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Copper Identified as Culprit in Alzheimer's Disease
Myriam
Posted: Monday, August 19, 2013 9:51 PM
Joined: 12/6/2011
Posts: 3326


Copper appears to be one of the main environmental factors that trigger the onset and enhance the progression of Alzheimer's disease by preventing the clearance and accelerating the accumulation of toxic proteins in the brain. 

 

That is the conclusion of a study appearing today in the journalProceedings of the National Academy of Sciences.

 

"It is clear that, over time, copper's cumulative effect is to impair the systems by which amyloid beta is removed from the brain," said Rashid Deane, Ph.D., a research professor in the University of Rochester Medical Center (URMC) Department of Neurosurgery, member of the Center for Translational Neuromedicine, and the lead author of the study. "This impairment is one of the key factors that cause the protein to accumulate in the brain and form the plaques that are the hallmark of Alzheimer's disease." 

 

Copper's presence in the food supply is ubiquitous. It is found in drinking water carried by copper pipes, nutritional supplements, and in certain foods such as red meats, shellfish, nuts, and many fruits and vegetables. The mineral plays an important and beneficial role in nerve conduction, bone growth, the formation of connective tissue, and hormone secretion. 

 

However, the new study shows that copper can also accumulate in the brain and cause the blood brain barrier -- the system that controls what enters and exits the brain -- to break down, resulting in the toxic accumulation of the protein amyloid beta, a by-product of cellular activity. Using both mice and human brain cells Deane and his colleagues conducted a series of experiments that have pinpointed the molecular mechanisms by which copper accelerates the pathology of Alzheimer's disease. 

 

Under normal circumstances, amyloid beta is removed from the brain by a protein called lipoprotein receptor-related protein 1 (LRP1). These proteins -- which line the capillaries that supply the brain with blood -- bind with the amyloid beta found in the brain tissue and escort them into the blood vessels where they are removed from the brain. 

 

The research team"dosed" normal mice with copper over a three month period. The exposure consisted of trace amounts of the metal in drinking water and was one-tenth of the water quality standards for copper established by the Environmental Protection Agency. 

 

"These are very low levels of copper, equivalent to what people would consume in a normal diet." said Deane. 

 

The researchers found that the copper made its way into the blood system and accumulated in the vessels that feed blood to the brain, specifically in the cellular "walls" of the capillaries. These cells are a critical part of the brain's defense system and help regulate the passage of molecules to and from brain tissue. In this instance, the capillary cells prevent the copper from entering the brain. However, over time the metal can accumulate in these cells with toxic effect. 

 

The researchers observed that the copper disrupted the function of LRP1 through a process called oxidation which, in turn, inhibited the removal of amyloid beta from the brain. They observed this phenomenon in both mouse and human brain cells. 

 

The researchers then looked at the impact of copper exposure on mouse models of Alzheimer's disease. In these mice, the cells that form the blood brain barrier have broken down and become "leaky" -- a likely combination of aging and the cumulative effect of toxic assaults -- allowing elements such as copper to pass unimpeded into the brain tissue. They observed that the copper stimulated activity in neurons that increased the production of amyloid beta. The copper also interacted with amyloid beta in a manner that caused the proteins to bind together in larger complexes creating logjams of the protein that the brain's waste disposal system cannot clear. 

 

This one-two punch, inhibiting the clearance and stimulating the production of amyloid beta, provides strong evidence that copper is a key player in Alzheimer's disease. In addition, the researchers observed that copper provoked inflammation of brain tissue which may further promote the breakdown of the blood brain barrier and the accumulation of Alzheimer's-related toxins. 

 

However, because metal is essential to so many other functions in the body, the researchers say that these results must be interpreted with caution. 

 

"Copper is an essential metal and it is clear that these effects are due to exposure over a long period of time," said Deane. "The key will be striking the right balance between too little and too much copper consumption. Right now we cannot say what the right level will be, but diet may ultimately play an important role in regulating this process." 

 

Additional contributors include first author Itender Singh and Abhay Sagare, Mireia Coma, David Perimutter, Robert Gelein, Robert Bell, Richard Deane, Elaine Zhong, Margaret Parisi, Joseph Ciszewski, and R. Tristan Kasper, all with URMC. The study was funded by the Alzheimer's Association, the National Institutes of Aging, and a pilot grant from the National Institute of Environmental Health Sciences. 


Lane Simonian
Posted: Thursday, August 22, 2013 10:49 AM
Joined: 12/12/2011
Posts: 4986


Here is a link to the discussion of copper on the Alzheimer's Reading Room 

 

http://www.alzheimersreadingroom.com/2013/08/Copper-Alzheimers-Disease-.html#disqus_thread 

 

Particularly interesting are the comments made by Carlos Oliveira in regards to heavy metal toxication being a late factor in Alzheimer's disease and how other factors such as peroxynitrite accumulation, neuroinflammation, mitochondrial dysfunction, and vascular problems can precede it.   

 

Carlos works in the health field in Brazil and we came to similar conclusions independently of each other (although we have been learning from each other over the last year and a half).  The compounds he recommends as treatments for Alzheimer's disease (glucuronolactones, acetyl-L-carnitine, and L-carnosine) work much the same way as methoxyphenols (eugenol, ferulic acid, curcumin, vanillin, and sinapic acid) in limiting the formation of peroxynitrites, scavenging them, and reversing part of their damage, inhibiting neuroinflammation, protecting the mitochondria, and acting as mild metal chelators.   


Shellasim
Posted: Thursday, August 22, 2013 11:20 AM
Joined: 10/6/2012
Posts: 499



So, in other words, they need to find out what causes someone who is likely to get alzheimer's, what they lack or excede, that copper is not being fully utilized or metabolized. 
My mom and dad's house had well water and I am sure it was heavily laden with copper. Dad did not get Alzheimer's, but, mom did. 
So I wonder what is in my mom's DNA and other's with Alzheimer's  that possibly their bodies didn't metabolize the copper in their system when other's bodies/brains are not affected. A deformed gene?
Shelley 

Lane Simonian
Posted: Thursday, August 22, 2013 11:46 AM
Joined: 12/12/2011
Posts: 4986


This is a possibility, but I think more likely people whose blood-brain barrier has been disrupted end up with more copper in the brain.  This would explain in part why some people might be exposed to similar levels of copper and yet one could develop Alzheimer's and the other not. 

 

I believe that peroxynitrites are the main cause of the disruption of the blood-brain barrier in regards to Alzheimer's disease.  The factors that lead to peroxynitrite formation include but are not limited to high glucose levels (diabetic or pre-diabetic), high blood pressure, Down syndrome, the APOE4 gene, presenilin gene mutations, biphosphonate osteoporosis drugs (such as Fosamax), late estrogen replacement therapy, stress, inorganic mercury, aluminum fluoride, sodium fluoride, organophosphate pesticides, diesel exhaust, smoking (including second hand smoke), alcohol (with the exception of moderate consumption of alcohol high in phenols such as red wine), certain chronic bacterial and viral infections, very low density lipids (bad cholesterol), and high saturated fats.  Anyone of these would increase the amount of copper in one's brain.  My guess is that your mother had one or more of these factors whereas your father did not.  If this is not the case, I would have to search for another causal factor. 


Lane Simonian
Posted: Thursday, August 22, 2013 11:49 AM
Joined: 12/12/2011
Posts: 4986


I like it that more people are starting to come over and comment on this forum.  We need you.
Shellasim
Posted: Thursday, August 22, 2013 12:13 PM
Joined: 10/6/2012
Posts: 499


I understand the trials using mice and distributing high levels of copper to find results such as this leading to Alzheimer's. But, if we can figure out what limits the breakdown of substances such as copper in normal levels and like you said along with other contributing factors, that one's brain is destroyed resulting in Alzheimer's. 

Could it possibly be a gene or chromasone that is mutating differently via genetics?

I am not a scientist by no means, but, I do believe some day there will be a preventative at least. And will continue to pray for a cure. But, like, insulin levels are a factor in diabetis, I pray someday we find the missing link to Alzheimer's, ALS, MS and the list goes on. 

Shelley


Lane Simonian
Posted: Thursday, August 22, 2013 12:53 PM
Joined: 12/12/2011
Posts: 4986


Wilson's disease is a disease where genetics and copper play a role (mainly as a result in a defect in the transport of copper). 

 

http://en.wikipedia.org/wiki/Wilson's_disease 

 

Interesting in that there may also be a link to the APOE4 gene which increases the risk for Alzheimer's disease.  The APOE4 gene may reduce the binding of copper.  I doubt this is the main reason why the APOE4 gene increases the risk for Alzheimer's disease but it may be one of them. 

 

Overall, present data suggest that the APOE genotype is an important determinant of tissue MT levels in mice and that MT gene expression may be impaired by the APOE4 genotype...Metallothioneins (MT) are low molecular weight cysteine-rich intracellular proteins with a high binding affinity for essential transition metals, such as zinc and copper.

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316750/ 

 

The APOE4 gene likely increases the production of peroxynitrites. 

 

My belief is that peroxynitrites if not the sole cause are a major cause of many neurological diseases. 

 

http://www.ncbi.nlm.nih.gov/pubmed/10525172 

 

Peroxynitrite scavengers show particular promise in the treatment of Alzheimer's disease. 


Lane Simonian
Posted: Thursday, August 22, 2013 8:12 PM
Joined: 12/12/2011
Posts: 4986


In the presence of nitric oxide and hydrogen peroxide (which are present early in Alzheimer's disease), copper (II) forms a complex with peroxynitrites and this complex does much the same oxidative and nitration damage as peroxynitrites themselves, including the nitration of amyloid which greatly enhances it aggregation. 

 

http://pubs.rsc.org/en/Content/ArticleLanding/2012/CC/c2cc31117h 

 

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2920632/ (skip this article unless you love chemistry). 

 

http://www.ncbi.nlm.nih.gov/pubmed/21903077 

 

By itself, copper is not likely a cause of Alzheimer's disease but when combined with other factors that increase peroxynitrite formation it can make matters worse. 


Lane Simonian
Posted: Monday, September 9, 2013 11:39 PM
Joined: 12/12/2011
Posts: 4986


The role of copper in increasing peroxynitrite levels may help explain why amyloid plaques are not cleared from the brain. 

 

The causes of the sporadic form of Alzheimer’s disease (AD) are unknown. In this study we show that copper (Cu) critically regulates low-density lipoprotein receptor-related protein 1–mediated Aβ clearance across the blood–brain barrier (BBB) in normal mice. Faulty Aβ clearance across the BBB due to increased Cu levels in the aging brain vessels may lead to accumulation of neurotoxic Aβ in brains. In a mouse model of AD low levels of Cu also influences Aβ production and neuroinflammation. Our study suggests that Cu may also increase the severity of AD.

 

In human brain endothelial cells, Cu, at its normal labile levels, caused LRP1-specific down-regulation by inducing its nitrotyrosination and subsequent proteosomal-dependent degradation due in part to Cu/cellular prion protein/LRP1 interaction...Sodium nitroprusside, a nitric oxide (NO) donor, decreased LRP1 levels by 2.5-fold whereas nitro-l-arginine (l-NNA), a NO synthase inhibitor, rescued LRP1 from Cu-induced nitrotyrosination.  A decomposition catalyst of peroxynitrite prevented Cu-induced LRP1 reduction...

 

http://www.pnas.org/content/110/36/14771.full 

 

The combination of increased amyloid and decreased endothelial nitric oxide in capillaries may be the principal cause of vascular dysfunction in Alzheimer's disease and the use of peroxynitrite scavengers/decomposition catalysts may prevent further damage and possibly reverse the damage that has already occurred. 


Serenoa
Posted: Tuesday, September 10, 2013 12:33 PM
Joined: 4/24/2012
Posts: 484


Excellent, thanks Lane. LRP1 is popping up a lot lately. Here's something else on copper.

 

 

Copper homeostasis in the CNS 

  • show all 2 hide  
 Abstract

Copper is an essential nutrient that plays a fundamental role in the biochemistry of the central nervous system, as evidenced by patients with Menkes disease, a fatal neurodegenerative disorder of childhood resulting from the loss-of-function of a copper-transporting P-type adenosine triphosphatase (ATPase). Despite clinical and experimental data indicating a role for copper in brain function, the mechanisms and timing of the critical events affected by copper remain poorly understood. A novel role for the Menkes ATPase has been identified in the availability of an N-methyl-d-aspartate (NMDA) receptor-dependent, releasable pool of copper in hippocampal neurons, suggesting a unique mechanism linking copper homeostasis and neuronal activation within the central nervous system. This article explores the evidence that copper acts as a modulator of neuronal transmission, and that the release of endogenous copper from neurons may regulate NMDA receptor activity. The relationship between impaired copper homeostasis and neuropathophysiology suggests that impairment of copper efflux could alter neuronal function and thus contribute to rapid neuronal degeneration.

 

http://link.springer.com/article/10.1385/MN:33:2:81 

 

 

 


Lane Simonian
Posted: Tuesday, September 10, 2013 5:50 PM
Joined: 12/12/2011
Posts: 4986


Very, very, good!  The connections between the NMDA receptor, copper, LRP1, insulin-degrading enzyme, altered prion proteins, peroxynitrites, and amyloid plaques are all starting to fit together.