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Iron's Impact on Brain
Posted: Thursday, January 19, 2012 6:48 PM
Joined: 12/6/2011
Posts: 3326

(Source: Alzheimer Research Forum) - If a shortage of iron harms development, yet having too much is linked to cognitive decline and neurodegeneration, what's the lowdown on how this metal influences brain health?

Paul Thompson of the University of California (LA) and colleagues looked for clues in brain scans and blood tests of healthy young volunteers. They found greater white matter integrity in people with high brain iron. The research also correlated healthier brain structure with mild iron excess. The study "links a lot of information about iron regulation to something that's physically happening in the brain," Thompson reported. However, the big picture remains complex, he and others noted. Iron accumulates in the brains of older adults and in people with neurodegenerative disease, such as Alzheimer's, yet the impact of the buildup differs with age and other factors.

As part of an ongoing effort to understand how genetic and environmental factors might affect brain health, Thompson's lab became interested in iron. "We knew iron is needed to make myelin, but we also knew that high iron levels in older people can promote degenerative disease. So we thought that iron might be a good predictor of brain integrity."

"The simplest reading of all this might be that it's really crucial when you're young to have good iron intake, since you're building your brain," Thompson said. "But as you get older, (excess iron) is a double-edged sword." Biological reactions involving iron produce harmful free radicals, and in old age "your liver becomes less able to handle the iron accumulation, so it just builds up in the brain with no means to clear it."

Go to full story:

Posted: Saturday, January 21, 2012 10:41 AM
Joined: 11/30/2011
Posts: 740

Myriam, it's good to see you reading on the Alzheimer Research Forum.  That's one of the most reliable resources on the web.
Iris L.
Posted: Monday, January 23, 2012 1:14 AM
Joined: 12/15/2011
Posts: 17565

I started taking supplemental iron for painful restless legs syndrome.  The doctors were of no help.  My ferritin level is mid-level.  I could barely walk unaided before I began iron therapy.  I won't easily give it up.


Iris L.

Posted: Wednesday, September 28, 2016 6:00 PM
Joined: 4/24/2012
Posts: 484

This is a great article on the involvement of iron in Alzheimer's. It seems accurate and well researched. I know excess iron in the brain plays a role in disease from my mother's (Alzheimer's patient) MRIs. I also know it is connected to oxidative damage and Abeta plaques, as well as many other things. It's a long paper but worth the read. Lane, I'm hoping you may have some comments on this one.

HFE gene variants, iron, and lipids: a novel connection in Alzheimer’s disease

Posted: Thursday, September 29, 2016 5:37 AM
Joined: 4/24/2012
Posts: 484

This earlier article (2004) was cited by the above article. It doesn't explore any details but it nicely sums up the hypothesis that iron and cholesterol are the causal factors promoting oxidative damage. And, not having a clearly defineable and highly likely cause for oxidative damage has always bothered me.

Iron, Atherosclerosis, and Neurodegeneration: A Key Role for Cholesterol in Promoting Iron-Dependent Oxidative Damage?

Posted: Thursday, September 29, 2016 6:08 AM
Joined: 4/24/2012
Posts: 484

This article links caveolae/caveolin-1 (a factor discussed in another Topic) to iron (heme oxygenase), NOS, and oxidative damage. Posible convergence of many factors may revolve around these caveolae (lipid raft invaginations in the cell membrane).

Caveolae compartmentalization of heme oxygenase-1 in endothelial cells

Posted: Thursday, September 29, 2016 6:49 AM
Joined: 4/24/2012
Posts: 484

Here's more...

 "The most striking risk associated with H63D is for the neurodegenerative diseases. Connor, et al  were among the first investigators to consider the role of H63D in brain iron accumulation, oxidative stress and neurotransmitter performance. Connor reported that the H63D HFE variant contributes to many of the processes associated with Alzheimer’s  Disease (AD). These processes include increased cellular iron, oxidative stress (free radical activity), glutamate dyshomeostasis (abnormal balance), and an increase in tau phosphorylation (abnormal levels of tau proteins can result in dementias such as Alzheimer’s). Connor continues that HFE H63D cells were shown to have more oxidative stress, further supporting their role as neurodegenerative disease modifiers. Connor found that patients homozygous for H63D had earlier signs of mild cognitive impairment and earlier onset of Alzheimer’s compared to those with normal HFe or H63D heterozygotes"


Lane Simonian
Posted: Thursday, September 29, 2016 10:53 AM
Joined: 12/12/2011
Posts: 4998

They sure pack a lot of good information into the frontiersin articles.  I am going to try to focus in on that article for now, rereading it, and responding to the more interesting points as they come up.

Iron through Fenton reactions can contribute to hydroxyl radicals, although this requires hydrogen peroxide which is high only during the early stages of Alzheimer's disease. More importantly, though, iron increases the production of inducible nitric oxide which combines with superoxide anions to produce peroxynitrite (once copper and zinc are entombed in amyloid plaques less hydrogen peroxide is produced from superoxide anions).

Alterations in iron load and the proteins responsible for iron metabolism can exacerbate the excess formation and harmful effects of reactive oxygen (ROS) and nitrogen species (RNS), leading to cell death.

Genes that increase the uptake of iron would indeed increase oxidative stress and the risk for Alzheimer's disease.

The next part contradicts parts of the article so I will try to find some common ground. Excess cholesterol is not being removed from the brain (or not efficiently being removed from the brain) during Alzheimer's disease.  This increases cholesterol in lipid rafts where most of the processes that lead to Alzheimer's disease take place.  Oxidized LDL disrupts the blood-brain barrier which may allow more cholesterol from the rest of the body to enter the brain.

It appears that lipid raft function is disrupted by oxidative stress (from article):

One possible explanation for the effects of a high iron diet is that they are mediated by iron-induced oxidative stress (Dabbagh et al., 1994) and lipid peroxidation (Britton et al., 1987). Depletion of energy (ATP and NADPH) due to oxidative stress and lipid-peroxidation mediated membrane damage were shown to cause disruption of lipid synthesis and transport (Kehrer, 1993).

So maybe the processes that lead to oxidative stress and Alzheimer's disease via phospholipase C activity in lipid rafts become partially disrupted by oxidative stress as the disease progresses.

I am going to try to work off this clue:

On the contrary, the brains of AD patients show a specific down-regulation of seladin-1, a protein involved in cholesterol synthesis, and low membrane cholesterol was observed in hippocampal membranes of ApoE4 (apolipoprotein E4) AD cases. This effect was also evidenced by altered cholesterol-rich membrane domains (rafts) and raft-mediated functions, such as diminished generation of the Abeta-degrading enzyme plasmin.

This enzyme appears to be down-regulated by chronic oxidative stress.

The increase in brain cholesterol may be a problem during the early stages of Alzheimer's disease, but the decrease in cholesterol (if that is what is happening) during the later stages of Alzheimer's disease may not be a problem.


Posted: Thursday, September 29, 2016 1:21 PM
Joined: 2/26/2016
Posts: 243

In my earlier post on "Hope for a leaky brain" in June this year, I mentioned a study done recently in the Netherlands. It compared patients diagnosed with early stage AD with age matched healthy patients and measured blood-brain barrier (BBB) leakage rates using special MRI's. They found that early stage AD patients had significantly higher BBB leakage rates, thus pointing out that a leaky BBB is a characteristic of Alzheimer's.

Possibility, if a person had a leaky BBB, more iron could be entering the brain and causing damage. There would likely be other substances and cells slipping through the BBB which could also cause brain inflammation and damage. Further when you age, there are more inflammatory substances circulating in your blood stream, and having a leaky BBB would result in more damage than having a stable one. Football and boxers who have received repeated blows to the head have much greater chances of developing Alzheimer's and Parkinson disease, and upon there death, a high percentage of those examined are found to have damaged BBB's. 

Now that we can measure BBB leakage in live patients, my hope is that researchers will be looking for how certain drugs can normalize the BBB. In particular the asthma drug montelukast (Singulair) would be a good candidate because it has been shown to decease BBB leakage in animal studies by blocking the pro-inflammatory cysteinyl leukotrienes.

To put it in simplier terms, if the wall around your house has holes and your enemies are getting through, maybe hiring more guards is not the best way. Maybe you should close the holes.

Lane Simonian
Posted: Thursday, September 29, 2016 1:50 PM
Joined: 12/12/2011
Posts: 4998

The damage done to the blood-brain barrier during the early stages of cognitive dysfunction is probably a key element in the progression of Alzheimer's disease.  And oxidative stress is at least partially responsive for that damage.  Then as more iron, copper, zinc, viruses, bacteria etc. enter the brain it magnifies the oxidative stress and to some degree inflammation as well.

The damage to the blood-brain barrier (by oxidized LDL for instance) may also increase the size of lipid rafts by allowing more cholesterol into the brain.  The way it appears is that the activation of phospholipase C in lipid rafts is what leads to both amyloid (in part via intracellular calcium release) and peroxynitrite (via NMDA receptors).  But excitotoxicity via NMDA receptors continues even after lipid rafts have been disrupted by oxidation.

Here is a montelukast connection:

Montelukast and pranlukast are orally active leukotriene receptor antagonists selective for the CysLT1 receptor...CysLT1 antagonists inhibited both the P2Y agonist-induced activation of phospholipase C and intracellular Ca2+ mobilization.

Posted: Friday, September 30, 2016 5:20 AM
Joined: 4/24/2012
Posts: 484

Just a few thoughts. Thanks for the reminder of how important the BBB is in neurodegeneration Larry. Do you have a link to that study? Two things immediately come to mind regarding my mother. She was diagnosed via MRI with microvascular ischemia, which are very small strokes. This is common in AD and I suppose relates to the BBB which is just the endothelial cells lining the blood vessels of the brain. This condition is attributed to things like diabetes, high cholesterol, and head injury. I think there is an important clue here somewhere. Why would the tips of very small blood vessels in the brain fail before other blood vessels, larger vessels or vessels in other parts of the body.

Another thing I notice is the deterioration in my mother's skin beyond what would be expected with age. Doctor diagnosed as Eczema. Seems like this could possibly derive from the same cause(s) as microvascular ischemia or BBB breakdown.

Good article Lane on iron dysregulation, lots of clues there. Still reading...

Lane Simonian
Posted: Friday, September 30, 2016 9:32 AM
Joined: 12/12/2011
Posts: 4998

For some reason I never gave a thought as to what the blood-brain barrier consists of. This opens up some new avenues.

Peroxynitrite causes endothelial cell monolayer barrier dysfunction.

Peroxynitrite mediates nitric oxide-induced blood-brain barrier damage.

Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

Macrovascular protection is essential for neuroprotection in stroke

Experimental studies have consistently shown that oxygen and nitrogen radicals generated in excess amounts during reperfusion play an important role in loss of BBB integrity and consequent vasogenic edema and hemorrhagic transformation.

Nitric oxide-peroxynitrite-poly(ADP-ribose) polymerase pathway in the skin

In the last decade it has become well established that in the skin, nitric oxide (NO), a diffusable gas, mediates various physiologic functions ranging from the regulation of cutaneous blood flow to melanogenesis. If produced in excess, NO combines with superoxide anion to form peroxynitrite (ONOO-), a cytotoxic oxidant that has been made responsible for tissue injury during shock, inflammation and ischemia-reperfusion. The opposite effects of NO and ONOO- on various cellular processes may explain the 'double-edged sword' nature of NO depending on whether or not cellular conditions favour peroxynitrite formation. Peroxynitrite has been shown to activate the nuclear nick sensor enzyme, poly(ADP-ribose) polymerase (PARP). Overactivation of PARP depletes the cellular stores of NAD+, the substrate of PARP, and the ensuing 'cellular energetic catastrophy' results in necrotic cell death. Whereas the role of NO in numerous skin diseases including wound healing, burn injury, psoriasis, irritant and allergic contact dermatitis, ultraviolet (UV) light-induced sunburn erythema and the control of skin infections has been extensively documented, the intracutaneous role of peroxynitrite and PARP has not been fully explored. We have recently demonstrated peroxynitrite production, DNA breakage and PARP activation in a murine model of contact hypersensitivity, and propose that the peroxynitrite-PARP route represents a common pathway in the pathomechanism of inflammatory skin diseases. Here we briefly review the role of NO in skin pathology and focus on the possible roles played by peroxynitrite and PARP in various skin diseases.

Lane Simonian
Posted: Saturday, October 1, 2016 9:57 PM
Joined: 12/12/2011
Posts: 4998

I am comfortable with the role of lipid rafts in early to perhaps moderate Alzheimer's disease, but less certain how much these rafts may be disrupted as the disease progresses and whether this is significant.  I did find an interesting observation:

Article title: Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and post-synaptic densities following transient global ischemia in the rat brain

Between 50 and 60% of NMDA receptors were associated with lipid rafts.

So NMDA receptor activation in lipid rafts is probably critical for the progression of the disease at least during it early stages, the presence of some of these receptors outside of lipid rafts may be important to the later progression of the disease.

I have also found a series of articles linking mutations that lead to early onset Alzheimer's disease to oxidative stress.

“Mutations in APP, PS1, and PS2 genes are causes for early onset AD. Several animal models have demonstrated that alterations in these proteins are able to induce oxidative damage, which in turn favors the development of AD. This paper provides a review of many, although not all, of the mutations present in patients with familial Alzheimer’s disease and the association between some of these mutations with both oxidative damage and the development of the pathology.”

“Nitric oxide synthase inhibitors and the peroxynitrite scavenger uric acid blocked the apoptosis-enhancing action of PS-1 mutations. The data suggest pivotal roles for superoxide production and resulting peroxynitrite formation in the pathogenic mechanism of PS-1 mutations.”

“Together, our data indicate that the neuroprotective role of PS1 depends on its ability to activate the PI3K/Akt signaling pathway and that PS1 FAD mutations increase GSK-3 activity and promote neuronal apoptosis by inhibiting the function of PS1 in this pathway. These observations suggest that stimulation of PI3K/Akt signaling may be beneficial to FAD patients.”

“Presenilin-2 Mutations Modulate Amplitude and Kinetics of
Inositol 1,4,5-Trisphosphate mediated Calcium Signals*”

This increases intracellular calcium release which increases gamma secretase activity (the second cut in the amyloid precursor protein) and hyperphosphorylation of tau (via Cdk 5 dysregulation) but it also leads to increased protein kinase C activity and peroxynitrite formation.

“In parallel, caspase-3 activity was markedly elevated in APPsw PC12 [double Swedish mutation] after stimulation with hydrogen peroxide for 6 hr, whereas caspase-1 activity was unaltered. In addition, oxidative stress-induced cell death could be reduced after pretreatment of APPsw cells with (±)-alpha-tocopherol. The protective potency of (±)-alpha-tocopherol was even greater than that of caspase-3 inhibitors. Our findings further emphasize the role of mutations in the amyloid precursor protein in apoptotic cell death and may provide the fundamental basis for further efforts to elucidate the underlying processes caused by FAD-related mutations.”


And I think this is the key to treating Alzheimer's disease:

We suggest that oxidative stress mediated through NMDAR and their interaction with other molecules might be a driving force for tau hyperphosphorylation and synapse dysfunction. Thus, understanding the oxidative stress mechanism and degenerating synapses is crucial for the development of therapeutic strategies designed to prevent AD pathogenesis.

Posted: Sunday, October 2, 2016 8:10 AM
Joined: 4/24/2012
Posts: 484

I've been beating the bushes hard the last two days with very little to show for it. I've studied everything from iron overload diseases to causes of microvascular ischemia. I just can't seem to make conclusive connections, only more clues.

 Still analyzing your above info Lane. Here's something that might relate on how PKC is involved with ischemia.

PKC-beta Exacerbates in vitro Brain Barrier Damage in Hyperglycemic Settings via Regulation of RhoA/Rho-kinase/MLC2 Pathway

"These results suggest that HG-induced exacerbation of the BBB breakdown after an ischemic stroke is mediated in large part by activation of PKC-beta."

Lane Simonian
Posted: Sunday, October 2, 2016 9:38 AM
Joined: 12/12/2011
Posts: 4998

There are days like this while researching this disease.

I think in both ischemic stroke and Alzheimer's disease there is usually an upregulation than a downregulation of protein kinase C isoforms.  Part of the connection to the disruption of the blood brain barrier may be related to the increased activity of metalloproteinases.

Protein kinase C-mediated regulation of matrix metalloproteinase and tissue inhibitor of metalloproteinase production in a human retinal müller cells.

Matrix Metalloproteinases and Blood-Brain Barrier Disruption in Acute Ischemic Stroke

Lane Simonian
Posted: Sunday, October 2, 2016 6:47 PM
Joined: 12/12/2011
Posts: 4998

PKC via activation of src and NMDA receptors forms part of a pivotal juncture in pathways in the brain.  PKC activation can lead to the activation of the neuroprotective phosphatidylinositol 3-kinase/Akt pathway, but when this pathway is inhibited by nitration or the presenilin-1 gene mutation it can lead to the death of neurons via peroxynitrite and caspase-3.

Src kinase mediates phosphatidylinositol 3-kinase/Akt-dependent rapid endothelial nitric-oxide synthase activation by estrogen.

Oxidation of g protein-coupled receptors and nitration of phospholipase C-gamma may be among the factors that eventually inhibit protein kinase C activity in ischemic strokes and Alzheimer's disease. 

Common Mechanisms of Alzheimer’s Disease and Ischemic Stroke: The Role of Protein Kinase C in the Progression of Age-Related Neurodegeneration


PKC isoforms have varied roles in normal and age-related physiology. Alterations in these isoforms contribute to the development of ischemic stroke and AD. Once ischemic stroke has occurred, altered PKC beta, delta, and zeta contribute to BBB disruption and reperfusion injury. If PKC-epsilon is properly translocated, it can provide neuroprotection. Often, however, pre-existing comorbidities lead to disrupted PKC translocation and worse outcome following ischemic infarction. PKC-epsilon is also protective against memory decline in AD, but toxic Abeta contributes to epigenetic downregulation of PKC isoforms with time. Shared pathways between the two diseases such as iron mediated toxicity and immune suppression highlight important targets in injury development and progression. Although much work is yet to be done to increase our understanding about PKC activity in the brain, modulating PKC activity/translocation will enhance neuroprotective strategies for treating neurodegenerative diseases. Future studies are needed to investigate the time points at which PKC isoforms are neuroprotective, and furthermore when they switch to being detrimental.

Lane Simonian
Posted: Sunday, October 9, 2016 10:45 AM
Joined: 12/12/2011
Posts: 4998

This is an interesting study regarding iron and excitotoxicity:

Lysosomal iron modulates NMDA receptor-mediated excitation via small GTPase, Dexras1

Activation of NMDA receptors can induce iron movement into neurons by the small GTPase Dexras1 via the divalent metal transporter 1 (DMT1). This pathway under pathological conditions such as NMDA excitotoxicity contributes to metal-catalyzed reactive oxygen species (ROS) generation and neuronal cell death, and yet its physiological role is not well understood.

Lane Simonian
Posted: Sunday, October 9, 2016 11:20 AM
Joined: 12/12/2011
Posts: 4998

More interesting yet:

Dexras1, a small GTPase, is required for glutamate-NMDA neurotoxicity

Previous studies in our laboratory showed that NMDA receptor activation, via NO and Dexras1, physiologically stimulates DMT1, the major iron importer. A membrane permeable iron chelator substantially reduces NMDA-excitotoxicity suggesting that Dexras1-mediated iron influx plays a crucial role in NMDA/NO-mediated cell death. We here report that iron influx is elicited by nitric oxide but not by other pro-apoptotic stimuli such as H2O2 or staurosporine. Deletion of Dexras1 in mice attenuates NO-mediated cell death in dissociated primary cortical neurons and retinal ganglion cells in vivo. Thus Dexras1 appears to mediate NMDA-elicited neurotoxicity via NO and iron influx.