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Oxidized Iron in the brain is ignored piece of the Alzheimer's/dementia puzzle

alzheimers iron

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#1 Phoebus

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Posted 08 October 2018 - 03:08 PM


This thread is to discuss the role of iron and other metals in dementia/alzheimers

 

Really interesting study here, it shows misbehaving brain iron is the difference between those with amyloid in the brain with NO dementia symptoms and those with amyloid in the brain WITH dementia symptoms. Very few seem to be aware of this study. 

 

 

Previous research has long linked Alzheimer’s to a build-up in amyloid protein fragments in the brain that are normally broken down in healthy brains. But efforts to treat Alzheimer’s by using drugs that reduce amyloid levels have so far failed, leading to speculation that something else is driving the disease.

 

New research from the Florey Institute of Neuroscience and Mental Health and the University of Melbourne has found that iron might be the culprit. Iron has a special property that allows it to exchange electrons, which is crucial in allowing our bodies to generate energy from oxygen and fuels such as sugars. But it can also damage neurons in the same way that iron metal rusts in the presence of oxygen.

The researchers used cutting edge magnetic resonance imaging techniques to measure iron levels in the brain.

 

They found that people with high levels of iron in combination with high levels of amyloid were suffering rapid cognitive decline, but that people with high levels of amyloid but low levels of iron in the brain, were stable.

 

They are now going to carry out a five year trial to test whether an anti-iron drug can slow the progress of Alzheimer’s, in what would be a major breakthrough in finding a treatment.

https://pursuit.unim...-to-alzheimer-s

 


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#2 Phoebus

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Posted 08 October 2018 - 03:18 PM

 

AD pathology remain incompletely understood. It

has been proposed that neurotoxicity arising from
aggregation of the Ab1-42 peptide can in part be explained
by metal ion binding interactions. Using
advanced X-ray microscopy techniques at submicron
resolution, we investigated relationships between
iron biochemistry and AD pathology in intact
cortex from an established mouse model over-producing
Ab.
 
 We found a direct correlation of amyloid
plaque morphology with iron, and evidence for the
formation of an iron-amyloid complex. 
 
We also
show that iron biomineral deposits in the cortical tissue
contain the mineral magnetite, and provide evidence
that Ab-induced chemical reduction of iron
could occur in vivo. Our observations point to the
specific role of iron in amyloid deposition and AD pathology,
and may impact development of iron-modifying
therapeutics for AD.
 

 

 

so this is in cell.com, a highly respected publication 

 

so you can have amyloid plaque in teh brain with no symptoms of dementia, but once again we see here there seems to be a reaction between amyloid and iron in the brian that leads to severe problems. It seems like you need BOTH amyloid AND disregulated iron to create dementia. Just one or just the other will not do it. Also note its says amyloid could be reducing iron, so there seems to be some chemical reaction between amyloid and iron that is destructive to brain cells


Edited by Phoebus, 08 October 2018 - 03:26 PM.

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#3 Phoebus

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Posted 08 October 2018 - 03:39 PM

 

Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis

 
Dysregulation of iron metabolism has been observed in patients with neurodegenerative diseases (NDs). Utilization of several importers and exporters for iron transport in brain cells helps maintain iron homeostasis. 
 
Dysregulation of iron homeostasis leads to the production of neurotoxic substances and reactive oxygen species, resulting in iron-induced oxidative stress.
 
 In Alzheimer's disease (AD) and Parkinson's disease (PD), circumstantial evidence has shown that dysregulation of brain iron homeostasis leads to abnormal iron accumulation. Several genetic studies have revealed mutations in genes associated with increased iron uptake, increased oxidative stress, and an altered inflammatory response in amyotrophic lateral sclerosis (ALS). Here, we review the recent findings on brain iron metabolism in common NDs, such as AD, PD, and ALS.
 
 We also summarize the conventional and novel types of iron chelators, which can successfully decrease excess iron accumulation in brain lesions. For example, iron-chelating drugs have neuroprotective effects, preventing neural apoptosis, and activate cellular protective pathways against oxidative stress.
 
 Glial cells also protect neurons by secreting antioxidants and antiapoptotic substances. These new findings of experimental and clinical studies may provide a scientific foundation for advances in drug development for NDs. 
 
(PDF) Dysregulation of Iron Metabolism in Alzheimer's Disease, Parkinson's Disease, and Amyotrophic Lateral Sclerosis. Available from: https://www.research...teral_Sclerosis [accessed Oct 08 2018].

 

study shows that iron oxide creates neurotoxic  substances in the brain

 

also proposes using iron chelators to treat dementia, PD, and ALS 



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#4 Phoebus

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Posted 08 October 2018 - 08:03 PM

 

Redox-active iron mediates amyloid-β toxicity

 
 
Abstract
 
 
While amyloid-β toxicity is mediated by oxidative stress and can be attenuated by antioxidants, the actual biochemical mechanism underlying neurotoxicity remains to be established. However, since aggregated amyloid-β can interact with transition metals, such as iron, both in vitro and in vivo, we suspected that bound iron might be the mediator of toxicity such that holo- and apo-amyloid would have differential effects on cellular viability. 
 
Here we demonstrate that when amyloid-β is pretreated with the iron chelator deferoxamine, neuronal toxicity is significantly attenuated while conversely, incubation of holo-amyloid-β with excess free iron restores toxicity to original levels. These data, taken together with the known sequelae of amyloid-β, suggest that the toxicity of amyloid-β is mediated, at least in part, via redox-active iron that precipitates lipid peroxidation and cellular oxidative stress.

 

 

so if they treat the amyloid plaque with an iron chelator its toxicity drops dramatically, but when re-exposed to iron that same plaque is now very toxic. 

 

so again we see that its not amyloid by itself that is toxic its amyloid + iron

 

here the iron is described as 'redox active iron' a term I am unclear on. Is that oxidized iron? 


Edited by Phoebus, 08 October 2018 - 08:05 PM.

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#5 Phoebus

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Posted 08 October 2018 - 09:12 PM

I've been told  'redox active iron' is iron that is bound (to protein or other structures, sometimes free in solution) in such a way that it can easily cycle between iron(II) and iron(III) states.



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#6 Phoebus

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Posted 08 October 2018 - 09:26 PM

 

Iron is also potentially toxic. Its ability to donate and accept electrons means that it can catalyze the conversion of hydrogen peroxide into free radicals. Free radicals can cause damage to a wide variety of cellular structures, and ultimately kill the cell.[1]

Iron bound to proteins or cofactors such as heme is safe. Also, there are virtually no truly free iron ions in the cell, since they readily form complexes with organic molecules. However, some of the intracellular iron is bound to low-affinity complexes, and is termed labile iron or "free" iron. Iron in such complexes can cause damage as described above.[2]

To prevent that kind of damage, all life forms that use iron bind the iron atoms to proteins. This binding allows cells to benefit from iron while also limiting its ability to do harm.[1][3] Typical intracellular labile iron concentrations in bacteria are 10-20 micromolar,[4] though they can be 10-fold higher in anaerobic environment,[5] where free radicals and reactive oxygen species are scarcer. In mammalian cells, intracellular labile iron concentrations are typically smaller than 1 micromolar, less than 5 percent of total cellular iron.[2]

 

 

thats from wikipedia

 

so basically bound iron is likely fine, its free iron that is highly reactive that seems to be the issue 

 

so why is there so much free unbound iron in the brains of some people but not others? 



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