Ralph Sanchez, MTCM, CNS, D.Hom.
The research demonstrating the deleterious and toxic effects of mercury on brain function and structure in neurodegenerative disease processes is plentiful. Adding to the research literature, a May/2009 study demonstrated that methylmercury* induces neurotoxicity, by significantly inactivating one the brain’s primary antioxidant defense buffers, glutathione peroxidase (GPx). (1)
Methylmercury, the organic form of mercury, is formed from the methylation of inorganic mercury in the environment (biotransformation). Fish and fish products is the more common source of methylmercury exposure. Another form of mercury, elemental mercury, is used in dental amalgams. Although methylmercury is considered to be a more toxic form of mercury, elemental mercury also poses a serious health hazard to the central nervous system.
For more information about the role of mercury and Alzheimer’s disease, please read my article: “Alzheimer’s Disease And Mercury In Your Teeth – Can Neurotoxins Like Mercury Be Putting You At Risk For Alzheimer’s Disease?”
Glutathione is composed of three (tripeptide) amino acids– cysteine, glutamate, and glycine. Reduced glutathione and selenium form an integral complex (selenoprotein) of the glutathione peroxidase (GPx1) antioxidant enzyme. More specifically, a selenium atom is incorporated into the cysteine component of GPx1 and is termed selenocysteine.
Glutathione peroxidase, is one of three innate intracellular antioxidant enzymes that function as powerful cellular scavengers of free radicals.***. Superoxide dismutase (SOD) and catalase (CAT) are the other two. There are eight types (isoforms) of GPx, GPx1 through GPx8, and they do not all have the same selenocysteine-glutathione structure. GPx1 is the most abundant of the lot.
Mercury inactivates (GPx) in the brain, leaving it vulnerable to the damaging effects of free radicals, hydrogen peroxide and superoxide, and their more toxic downstream oxidative and nitrative radicals**** (hydrochlorous acid, peroxynitrate). (2) Apart from the effect of mercury on GPx, mercury is powerful generator of free radical activity and subsequently compromises the brain’s core antioxidant defenses.(3) Depletion of the brain’s cellular antioxidant defenses, creates an oxidative stress milieu** that contributes to the neurodegenerative disease process associated with Alzheimer’s disease (AD). (4)
The generation of free radicals (i.e. Reactive Oxygen Species-ROS, Reactive Nitrative Species-RNS), and the subsequent depletion of the core antioxidant defenses creates a ripe environment for oxidative/nitrative damage that is considered to be an integral component of brain cell (neuron) death (apoptosis) in neurodegenerative diseases.(3) Oxidative stress damage to cellular lipids, proteins, and DNA as evidenced in postmortem tissues and are classical indicators of the pathology that occurs in neurological diseases such as AD.(2)
Free Radical damage
Brain tissue is largely made up of fats (60-70%) that are particularly at risk to damage by oxidative/nitrative reactions mediated by free radicals. Lipid (fats) rich membranes that form the enveloping structure of the cell, and the mitochondrial membranes where energy production is enabled, are extremely vulnerable to oxidative damage. GPx protects against hydrogen peroxide radical mediated damage to lipids that take place in the presence of fatty acid peroxides-toxic byproducts of oxidative reactions. Thus, GPx functions in part to protect lipid rich membranes from oxidation (peroxidation), and protects cellular structure and it’s functional integrity. (See illustration below)
While lipid structures are at particular risk to peroxidation, other vital components to the integrity of the neuron are vulnerable to the assaults initiated by free radicals. DNA and protein structures of the neuron are also at high risk for oxidative damage induced by mercury and Reactive Oxygen Species.
Neurons are highly dependent on their cytoskeletal structure that is functions as a support scaffold and a critical conveyance network that shuttles nutrients and organelles from the cell body to the axon terminal and transports them back for recycling. Methylercury binds to and depresses synthesis of tubulin proteins that make up the structural elements of the neuronal skeletal framework and subsequently disrupt a host of cellular processes vital to it’s survival.(5)
Membranes that surround the neuron, and form the outer structural layer, and similar membranes (endoplasmic reticulum) in the mitochondrial organelles of cells,***** are comprised of fats (lipids) that are easily damaged by free radicals. This destructive process, referred to as lipid peroxidation, (oxidation of fats), disrupts essential signaling mechanisms that takes place at important cellular junctures (the synapse), and to energy metabolism that occurs within the mitochondria.
Lipid peroxidation of brain tissue, has been identified as a component in pre-Alzheimer’s (amnestic mild cognitive impairment) events that trigger and contribute to the neurodegenerative features of AD. (3) While oxidative damage has been theorized to be a key component to the neurodegenerative processes of AD, it is now being placed front and center as an early event phenomena in the genesis of AD.(6)
The subsequent endpoint to glutathione depletion and the oxidation of fats, is the disruption of communication pathways between neurons. The signaling mechanisms that comprise the communication circuitry between brain cells, is a dynamic process that is ultimately dependent on the structural and functional integrity of the junctures (the synapse) between neurons. The synapse, and it’s plasticity, ******is the foundational mechanism for forming memories, and retaining them.
Reactive Oxygen Species are not all bad
It is important to understand that in the discussion of radicals like ROS, that the key principle in the issue of oxidative stress in the development of AD, is the balance of antioxidants to the level of radicals being generated, normally or abnormally. ROS are a normal and essential component to the process of life and death of the cell. For example, if the generation of ROS overwhelms the counter balance of antioxidants, cell suicide mechanisms are triggered that lead to the demise of the cell. On the other hand, ROS function as critical signaling agents that down regulate metabolism and blunt oxidative stress threats to the survival of the cell. (3) This dynamic homeostatic dance is easily tripped by toxic influences of heavy metals like mercury.
Not to be lost in this overview is the susceptibility that ApoE4 genotypes have to the neurotoxic effects of mercury (please read:). ApoE4 genotypes are relatively poor detoxifiers of mercury and do not detoxify mercury as well as an ApoE2 carrier.(7) For more information on the role of ApoE4 in Alzheimer’s disease risk, please read my article: “The Alzheimer’s Gene Puzzle – Genetic Links To Late Onset Alzheimer’s Disease”
The generation and maintenance of optimal glutahione levels in the brain is critical for protecting neurons from damage, and for the integrtiy of neuronal communication dynamics that underlie higher cognitive processes. However, glutathione is but one of several layers of antioxidant protection that are pivotal players in controlling the damaging cascade of free radical damage to the brain.
Apart from the family of antioxidant enzymes detailed above, vitamin E & C, alpha lipoic-acid, and CoQ10, scavenge free radicals before they cascade into more damaging oxidative/nitrative reactions. These fundamental antioxidant nutrients rely on the inherent and regenerative reactions (redox) that maintain the levels of the endogenous antioxidant pool as they are inevitably metabolized in redox reactions******* as they do their work.
* Methylmercury…organic form which is more readily absorbed. Methylmercury exposure is from dietary ingestion (fish and shellfish).
For ore information on the types of mercury, please visit: http://www.epa.gov/ttn/atw/hlthef/mercury.html
** Oxidative Stress: Oxidative stress is a physiological condition whereby there is an imbalance between protective antioxidants and oxidative free radicals and other oxidants (highly reactive forms of oxygen). The “oxidative balance” between antioxidants and oxidants that they quench (free radicals), is a key element in optimizing health and buffering against ” oxidative damage” in the aging process, and the degenerative diseases associated with it.
*** Free Radical is any oxygen or nitrogen atom or molecule (group of atoms), which has an “unpaired electron” in the outer ring. This renders a highly unstable and reactive atom/molecule. When the attacked molecule loses its electron, it becomes a free radical itself, and triggers the subsequent generation of a chain reaction of free radical damage to cellular membranes, proteins and DNA. Free radicals are linked to the progression of cancer, cardiovascular disease, neurological disease, and other age-related diseases.
**** Nitration: Just as the biochemical reactions of oxidation are a potentially damaging process in the body, nitration also can exert ” Nitrative Stress”. The same proteins, lipids, and cellular DNA damaged by oxidative reactions, are also mediated by nitrative reactions. “Oxidative Stress” involves reactions mediated by oxygen containing molecules, while “Nitrative Stress” involves reactions mediated by nitrogen containing molecules.
***** Mitochondria: The mitochondria are the cells energy factories that power the body’s energy metabolism. Nutrient deficiencies, toxins and genetic influences can disrupt the optimum functioning of the mitochondria.
Note: Peroxynitrate (ONOO) contains both oxygen and nitrogen compounds and is a potent oxidation and nitration agent.
****** Brain plasticity refers to the brain’s malleability-its capacity for adaptive change.
******* Redox—the term describes the oxidation-reduction reactions that are a normal component of the ebb and flow in the loss and gain of electrons (see free radicals above) as they are utilized in the regulation of oxidants and free radicals, and as antioxidants are regenerated via reduction mechanisms that nets a gain of an electron. (Reduction is gain of electrons and oxidation results in the loss of electrons).
1. Methylmercury neurotoxicity is associated with inhibition of the antioxidant enzyme glutathione peroxidase
Jeferson L. Francoa, Thaís Possera, Peter R. Dunkleyb, Phillip W. Dicksonb, Jacó J. Mattosa, Roberta Martinsa, Afonso C.D. Bainya, Maria R. Marquesa, Alcir L. Dafrec and Marcelo Farina
Free Radical Biology and Medicine Volume 47, Issue 4, 15 August 2009, Pages 449-457
2. Oxidative stress and nitration in neurodegeneration: Cause, effect, or association?
Harry Ischiropoulos and Joseph S. Beckman
J Clin Invest. Volume 111, Issue 2, January 15, 2003
3. Methylmercury-induced reactive oxygen species formation in neonatal cerebral astrocytic cultures is attenuated by antioxidants
Gouri Shanker and Michael Aschner
Molecular Brain Research Volume 110, Issue 1, 31 January 2003, Pages 85-91
4. Free Radicals and Oxidative Stress in Neurodegenerative Diseases:
Relevance of Dietary Antioxidants
Ravindra Pratap Singh, Shashwat Sharad, Suman Kapur.
JIACM 2004; 5(3): 218-25
5. Mechanism of cytotoxicity of methylmercury. With special reference to microtubule disruption.
Miura K1, Imura N.
Biol Trace Elem Res. 1989 Jul-Sep;21:313-6.
6. Lipid peroxidation is an early event in the brain in amnestic mild cognitive impairment
William R. Markesbery, MD, Richard J. Kryscio, PhD, Mark A. Lovell, PhD, Jason D. Morrow, MD.
Annals of Neurology Volume 58 Issue 5, Pages 730 – 735
7. Apolipoprotein E modulates Alzheimer’s Abeta(1-42)-induced oxidative damage to synaptosomes in an allele-specific manner.
Lauderback CM, Kanski J, Hackett JM, Maeda N, Kindy MS, Butterfield DA.
Brain Res. 2002 Jan 4;924(1):90-7.