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Iron Is at Core of Alzheimer's Disease, Study Suggests
Myriam
Posted: Tuesday, August 20, 2013 6:29 PM
Joined: 12/6/2011
Posts: 3326


Looks like metals are a cause of Alzheimer's Disease. A couple of days ago, I posted about copper, but this study is about iron.  Would love your take on this, Lane. 

Alzheimer's disease has proven to be a difficult enemy to defeat. After all, aging is the No. 1 risk factor for the disorder, and there's no stopping that. 

 

Most researchers believe the disease is caused by one of two proteins, one called tau, the other beta-amyloid. As we age, most scientists say, these proteins either disrupt signaling between neurons or simply kill them. 

 

Now, a new UCLA study suggests a third possible cause: iron accumulation. 

 

Dr. George Bartzokis, a professor of psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and senior author of the study, and his colleagues looked at two areas of the brain in patients with Alzheimer's. They compared the hippocampus, which is known to be damaged early in the disease, and the thalamus, an area that is generally not affected until the late stages. Using sophisticated brain-imaging techniques, they found that iron is increased in the hippocampus and is associated with tissue damage in that area. But increased iron was not found in the thalamus. 

 

The research appears in the August edition of the Journal of Alzheimer's Disease. 

 

While most Alzheimer's researchers focus on the buildup of tau or beta-amyloid that results in the signature plaques associated with the disease, Bartzokis has long argued that the breakdown begins much further "upstream." The destruction of myelin, the fatty tissue that coats nerve fibers in the brain, he says, disrupts communication between neurons and promotes the buildup of the plaques. These amyloid plaques in turn destroy more and more myelin, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer's. 

 

Myelin is produced by cells called oligodendrocytes. These cells, along with myelin, have the highest levels of iron of any cells in the brain, Bartzokis says, and circumstantial evidence has long supported the possibility that brain iron levels might be a risk factor for age-related diseases like Alzheimer's. Although iron is essential for cell function, too much of it can promote oxidative damage, to which the brain is especially vulnerable. 

 

In the current study, Bartzokis and his colleagues tested their hypothesis that elevated tissue iron caused the tissue breakdown associated with Alzheimer's disease. They targeted the vulnerable hippocampus, a key area of the brain involved in the formation of memories, and compared it to the thalamus, which is relatively spared by Alzheimer's until the very late stages of disease. 

 

The researchers used an MRI technique that can measure the amount of brain iron in ferritin, a protein that stores iron, in 31 patients with Alzheimer's and 68 healthy control subjects. 

 

In the presence of diseases like Alzheimer's, as the structure of cells breaks down, the amount of water increases in the brain, which can mask the detection of iron, according to Bartzokis. 

 

"It is difficult to measure iron in tissue when the tissue is already damaged," he said. "But the MRI technology we used in this study allowed us to determine that the increase in iron is occurring together with the tissue damage. We found that the amount of iron is increased in the hippocampus and is associated with tissue damage in patients with Alzheimer's but not in the healthy older individuals -- or in the thalamus. So the results suggest that iron accumulation may indeed contribute to the cause of Alzheimer's disease." 

 

But it's not all bad news from this study, Bartzokis noted. 

 

"The accumulation of iron in the brain may be influenced by modifying environmental factors, such as how much red meat and iron dietary supplements we consume and, in women, having hysterectomies before menopause," he said. 

 

In addition, he noted, medications that chelate and remove iron from tissue are being developed by several pharmaceutical companies as treatments for the disorder. This MRI technology may allow doctors to determine who is most in need of such treatments. 

 

Other authors of the study included Erika Raven, Po Lu, Todd Tishler and Panthea Heydari. Funding was provided by National Institutes of Health grants MH 0266029, AG027342 and T32 NS041231 and by the RCS Alzheimer's Foundation. 


Mimi S.
Posted: Tuesday, August 20, 2013 6:46 PM
Joined: 11/29/2011
Posts: 7035


OK all you people who understand science.

 

While most Alzheimer's researchers focus on the buildup of tau or beta-amyloid that results in the signature plaques associated with the disease, Bartzokis has long argued that the breakdown begins much further "upstream." The destruction of myelin, the fatty tissue that coats nerve fibers in the brain, he says, disrupts communication between neurons and promotes the buildup of the plaques. These amyloid plaques in turn destroy more and more myelin, disrupting brain signaling and leading to cell death and the classic clinical signs of Alzheimer's. 

 

Note the words I italicized. In addition to AD, I also have myasthenia gravis and take a lot of mestinon. MG is caused by the failure of communication between nerves and muscles. Can't remember but myelin is in there somehow. I have often wondered if there is any connection between the drugs I take for the MG and my longer than average stay in the early stage of MG. So, at a MG meeting I asked a neurologist. His immediate reaction was NO, they are designed to do completely different things. Then he went on to a very lengthy explanation, part of which involved organic chemistry and none of which I understood. As he finished he shrugged his shoulders and said, "Who knows?"

 

Reading the quoted paragraph above again makes me wonder.

 

 


Lane Simonian
Posted: Tuesday, August 20, 2013 7:58 PM
Joined: 12/12/2011
Posts: 4813


I am going to take a deep breath and try to figure out how much of this I can understand.  I spent quite a bit of time researching the potential connection between copper and Alzheimer's disease yesterday based on Myriam's post.  Copper does appear to increase intracellular calcium release and that is what is needed to produce amyloid plaques.  Some researchers believe copper is involved in the aggregation of amyloid plaques.  Copper also plays a role in an enzyme (superoxide oxidase) that converts superoxide anions into hydrogen peroxide.  Early in Alzheimer's disease, too much copper and zinc cluster around oligomers and you get a lot of hydrogen peroxide which combines with nitrites (a product of peroxynitrite scavenging) to reform peroxynitrites.  Copper and zinc latter become entombed in the plaques and all the superoxide anions combine with inducible nitric oxide to produce peroxynitrites.  So copper levels can effect the progression of Alzheimer's disease (anytime I see amyloid causes this or that I substitute peroxynitrites because I believe peroxynitrites are causing most of the things attributed to  amyloid plaques). 

 

Iron ions convert nitrite anions into nitrite which directly nitrate critical proteins in the brain.  Perhaps, most importantly they nitrate NMDA receptors which leads to the influx of calcium, the further production of peroxynitrites, and the death of neurons.  So iron levels in the brain can also be a problem. 

 

Peroxynitrites damage oligodendrocytes and thus myelin.  This certainly is a factor in multiple sclerosis and perhaps it plays some role in Alzheimer's disease as well. 

 

http://www.ncbi.nlm.nih.gov/pubmed/9688323 

 

http://www.ncbi.nlm.nih.gov/pubmed/11733726 

 

http://www.ncbi.nlm.nih.gov/pubmed/21708260 

 

http://www.ncbi.nlm.nih.gov/pubmed/20696774 

 

Mestinon (pyridostigmine) is a cholinesterase inhibitor (like many of the other drugs prescribed for Alzheimer's disease) and is a cholinergic upregulator.   

 

http://www.ncbi.nlm.nih.gov/pubmed/15694272 

 

http://europepmc.org/abstract/MED/6661730/reload=0;jsessionid=DrrTaCOH1NPzoDbMDvJ1.2 

 

So perhaps it is doing some good. 


Myriam
Posted: Tuesday, August 20, 2013 9:56 PM
Joined: 12/6/2011
Posts: 3326


Again, you never cease to amaze me, Lane, with your ability to distill what your read and restate it is a clearer way.
Serenoa
Posted: Wednesday, August 21, 2013 8:33 AM
Joined: 4/24/2012
Posts: 484


Sorry I can't address the MG question Mimi S. But, you have put it on my radar.

 

I just read the copper study: http://www.pnas.org/content/early/2013/08/14/1302212110.abstract 

 

Several very interesting things occur to me right off the bat. Like you Lane I have read a lot about the involvement of copper and concluded that it wasn't causal. Now that I understand peroxinitrites and vascular functioning better, this article excites me.

 

THe Leukine researcher I know has shown me the importance of the small capillaries/blood vessels in the brain in thier ability to move amyloid from the brain into the blood stream thus removing it. He says that these capillaries lose that ability as plaques form around them and kill these small blood vessels, forming small strokes. As these vessels die so do the neurons around them creating inflamation.

 

The copper study is saying something very similar:

 

"In aging mice, accumulation of Cu in brain capillaries was associated with its reduction in low-density lipoprotein receptor-related protein 1 (LRP1), an Aβ transporter, and higher brain Aβ levels."

 

The cappillaries can't remove the amyloid! The study says copper can accumulate in thes cappillaries but doesn't enter the brain or dammage the cappillaries until oxidative dammage occurs with age:

 

"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."

 

http://www.urmc.rochester.edu/news/story/index.cfm?id=3916 

 

And this is where peroxinitrite dammage comes into play as a causal agent breaking down the blood-brain barrier (the walls of the capillaries) reducing their ability to transport amyloid and allowing copper into the brain resulting in the coagulation/folding of amyloid into plaques which then can no longer be removed and wrap themselves around capillaries killing them!!!

Then you throw in super oxide dismutase, as Lane pointed out, that depends on copper to function properly in limiting peroxinitrite formation. The copper is now being gobbled up by amyloid in the formation of plaques which may produce a copper deficiency in to brain.

Could this be the "perfect storm" that leads to Alzheimer's?!!! Peroxynitrite - APP - inflamation - copper - plaques - vascular dammage - etc. Is it all fitting together now?

 

 

 

 


Serenoa
Posted: Wednesday, August 21, 2013 11:56 AM
Joined: 4/24/2012
Posts: 484


Lane, can we prove that peroxynitrite damage is occuring in these capillaries, in the endothelial cells or specifically with the low-density lipoprotein receptor-related protein 1 (LRP1)? How does copper normally get into a healthy brain? As I understand the article, it does not pass through a healthy blood-brain barrier. It seems we need to solve the the mechanism of excess copper getting into the brain. The article mentions the accumulation of copper in the capillaries as being toxic and eventually leading to the breakdown of the blood-brain barrier, but I suspect peroxynitries or other oxidative dammage may be what lets copper in.

If capillaries are dammaged then I suspect that other cells in the body are also dammaged from the same thing. Which means that dammaged neurons are probably already producing excess amyloid before copper starts to leak thourgh into the brain. Therefore copper may not have to play a role in amyloid production at all. I have no doubt that is causes the formation of plaques which then cut off capillaries. The question here is, how is copper (or the lack of copper) messing with super oxide dismutase? Is there a lack of copper due to plaque formation, or is there an excess of copper affecting super oxide dismutase - which leads to NO and super oxide dysregulation.

Then there is the question of iron. Could it be leaking into the brain like copper?


Lane Simonian
Posted: Wednesday, August 21, 2013 2:39 PM
Joined: 12/12/2011
Posts: 4813


These are going to be round about answers because I cannot find direct answers yet. One link between endothelial dysfunction and peroxynitrites is the peroxynitrite oxidation of BH4 (the importance of which Tom(ek) realized a long time ago on these boards).

 

  2007 Feb 20;581(4):702-6. Epub 2007 Jan 24.

TAT-BH4 counteracts Abeta toxicity on capillary endothelium.

Source

Department Molecular Biology, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy. cantara@unisi.it

Abstract

Oxidative stress is one of the factor contributing to blood brain barrier degeneration. This phenomenon is observed during pathological conditions such as Alzheimer's disease or cerebral amyloid angiopathy in which brain haemorrhages are very frequent. Both diseases are characterized by beta amyloid peptide deposition either in neurons or in vessels. Oxidative stress leads to impairment of mitochondrial functions and apoptotic cell death subsequent to caspases activation. In this paper we demonstrate that BH4 domain of Bcl-xl administrated to endothelial cells as the conjugated form with TAT peptide, reverts Abeta-induced apoptotic cell death by activating a survival programme which is Akt/endothelial nitric oxide synthase dependent.

 

http://www.ncbi.nlm.nih.gov/pubmed/17274989 

 

Peroxynitrites perhaps through this process help breakdown the blood-brain barrier allowing more copper into the brain. 

 

http://www.ncbi.nlm.nih.gov/pubmed/15038605 

 

http://web.ics.purdue.edu/~wzheng/Publications/Epapers/2012_Zheng&Monnot_Pharm&Ther_Fe-CuTransportReview.pdf 

 

Peroxynitrites oxidize a variety of g-protein coupled receptors including those involved in short-term memory, mood, smell, sleep, social recognition, and alertness.  Peroxynitrites might also oxidize the low density lipoprotein related protein limiting the export of amyloid across the blood-brain barrier. 

 

http://www.ncbi.nlm.nih.gov/pubmed/20869432 

 

I am not quite at the point of declaring that everything attributed to amyloid plaques is due to peroxynitrites instead, but it seems that most of the things attribute to amyloid are due peroxynitrites instead. 

 

I am still smiling from your compliment, Myriam.  This is really tough stuff to synthesize and describe clearly, so to the extent that we are doing a decent job, I am pleased. 


Lane Simonian
Posted: Wednesday, August 21, 2013 4:52 PM
Joined: 12/12/2011
Posts: 4813


Part of the difficult thing about understanding Alzheimer's disease is to separate causation from parallel events.  It may well be that amyloid oligomers do not attract copper and zinc, for instance.  The peroxynitrite damage to the blood-brain barrier may simply be allowing more copper and zinc to enter the brain.  The high early concentrations of copper and zinc would result in more hydrogen peroxide being created (due to increased superoxide dismutase activity) and hydrogen peroxide combines with the nitrite anion to reform peroxynitrites.  Copper and zinc may play a role in the aggregation of amyloid plaques and copper and zinc deficiency would lead to more production of superoxide anions which would combine with inducible nitric oxide to form peroxynitrites. 

 

A number of phenolic compounds (such as curcumin and coriander) are metal ion cheiators and this be another reason why they be helpful in the treatment of Alzheimer's disease. 


Serenoa
Posted: Wednesday, August 21, 2013 5:22 PM
Joined: 4/24/2012
Posts: 484


Yes, the complexity does come back and slap you in the face just when you think you are getting a good grip on it. But thank you for more good info on this Lane. I'll be looking at it more but I feel confident there are solid connections here.

I'm thinking that plaque formation around the outside of capillaries prevents removal of amyloid by the blood and then causes infarc (lack of oxygen due to closing off) which kills neurons that depend on those capillaries. This vascular dammage is common in AD. It shows up on my mom's MRI. So what's causing the amyloid to form plaques? Copper fits nicely. Especially if the capillary cells are dammaged by peroxinitrites with age. I will look into it more.

 

 


Lane Simonian
Posted: Wednesday, August 21, 2013 6:57 PM
Joined: 12/12/2011
Posts: 4813


I suppose if we don't let complexity get the better of us, we are ok.  I found this article to be suggestive of what might be part of the process of brain damage in Alzheimer's disease.  The uncoupling of the endothelial nitiric oxide synthase due to the peroxynitrite-mediated oxidation of BH4 may result in micro-embolisms and endema, and the nitration of amyloid may play a role in its aggregation.  Endothelial nitric oxide synthase can be activated by intracellular calcium release--the same pathway that leads to the formation of amyloid.  Amyloid plaques may elicit an immune response that leads to the further production of peroxynitrites.  


 

Nitric oxide (NO) toxicity is in part mediated by generation of peroxynitrite with concomitant production of superoxide under pathological brain conditions such as ischemia and Alzheimer's disease. The pathophysiological relevance of endothelial nitric oxide synthase (eNOS) to brain embolism-induced neurovascular injury has not been documented. We found that microsphere embolism (ME)-induced aberrant eNOS expression in vascular endothelial cells likely mediates blood-brain barrier (BBB) disruption via peroxynitrite formation and in turn causes brain edema. We also demonstrated that a mild ME model was useful for investigating the sequential events of neurovascular injury followed by beta-amyloid accumulation and tau hyperphosphorylation. Indeed, immunoblotting of purified brain microvessels revealed that beta-amyloid accumulation significantly increased one week after ME induction and remained elevated for twelve weeks in those animals. Moreover, we also confirmed thatperoxynitrite formation and eNOS uncoupling-mediated superoxide generation in microvessels are inhibited by a novel calmodulin inhibitor. Thus, peroxynitrite formation via elevated eNOS is associated with endothelial cell injury with concomitant beta-amyloid accumulation in microvessels of aged rats. In this review, we focus on the detrimental effects of eNOS expression following brain embolism and introduce an attractive model representing progressive Alzheimer's disease pathology in brain.

http://europepmc.org/abstract/MED/19783863/reload=0;jsessionid=lVEqeazM0VwPujXrYs9A.26 


Myriam
Posted: Wednesday, August 21, 2013 10:37 PM
Joined: 12/6/2011
Posts: 3326


This may be a restatement of one of the studies you site: 

Metals such as iron, copper, and zinc are important for many biological processes. In recent years, studies have shown that these nutritionally-essential metals are elevated in human Alzheimer's disease (AD) brains and some animal models of AD. Scientists are now exploring whether these metals are causing the neurodegeneration seen in AD or are indicative of other ongoing pathologic processes. 


In a new study, investigators used synchrotron x-ray fluorescence microscopy to image metal ions in the brain, focusing on the amyloid plaques that are the hallmark of AD. They found that, in two AD mouse models that exhibit neurodegeneration, the plaques contained about 25% more copper than an AD mouse model that shows little neurodegeneration. Looking at other metals, they found that none of the mouse models had significant increases in iron and very little increases in zinc. Metal content was not related to the age of the plaque. The study is reported in the current issue of Biomedical Spectroscopy and Imaging. 

 

"Since excess copper should not be 'free' in the brain to bind to the plaques, these data suggest that the cellular control of copper is altered in AD, which may lead to toxic reactions between free copper ions and neurons," comments lead investigator Lisa M. Miller, PhD, a biophysical chemist in the Photon Sciences Directorate at Brookhaven National Laboratory. In previous work, Dr. Miller's group found very high levels of copper in human AD plaques.

 

Since elevated iron in the AD brain is well documented in both human brains and AD mouse models, the researchers measured iron content in the cortex of all three mouse models. They found that iron content was doubled in all AD mouse model cortices compared to controls, whether or not the models showed neurodegeneration. Upon further investigation, spectroscopic data revealed that the excess iron was present in the ferric (oxidized) state and consistent with the iron storage protein ferritin. "The increase in iron may be a reflection of changes in metalloprotein content and metal storage within the brain that is not well understood," says Dr. Miller. 

 

Nevertheless, since iron in ferromagnetic and detectable through MRI, Dr. Miller suggests that in the future iron may be used as a biomarker for AD at early stages of disease, even before plaques are formed. 

 

This work was completed at the National Synchrotron Light Source, beamlines X27A and X3B at Brookhaven National Laboratory. 


Lane Simonian
Posted: Wednesday, August 21, 2013 11:08 PM
Joined: 12/12/2011
Posts: 4813


Thanks very much for this valuable study, Myriam.  It does seem that levels of iron and copper play a role in Alzheimer's disease.  Iron increases tyrosine nitration early in Alzheimer's disease in the presence of hydrogen peroxide and the nitrite anion. 

 

http://www.researchgate.net/publication/10791359_The_nature_of_hemeiron-induced_protein_tyrosine_nitration?ev=pub_cit_inc 

 

Tyrosine nitration activates the NMDA receptor which leads to cell death and tyrosine nitration inhibits the neuroprotective phosphatidylinositol 4,5 biphosphate/Akt pathway.  

 

Interesting, I just found this connection between copper and peroxynitrites. 

 

 http://pubs.rsc.org/en/content/articlelanding/2012/cc/c2cc31117h   

 

So it looks like directly (the iron ion oxidation of the nitrite ion) and indirectly via peroxynitrites (in the case of copper ions), both metals lead to tyrosine nitration and the death of neurons in Alzheimer's disease. 

 


Vita99
Posted: Thursday, August 22, 2013 5:08 AM
Joined: 9/4/2012
Posts: 469


Interesting and disturbing to find that the small global strokes are probably caused by amyloid plaques in the brain.  My mother's MRI showed these small strokes also. Funny thing, the neurologist did not even mention these during our visit.  We were at the rheumatologist and asking her various questions when she happened to mention these.  Then quickly she said people  "our" age all have these.  I think it was her way of stopping more questions on my part.  
Lane Simonian
Posted: Thursday, August 22, 2013 9:26 AM
Joined: 12/12/2011
Posts: 4813


This seems to be a more common occurrence than I realized.  Maybe this is part of the link between vascular dementia and Alzheimer's disease.  It certainly appears the rheumatologist was trying to cut off further questions.
Lane Simonian
Posted: Thursday, August 22, 2013 9:51 AM
Joined: 12/12/2011
Posts: 4813


Maybe this is the direct role that amyloid plays in Alzheimer's disease. 

 

Growing evidence points to a connection between Alzheimer’s disease and poor blood flow to the brain.  Signs that a stroke has occurred are often found in the brains of Alzheimer’s patients.

 

However, beta-amyloid also accumulates in the blood vessels that feed the brain, a condition known as cerebral amyloid angiopathy (CAA).  These beta-amyloid deposits appear to gradually cut off the brain’s blood supply, adding to the damage caused by beta-amyloid in the brain.  But exactly how beta-amyloid causes a reduction in blood flow is unclear. 

 

Dr. Strickland’s team is among the first to investigate this question.

Their research points to an interaction between beta-amyloid and fibrin, a protein that forms a mesh-like structure at the core of blood clots.  The team found that beta-amyloid alters the structure of this fibrin mesh, making it resistant to clot-busting enzymes in the blood.  They also found that fibrin accumulates in blood vessels at the same sites as beta-amyloid.  This was true in a transgenic mouse model of Alzheimer’s disease carrying a rare mutation that is associated with the disease in humans, and in postmortem tissue from Alzheimer’s patients.

 

http://www.ninds.nih.gov/news_and_events/news_articles/alzheimers_amyloid_fibrin.htm 

 

Although even here, peroxynitrites may be the ultimate culprit. 

http://www.ncbi.nlm.nih.gov/pubmed/23200902