Metals That Might Make You Mental

I've said it once. I've said it a million times. They haven't found a cure for Alzheimer's Disease because they don't know what causes Alzheimer's Disease. They don't know the cause of AD because there is no cause, per say. There are genes that make you more prone to the disease (such as ApoE), but there is no AD gene. There is no vitamin deficiency, toxicity, gene or one thing that causes AD. Instead, it appears that AD is a multifactorial disease that is caused by a different mix of things in each individual person. The only true cause that continues to have overwhelming evidence confirming it's role in causation of AD is inflammation... But that's where the multifactorial thing comes in. Weather it be a bad diet, head injury, drugs, infections, thoughts, toxins or autoimmunity, many things cause inflammation. Therefore, many things can contribute to one developing Alzheimer's Disease. The Alzhimer's Disease brain is a brain on fire, and research continually shows us that the fire starts many, many years before we see the smoke. There is no magic bullet to prevent Alzheimer's Disease; you just have to live a healthy life.

Everybody has heard of heavy metals. The bad guys of the periodic table, heavy metals such as mercury and lead have been associated with a wide range of diseases and disorders. But what about other metals? What about the metals we thought all along were good for us? In comes Iron (Fe) and Copper (Cu), two transition metals that may be new culprits in the AD puzzle and inflammation in general. But everybody knows we need iron to make hemoglobin, so having too much couldn't possibly be a bad thing, right? Wrong. The type of Iron or Copper dictates how it functions in the body, and having too much of the "bad" kind can wreak all sorts of havoc on the body.

Transition metals are unique because they exhibit two or more oxidant states (for example, Fe+2 and Fe+3). This is what makes able to participate in chemical reactions and makes them particularly useful in day to day bodily functions. This characteristic also makes them remarkably able to bind with stuff we don't want them to bind to and create free radicals. Free radicals like the hydroxyl ion are then able to scamper about the body binding to molecules and altering their function... This is the hallmark of inflammation- free radical damage that alters the body's normal molecules, and subsequently alters the function of those molecules.

For simplicity's sake, there are two basic types of metals: free metals (inorganic) and metals that are bound to other stuff (organic). Weather or not these metal ions are bound to a molecule (such as a protein) will affect how they are absorbed and processed by the body. Organic Copper and Iron compounds are absorbed a little slower by the intestinal tract, but more importantly they are processed differently than their inorganic brethren. Food Copper (and Iron) must go through additional processing in the liver before it is allowed into systemic circulation (the blood stream). Typically the body keeps most of it's Copper bound to proteins and keeps the more unstable, inflammatory free Copper to a minimum (5-15% total Cu in the blood). When inorganic Copper is absorbed it immediately contributes to the free Copper pool in the blood steam, bypassing the liver and increasing the risk of inorganic Copper induced oxidative stress [1]. Similar is true of Iron's story.

The proposed mechanisms of how inorganic Copper and Iron contribute to the inflammation in AD are numerous, but here are a few.

Copper has been shown to bind with homocysteine (an inflammatory molecule that is related to one's intake of B vitamins) and increase the oxidation of LDL- the so-called "bad" cholesterol [1, 2]. Cu, unlike Zinc, Nickel, Aluminum, or Cadmium, has been shown to compromise the stability of Ubiquitin. The Ubiquitin-Proteasome System (UPS.. haha) is the main pathway by which we eliminate misfolded proteins from our cells such as the notorious Beta Amyloid of Alzheimer's Disease and the Lewy bodies that are seen in Parkinson's Disease [5]. This may result in decreased clearance of these proteins in the brain, eventually leading to a build-up, cellular toxicity and death. Even the so-called AD gene may be related to Cu metabolism! The three different ApoE Alleles differ in the number of cysteine binding sites they posses- the part of the molecule that is able to bind to Copper. ApoE 2 has two binding sites, ApoE3 has one and ApoE 4 has none. This correlates with the risk of AD associated with each of those alleles (2 is protective against AD, 3 is neutral and 4 increases your risk). It has now been postulated that the risk associated with the ApoE alleles is due to ApoE 4's inability to bind and remove Copper from the brain [2].

Like Copper, Iron is necissary for human life, but an excess of inorganic Iron may be one of the inflammatory triggers in the AD cascade. Several studies have shown that Fe accumulates in Beta Amyloid plaques [3]. Not only that, but the presence of Iron during plaque formation not only increases the synthesis of Beta Amyloid by it's interaction with PACE, but it has been shown to favor the more toxic form of the plaques [4].

As in all things in life, your current inflammatory status will play a role in how you handle further stressors. Inflammation disrupts the blood brain barrier (BBB) and alters it's ability to regulate the transport of Fe to and from the brain [4]. HAMP, the gene that is responsible for the production of Hepcidin (THE Iron homeostasis hormone in our bodies) is directly influenced by inflammatory cytokines such as IL-1B and IL-6 [4]. Similarly, the mechanism I mentioned above of how Copper binds to homocysteine to produce inflammation would probably not be that big of a deal if you didn't have high homocysteine levels in the first place!

So what can we do to avoid the damage caused by inorganic Copper and Iron?

1. Decrease your inflammatory burden. I've said it once. I've said it a thousand times. This is highly individual, since no two of us have the same health problems. Weather it be being overweight, not exercising, a crappy diet, diabetes, gastrointestinal issues, an autoimmune disease, or whathaveyou, get healthier. If you're not inflamed it appears that these pesky metals won't hurt you as much.

2. Avoid inorganic Copper and Iron. Brewer et al [1] and several others have identified the two major sources of inorganic Copper and Iron as being Copper in our drinking water from Copper pluming and multivitamins (like Centrum). Interestingly, Brewer et al [2] points out in his paper that all of the industrialized countries are dealing with increased rates of AD- Except Japan. This is noteworthy, because Japan is the only industrialized country that does not use Copper pluming. In contrast, about 85% of US homes have Copper pluming [2]. Here's what you can do to minimize the amount of Copper that leaches into your water and avoid inorganic Copper and Iron:
     A. Filter your water. Brita.com does state that their filters filter Copper, but I can not say to what extent. Reverse osmosis is the best at
     filtering things like Cu and Fe, but is more expensive.
     B. Do not get hot water from the tap- Hot water will leach more Cu from the pipes than cold water- Warm the water after it comes out of the
     faucet.
     C. Check the acidity of your water. The more acidic your water, the more it will etch the Copper pipes.
     D. Avoid multivitamins like Centrum. They look like a big ol' piece of metal that they painted red anyway, so who are we fooling when we
     take those? There is no substitute for the vitamins and minerals you get from a healthy diet. Period.

 3. Zinc has been shown to lower levels of free Copper in the blood [2], so making sure you have adequate Zinc levels may be a good idea if you think you're at risk of ingesting too much Copper (perhaps people who have really acidic water at home and can not afford to install a reverse osmosis system).

Healthfully yours,

Nikki

References:
[1] Brewer, G. Risks of Copper and Iron Toxicity during Aging in Humans. Chem Res Toxicol 2010, 23, 319-326 (PMID 19968254)
[2] Brewer, G. Copper Toxicity in Alzheimer's Disease: Cognitive Loss from Ingestion of Inorganic Copper. J of trace elements in medicine and biology 26 (2012) 89-92. (PMID 22673823)
[3] Batista-Nascimento, L. et al. Iron and Neurodegeneration: From Cellular Homeostasis to Disease. Oxidative Medicine and Cellular Longevity, May 2012 (PMID 22701145)
[4] Mesquita, S. et al. Modulation of Iron Metabolism in Aging in Alzheimer's Disease: Relevance of the Choroid Plexus. Frontiers in Cellular Neurosci. May 2012 (PMID 22661928)
[5] Arnesano, F. et al. Copper-Triggered Addregation of Ubiquitin. PLoS ONE 2009 Sept 16; 4(9) e7052 (PMID 19756145)