Does Inorganic Mercury Play a Role in Alzheimer's Disease? A Systematic Review and an Integrated Molecular Mechanism

Abstract

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, 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 inorganic mercury, 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 inorganic mercury reproduces all pathological changes seen in AD, and in animal models inorganic mercury produced changes that are similar to those seen in AD. Its high affinity for selenium and selenoproteins suggests that inorganic mercury may promote neurodegenerative disorders via disruption of redox regulation. Inorganic mercury 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 soon as possible.

Mercury Toxicity and Neurodegenerative Effects

“…When Hg 0 from dental amalgams ( Fig. 1 ) is inhaled as a vapor into the lungs, about 80% is absorbed (Schafer et al 1999 ;Mutter et al 2010 ). Due to its uncharged monoatomic form, Hg 0 is highly diffusible and lipid soluble, and easily crosses the blood-brain barrier and lipid bilayers of cells ( Opitz et al 1996 ).…”

“…However, inorganic mercury is excreted largely via urine and feces, and partially through sweat, tears and breast milk and cell organelles, such as mitochondria. Mercury vapor also penetrates the mucosa and connective tissue of the oral and nasal cavities and may be transported into nerve cells (Mutter et al 2010 ).…”

“…This mercuric ion immediately reacts with intracellular molecules, such as enzymes, GSH (glutathione), tubulin, ion channels, and transporters. These interactions inhibit the activities of such molecules and interfere with normal cellular functions; in addition, even very low concentrations of Hg ++ decrease GSH levels and increase oxidative and nitrosative stress (Mutter et al 2010 ).…”

Size Fractionation of Metal Species from Serum Samples for Studying Element Biodistribution in Alzheimer’s Disease

“…The most important neurotoxic effects of aluminum and lead are their ability to trigger the formation of senile plaques and neurofibrillary tangles, to cause failure in neurotransmission and the induction of oxidative stress [7,54]. Alternatively, it has been demonstrated that the exposure to mercury and arsenic induces the appearance of characteristic pathological hallmarks of AD, including the formation of amyloid deposits, hyperphosphorylation of protein tau, disruption of redox regulation and inflammation, among others [55][56]. In addition, lead and cadmium cause a reduction in the brain content of acetylcholine [57][58], an important neurotransmitter closely related to the pathogenesis of AD.…”

Concentrations of Metals, β-Amyloid and Tau-Markers in Cerebrospinal Fluid in Patients with Alzheimer’s Disease

“…Increased mercury concentrations have been reported in brain regions in some patients with AD. In in vitro and animal experiments, low levels of inorganic mercury did cause AD-typical nerve cell degeneration [15] . The increased risk in subjects with APOE 4 may be due to its reduced ability to bind heavy metals [15] .…”