Richard Deth P.h.D. testifies to the FDA about his recent study linking inorganic mercury to Alzheimer’s Disease.
Recently published in the Journal for Alzheimer’s Disease was a study that performed a meta-analysis of 106 case-control or comparative cohort studies to associate mercury as a causative factor in Alzheimer’s disease. Noting that the main source of mercury in the human body is dental amalgam (1 – 27 ug a day)
Richard Deth is a professor of pharmacology in the Bouvé College of Health Sciences and the School of Pharmacy at Northeastern University.
Does Inorganic Mercury Play a Role in Alzheimer’s Disease? A Systematic Review and an Integrated Molecular Mechanism Abstract:
Journal of Alzheimer’s Disease 22 (2010) 357–374
Joachim Mutter, Annika Curth, Johannes Naumann, Richard Deth and Harald Walach
ABSTRACT:
Mercury is one of the most toxic substances known to humans. It has been introduced into the human environment and has also been widely used in medicine. Since circumstantial evidence exists that the pathology of Alzheimer’s disease (AD) might be in part caused or exacerbated by inorganic mercury (IM), we conducted a systematic review using a comprehensive search strategy. Studies were screened according to a pre-defined protocol. Two reviewers extracted relevant data independent of each other.
One thousand and forty one references were scrutinized, and 106 studies fulfilled the inclusion criteria. Most studies were case control or comparative cohort studies. Thirty-two studies, out of 40 testing memory in individuals exposed to IM, found significant memory deficits. Some autopsy studies found increased mercury levels in brain tissues of AD patients. Measurements of mercury levels in blood, urine, hair, nails, and cerebrospinal fluid were inconsistent.
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 may play a role as a co-factor in the development of AD. It may also increase the pathological influence of other metals. Our mechanistic model describes potential causal pathways. As the single most effective public health primary preventive measure, industrial, and medical usage of mercury should be eliminated as quickly as possible.
INTRODUCTION:
Mercury (hydrargyrium = Hg) is well known as the most toxic, nonradioactive element, with a well described neurotoxicology [1–4]. There are various forms of mercury: Organicmercury and inorganicmercury (IM), which includes elemental mercury (Hg) and mercury ions (Hg+ and Hg++). Mercury has been used by humans since ancient times, when the Chinese and Romans usedmercury sulfide (cinnabar) for red dye and ink. Widespread use of inorganic mercury started around 1830, when dental amalgams became popular, and calomel (mercury chloride) was used as teething powder in infants [5]. In the early 1900s, the organ ic mercurial ethylmercury was synthesized, and has been used until today as a fungicidal and antimicrobial agent.
Mercury toxicity arises from several strands: Elemental or metallic mercury (Hgo) is the only metal that is liquid at room temperature and can evaporate quickly. As mercury vapor, it is taken up via the lungs, and 80% of it is absorbed. Due to its uncharged monoatomic form, it is highly diffusible and lipid soluble. It crosses the bloodbrain barrier easily, as well as the lipid bilayers of cells and cell organelles, such as mitochondria. Mercury vapor also penetrates the mucosa and connective tissue of the oral or nasal cavities and may be transported into nerve cells [6–8]. Intracellularly, it is oxidized from its comparatively inactive Hg state to its ionic form, Hg++. This mercuric ion reacts immediately with intracellular molecules or structures (e.g., enzymes, glutathione, tubulin, ion channels, or transporters), inhibiting their activities and interfering with normal cellular function.
Very low levels (180 nM) of Hg++ decrease glutathione levels (GSH) and increase oxidative and nitrosative stress, which may lead to cytotoxicity [9]. The extraordinarily high affinity of Hg++ for selenium, and selenoproteins (dissociation constant = 10−45) [10] can disrupt cellular redox balance [11,12], especially in the brain,which uniquely depends upon selenoenzymes for antioxidant protection and hence selenium [13,14]. The role of extracellular thiol groups for the transport and absorption of organic mercurials is well described for methylmercury [15], but for IM, their role as a vector is still under discussion. When bound to a thiol group (e.g., cysteine) methylmercury can cross the blood brain barrier easily and is transported into glial cells and neurons usingmolecularmimicry [16], where it is converted to IM. Due to its charge it is less able to cross cell membranes and can be trapped in cells and held within the brain. Further, IM has a very high affinity for thiol groups and forms strong bonds with them, giving rise to the term “mercaptans” [15,17,18].
The brain is the major target organ for elemental, gaseous Hgo. The halflife of mercury in the brain is unclear. Modeling mercury deposition in the brain using autopsy data of traffic victims and intake streams through food yielded a halflife estimate of 22 years [19], and autopsies of proven clinical cases of Hgo poisoning have found high mercury levels in the brain as long as 17 years after the event [20,21].
In contrast, the halflife of mercury in the body is around 30 to 60 days [22]. IM binding to selenium is almost irreversible and contributes to its longterm brain retention [23,24]. Mercury from gaseous sources, such as coal burning, and from human activities through waste water, is accumulated in the food chain, and comes back to humans mainly via fish as methylmercury. Methylmercury is also transported via the bloodstream to the brain, where it is again converted to IM. Administration of oralmethylmercury to nonhuman primates yielded a plasma clearance halflife of 21 days, while the halflife for clearance of IM from the brain was too slow to be estimated (> 120 days) during a 28 day washout period [25]. IM outside of the brain is accumulated in the kidneys, and is slowly excreted.
The potential role formercury toxicity in Alzheimer’s disease (AD) stems from(i) the relevance of the gaseous phase of elemental mercury for the brain with (ii) subsequent transformation to ionic mercury, and (iii) the conversion of methylmercury to inorganic mercury (Hg++) in the brain. Humans take in about 2.4 μg of organic mercury per week, if consuming one fish meal per week, 2.3 μg of which is retained [22]. The main source for the intake of Hgo are dental amalgam fillings [22]. Such fillings consist of 50% of mercury, which evaporates at a slowrate,but is released at a higher rate, when the fillings are put in place or removed. From this source, and other, less common ones, 1.2 to 27.0 μg of Hgo are taken up per day, and 1.0 to 22.0 μg of Hgo are retained. Other variable factors of mercury release include the number, age, and size of the fillings, the presence of dental alloys, individual chewing habits and drinking hot liquids, as well as bruxism.
AD, first described in 1907, is one of themajor forms of dementia, with about 15–50% of over 80 year old elderly being affected [26–34]. Currently about 24million people worldwide suffer from dementia, with the numbers projected to double every 20 years [29], and by 2050 nearly 1 in 45Americans are predicted to suffer from AD [35]. Since the population of most countries is aging, the problem will continue to increase. As of 1998, the lifetime risk of a 55 year old healthy woman developing dementia was 33% compared to 16% for men [27].
Clinically, AD reveals itself through increasing cognitive decline, impaired attention and shortterm memory, and, at later stages, other forms of cognitive incompetence, such as impaired language, face recognition, spatial orientation, and hearing. Pathologically, this is thought to result from a gradual build up of amyloid plaques that form as a consequence of amyloid (A ) being produced at a higher rate than can be removed [36]. Amyloid plaques induce inflammation and free oxygen radical production,which eventually yields a self reinforcing cycle of neuroinflammation, neurodegeneration, and further inflammation. A second, apparently independent process, involves hyperphosphorylation of the tauprotein, which leads to a breakdown of microtubules and the neuronal cytoskeleton. Accumulating neurofibrillary tangles (NFT) promote neuroinflammation and reinforce the cycle [37]. Both these processes play a pathological role in the causation of AD [38], potentially exacerbated by deficient microvascularization in the brain [31,39].
The degeneration process starts in the entorhinal cortex and the basal ganglia, especially in the nucleus basalisMeynert, spreads to the hippocampus, and eventually affects other parts of the cortex as well. Due to the loss of neurons of the projective cholinergic system, brain cognitive functions such as short term memory are the first to be noticeably affected.
At present, we do not know what causes AD. Several genetic factors contributing to AD have been revealed [36,40], however, no clearcut genetic cause has been isolated. Apolipoprotein E (ApoE) genotype is a consistent risk factor [41–46], and the “4 genotype confers up to a 15fold risk relative to the “3 genotype [47, 48], which is the most widely distributed, whereas the “2 genotype is protective. However, it is not entirely clear, how this risk can be fitted within a mechanistic model. ApoE is a transporter protein that may also operate as a freeradical scavenger. It is important to notice here that all three ApoE forms consist of 299 aminoacids, and the only differences are that ApoE “4 has an arginine in position 112 and 158,where ApoE “2 has two cysteines, and ApoE “3 one arginine and one cysteine [49]. Interestingly, cysteine contains a sulfhydryl, which is capable of binding metals, especially bivalent metals such as lead, copper, zinc, and mercury. This has led to the hypothesis that the wellknown differential genetic epidemiology of ApoE might have to do in part with the differential detoxification capacity regardingmercury [50], and potentially other metals as well. The ApoE lipoprotein complex is taken up into neurons via the ApoER2 receptor. Selenoprotein P (SelP), which provides selenium for selenoprotein synthesis, is also taken up byApoER2 [51]. Differential competition for uptake between ApoE isoforms and SelP might therefore affect selenoprotein status and vulnerability to oxidative stress. Notably, SelP is physically associated with both A plaques and NFTs in the AD brain [52], further suggesting a role for impaired selenoprotein function in AD pathology.
Because of the potential relevance of mercury as a causal factor for initiating AD, we set out to systematically review the literature. Because of the apparent special relevance of IM, we restricted our review to this formofmercury. Other forms ofmercury toxicity, such as ethylmercury added as a preservative to vaccines, or methylmercury from fish, or the presence of other metals, like aluminumor lead,may synergistically enhance IM toxicity. This will be reviewed separately.
Does Inorganic Mercury Play a Role in Alzheimer’s Disease?
