaction with other ions. Comp Biochem Physiol C. 1986;84(2):363-8, Iturri SJ, Pe�a A; & Interaction of the sugar carrier of intestinal brush-border membranes with HgCl2. Biochim Biophys Acta. 1980 May 8;598(1):100-14, Klip A, Grinstein S, Biber J, Semenza G.

(598) Overcoming Depression, Dr. Russell Blaylock, The Blaylock Wellness Report, Vol 5, No. 3, March 2008; & The Blaylock Wellness Report, Inflammatory Conditions, Vol 5, No. 3, Feb 2008, & Food Additives, What you eat can kill you, Vol 4, No. 10, http://www.blaylockreport.com/

(599) High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation. Magnes Res. 2006 Dec;19(4):237-43. Rayssiguier Y, Gueux E, et al; & (b) Dietary magnesium and fiber intakes and inflammatory and metabolic indicators in middle-aged subjects from a population-based cohort. Am J Clin Nutr . 2006 Nov;84(5):1062-9 Bo S, Durazzo M, Pagano G. et al; & (c) Hypomagnesemia, oxidative stress, inflammation, and metabolic syndrome. Diabetes Metab Res Rev. 2006 Nov-Dec;22(6):471-6. Guerrero-Romero F, Rodr�guez-Mor�n

(600) Annotated bibliography: Exposure levels and health effects related to mercury/dental amalgam and results of amalgam replacement ;B Windham(Ed.),(over 3000 medical study references documenting mechanism of causality of 40 chronic conditions and over 60,000 clinical cases of recovery or significant improvement of these conditions after amalgam replacement-documented by doctors) www.myflcv.com/amalg6.html

(601) Cognitive and Behavioral Effects of Toxic Metal Exposures; B. Windham (Ed), (over 150 medical study references www.myflcv.com/tmlbn.html

(602) The mechanisms by which mercury causes chronic immune and inflamatory condtions,B .Windham(Ed.), www.myflcv.com/immunere.html

(603) The environmental effects of mercury from amalgam affect everyone. B. Windham (Ed.) ( Gov�t studies) www.flcv.com/damspr2f.html

(604) "Health, Hormonal, and Reproductive Effects of Endocrine Disrupting Chemicals" (including mercury), Annotated Bibliography , B.Windham ,

www.myflcv.com/endohg.html & www.myflcv.com/endocrin.html

(605) Mechanisms of mercury release from amalgam dental fillings: vaporization, oral galvanism, and effects of Electromagnetic fields,

www.myflcv.com/galv.html

(606) Developmental and neurological effects of mercury vapor, B.Windham (Ed)

www.myflcv.com/damspr13.html

(607) Documentation of mercury exposure levels from dental amalgam, www.myflcv.com/damspr1.html

Note: etc. when it is used in a list of references means that Author knows of several more references supporting the statement, in #600 for example, but doesn � t think them necessary here.

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