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Glutathione and Alzheimer's Disease
Lane Simonian
Posted: Friday, November 27, 2015 9:14 AM
Joined: 12/12/2011
Posts: 4998


Glutathione is often described as the brain's master antioxidant and as it turns out is the best biomarker for mild cognitive impairment and Alzheimer's disease.  Better than amyloid and tau tangles which can be high in people with don't have Alzheimer's disease. 

As long as oxidants are being held in check by glutathione (or other antioxidants) it is possible to have relatively high levels of amyloid and tau tangles with little to no cognitive impairment.  But as glutathione levels drop due to increasing oxidative stress, cognitiion steadily declines. 

Here are some important conclusions from a recent study on the subject:

Glutathione: a molecular whistleblower for Alzheimer’s disease

Alzheimer’s disease: Neurons in select pockets of the brain begin to die off, slowly and incrementally erasing an individual’s memory and eroding their individuality. It is a devastating disease, one that affects more than 36 million individuals today, and one for which no reliable and definitive diagnostic test is available. In hopes of identifying a molecular signature for Alzheimer’s disease, there has been extensive research aimed at defining the early associated molecular events. One phenomenon that has gained a strong foothold as a lead player in Alzheimer’s pathology is ‘oxidative stress’. Oxidative metabolism – the process that yields all cells the energy required for survival – produces highly reactive oxidative byproducts, which if not curtailed wreak absolute havoc on a neuronal cell. To defuse these oxidizing products, the brain cells manufacture antioxidants, which act to police and neutralize these rabble-rousers.  

The hippocampi – the brain centres for learning and memory – are one of the earliest regions to be sabotaged by Alzheimer’s pathology. Our data revealed that GSH levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI (Fig.1). The frontal cortices – brain CEOs responsible for a variety of executive functions – are chronologically affected later in Alzheimer’s. GSH levels mimic this chronology with no changes in the cortices of MCI patients, but significant reduction in those of Alzheimer’s patients (Fig.1). Interestingly, GSH remains unaffected in the cerebellum – a brain region unaffected by Alzheimer’s till late stages. It appears GSH decline is not ubiquitous but rather a region-specific phenomenon that appears to precisely map the progression of Alzheimer’s in our brains.

Could it then be that GSH levels would be able to act like a detector test for MCI and Alzheimer’s? It appears that may well be the case. Using only GSH levels in the hippocampi and frontal cortices as indicators, we were able to differentiate between healthy subjects and MCI patients as well as between patients with MCI and Alzheimer’s with a remarkably high accuracy.

http://atlasofscience.org/glutathione-a-molecular-whistleblower-for-alzheimers-disease/ 

And here is the relationship between glutathione and peroxynitrite--the primary oxidant in Alzheimer's disease:

Glutathione protects astrocytes from peroxynitrite-mediated mitochondrial damage: implications for neuronal/astrocytic trafficking and neurodegeneration.

It is concluded that glutathione is an important intracellular defence against peroxynitrite and that when glutathione levels are compromised the mitochondrial respiratory chain is a vulnerable target and cell death ensues. 

Synergistic depletion of astrocytic glutathione by glucose deprivation and peroxynitrite: correlation with mitochondrial dysfunction and subsequent cell death.

 

Unfortunately, it is hard to get glutathione into brain cells.  And using one of the components of glutathione--cysteine--does not work much better either.  At this point, the best alternative is to use external antioxidant such as various essential oils via aromatherapy and panax ginseng.

 

 

 


Serenoa
Posted: Sunday, November 29, 2015 6:22 AM
Joined: 4/24/2012
Posts: 484


I agree, glutathione is key in preventing Alzheimer's. It seems I remember that the body (brain in this case) makes its own glutathione. Is there a way to promote this process in leu of not being able get glutathione accross the blood-brain barrier very well?

Lane Simonian
Posted: Sunday, November 29, 2015 9:44 AM
Joined: 12/12/2011
Posts: 4998


This question may hold the key to effectively treating Alzheimer's disease. Even if you could supplement with glutathione it may not help much because of the deficiency in reduced glutathione (the form of glutathione that scavenges antixodiants).  This is due to glucose 6-phosphate dehydrogenase deficiency.  


Reactive oxygen species (ROS) generated in oxidative metabolism inflict damage on all classes of macromolecules and can ultimately lead to cell death. Indeed, ROS are implicated in a number of human diseases (Section 18.3.6). Reducedglutathione (), a tripeptide with a free sulfhydryl group, is required to combat oxidative stress and maintain the normal reduced state in the cell. Oxidized glutathione () is reduced by  generated by glucose 6-phosphate dehydrogenase in the pentose phosphate pathway. Indeed, cells with reduced levels of glucose 6-phosphate dehydrogenase are especially sensitive to oxidative stress. This stress is most acute in red blood cells because, lacking mitochondria, they have no alternative means of generating reducing power.


Glucose 6-phosphate dehydrogenase also limits the conversion of glucose-6-phosphate into myo-inositol which is a precursor to oxidative stress in Down syndrome and in many cases of Alzheimer's disease.

Glucose 6-phosphate dehydrogenase levels and thus reduced glutathione levels (biologically speaking) are maintained through the neuroprotective phosphatidyinositol-3 kinase/Akt pathway. This is the very pathway cut off by oxidation in Alzheimer's disease.

http://www.ncbi.nlm.nih.gov/pubmed/9614103

http://www.ncbi.nlm.nih.gov/pubmed/16410804

To restore this pathway and to partially restore glutathione levels requires powerful antioxidants.  Panax ginseng provides an example. 

http://www.ncbi.nlm.nih.gov/pubmed/23084645

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659550/

http://www.ncbi.nlm.nih.gov/pubmed/19298205

http://www.ncbi.nlm.nih.gov/pubmed/22780999



Serenoa
Posted: Friday, December 4, 2015 5:11 AM
Joined: 4/24/2012
Posts: 484


This glucose-6-phosphate connection is very interesting. Seems that way back in the 1980s they found levels of this enzyme increased to be INCREASED in Alzheimer's. 

 Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer's disease may reflect oxidative stress.

Abstract

The activities of the hexose monophosphate pathway enzymes glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase were measured at autopsy in control and Alzheimer's disease brains. Enzyme activities did not vary between different areas of brain and were unaltered by age. In Alzheimer's disease, the activities of both enzymes were increased, the glucose-6-phosphate dehydrogenase activity being almost double the activity of normal controls. We propose that this increased enzyme activity is a response to elevated brain peroxide metabolism.


Serenoa
Posted: Friday, December 4, 2015 5:51 AM
Joined: 4/24/2012
Posts: 484


Oh my look at this research saying too much glucose-6-phosphate dehydrogenase is driving ROS production! What's going on!?

Increase in Glucose-6-Phosphate Dehydrogenase in Adipocytes Stimulates Oxidative Stress and Inflammatory Signals


Abstract

In adipocytes, oxidative stress and chronic inflammation are closely associated with metabolic disorders, including insulin resistance, obesity, cardiovascular disease, and type 2 diabetes. However, the molecular mechanisms underlying these metabolic disorders have not been thoroughly elucidated. In this report, we demonstrate that overexpression of glucose-6-phosphate dehydrogenase (G6PD) in adipocytes stimulates oxidative stress and inflammatory responses, thus affecting the neighboring macrophages. Adipogenic G6PD overexpression promotes the expression of pro-oxidative enzymes, including inducible nitric oxide synthase and NADPH oxidase, and the activation of nuclear factor-κB (NF-κB) signaling, which eventually leads to the dysregulation of adipocytokines and inflammatory signals. Furthermore, secretory factors from G6PD-overexpressing adipocytes stimulate macrophages to express more proinflammatory cytokines and to be recruited to the adipocytes; this would cause chronic inflammatory conditions in the adipose tissue of obesity. These effects of G6PD overexpression in adipocytes were abolished by pretreatment with NF-κB inhibitors or antioxidant drugs. Thus, we propose that a high level of G6PD in adipocytes may mediate the onset of metabolic disorders in obesity by increasing the oxidative stress and inflammatory signals.

 

 And from the Introduction of the article:

 

 "Previous reports have demonstrated that NADPH produced by G6PD is required for both the production of ROS, including superoxide anions and NO, and the elimination of these ROS via glutathione peroxidase and catalase"

 

 

 


Lane Simonian
Posted: Friday, December 4, 2015 11:19 AM
Joined: 12/12/2011
Posts: 4998


This is quite interesting.  Glucose 6-phosphate dehydrogenase may contribute both to oxidation (both superoxide anions via NADPH oxidase and inducible nitric oxide) and to the scavenging of these oxidants (by reduced glutathione).

Now I have to try to figure out the discrepancy between articles that say G6PD is increased in Alzheimer's disease and those that say it is decreased in Alzheimer's disease. This article links Glucose 6-phosphate dehydrogenase with platelet derived growth factor receptors (a receptor tyrosine kinase) whose activity is often high early in Alzheimer's disease but often low as the disease progresses.  Maybe there are other better explanations for the discrepancy.

http://www.ncbi.nlm.nih.gov/pubmed/8182086



Serenoa
Posted: Sunday, December 6, 2015 9:31 PM
Joined: 4/24/2012
Posts: 484


What if both are happening at the same time, high glucose 6-phosphate dehydrogenase and low glutathione? I'm just throwing stuff out there. What if the cells are producing more glucose 6-phosphate dehydrogenase in an attempt to restore depleted glutathione levels, but something is going wrong? The pathway is being hijacked.

One article pointed out the following: "Here we show that glucose deprivation and ONOO- synergistically deplete intracellular reduced glutathione..." We know that glutathione is being depleted because we know that inflamation and oxidative damage are taking place. But, can we conclude that the problem is not the lack of glucose 6 phosphate dehydrogenase?

We know that oxidative damage and insulin resistance interfere with the PI3k/Akt pathway and glutathione production (if I remember right). Could they also be leading to increased glucose 6 phosphate dehydrogenase? Any merit to these thoughts Lane?


Lane Simonian
Posted: Sunday, December 6, 2015 10:48 PM
Joined: 12/12/2011
Posts: 4998


I am inching toward the same conclusion.  Tryosine receptor kinases via phosphatidylinositol 3-kinase increases glucose 6-phosphate dehydrogenase levels and activity. Overactivation of receptor tyrosine kinases also leads to oxidative stress.  The nitration of the phoshatidylinositol 3-kinase inhibits its function as Alzheimer's disease progresses. But maybe the high levels and activity of glucose 6-dehydrogenase triggered at the beginning of Alzheimer's disease continue throughout the disease 

The building blocks of glutathione are cysteine, glutamate, and glycine.  Peroxynitrite inhibits glutamate and cystine transport in Alzheimer's disease.  In addition,  NADPH oxidase activity in Alzheimer's disease also lowers glutathione levels.  So maybe these are the actual problems.

http://www.ncbi.nlm.nih.gov/pubmed/8626378

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3545354/

http://jaha.ahajournals.org/content/3/1/e000555.full


Lane Simonian
Posted: Sunday, December 6, 2015 11:15 PM
Joined: 12/12/2011
Posts: 4998


I found a more direct route by which peroxynitrite depletes levels of the critical antioxidant reduced glutathione.


...inhibition of glutathione reductase (GR) has been demonstrated to cause a decrease in reduced glutathione (GSH) and increase in glutathione disulfide (GSSG)...

As GSH inactivates a number of oxidising species including peroxynitrite (ONOO-), we additionally investigated the susceptibility of glutathione reductase to ONOO- in vitro, using purified enzyme. ONOO- decreased glutathione reductase activity in a concentration dependent manner with an apparent 50% inhibition occurring at an initial concentration of 0.09 mM.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2709784/

http://discovery.ucl.ac.uk/1392451/

As peroxynitrite levels go up, levels of reduced glutathione go down.  Then the only real solution is to use external antioxidants to take the place of glutathione.

 


Serenoa
Posted: Wednesday, December 23, 2015 5:27 AM
Joined: 4/24/2012
Posts: 484


Ok Lane, I've been digesting your research and trying to make connections. Here are some thoughts.

Glucose 6 Phosphate dehydrogenase (G6Pd) overproduction seems to have the potential to stimulate macrophages to produce pro-inflamatory cytokines, an innate immune system response. If this is true, it supports an autoimmune hypothesis involving chronic inflamation.

G6Pd deficiency on the other hand is a well known condition that results in a lack of glutathione to protect cells from normally produced oxidative molecules leading to oxidative dammage and cell death.

The result from both overproduction and deficiency of G6Pd seems to be oxidative dammage, inflamation and cell death. 

Assuming this is the case, what could be causing the dysfunction in levels of G6Pd? There are clues related to PI3k. The inhibition of this protein and its pathway may allow G6Pd to leave the cell and activate macrophages to produce inflamation (per your PDGF article). Inhibition of PI3k also prevents glucose uptake in the cell (insulin resistance) thus preventing the reaction that G6Pd catalyzes maybe leading to a build up of G6Pd as well as reduction in glutathione production.

 


Lane Simonian
Posted: Wednesday, December 23, 2015 11:07 AM
Joined: 12/12/2011
Posts: 4998


The loss of function of the phoshatidylinositol 3-kinase may be a critical event in the onset and progression of Alzheimer's disease.  This loss of function does not appear to inhibit the activity of G6DP but it does seem via peroxynitrite formation to inhibit the synthesis and maintenance of reduced glutathione levels.

The role of inflammation in Alzheimer's disease continues to be perplexing.  Some of the pathways that lead to inflammation are up-regulated and some are down-regulated (such as via the phosphatidylinositol 3-kinase).  Peroxynitrite itself seems to have a dual effect on inflammation.

Our results point to a physiological role for ONOO as a down-modulator of immune responses and also as key mediator in cellular and tissue injury associated with chronic activation of the immune system.

http://www.jimmunol.org/content/162/6/3356.long

Microglia--the brain's immune cells--appear to be resistant to oxidative stress but maybe there are some exceptions.

However, just why the microglial cells, which cluster around the deposits, are inactivated or lose their functionality is still not fully understood.

www.mdc-berlin.de/40766477/en/news/archive/2013/20130411-new_findings_on_the_brain_s_immune_cells_d

Alzheimer's disease may be primarily an oxidative disease accompanied by some degree of inflammation.


Lane Simonian
Posted: Thursday, December 24, 2015 12:19 AM
Joined: 12/12/2011
Posts: 4998


Here is one more that ties several threads together: microglia activation, peroxynitrite formation, decrease in cytochrome c oxidase activity, mitochondrial failure, partial downregulation of microglia.

Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates a key mitochondrial enzyme in microglia.

 

Microglial activation, oxidative stress, and dysfunctions in mitochondria, including the reduction of cytochrome oxidase activity, have been implicated in neurodegeneration. The current experiments tested the effects of reducing cytochrome oxidase activity on the ability of microglia to respond to inflammatory insults. Inhibition of cytochrome oxidase by azide reduced oxygen consumption and increased reactive oxygen species (ROS) production but did not affect cell viability. Azide also attenuated microglial activation, as measured by nitric oxide (NO.) production in response to lipopolysaccharide (LPS). It is surprising that the inhibition of cytochrome oxidase also diminished the activity of the alpha-ketoglutarate dehydrogenase complex (KGDHC), a Krebs cycle enzyme. This reduction was exaggerated when the azide-treated microglia were also treated with LPS. The combination of the azide-stimulated ROS and LPS-induced NO. would likely cause peroxynitrite formation in microglia. Thus, the possibility that KGDHC was inactivated by peroxynitrite was tested. Peroxynitrite inhibited the activity of isolated KGDHC, nitrated tyrosine residues of all three KGDHC subunits, and reduced immunoreactivity to antibodies against two KGDHC components. Thus, our data suggest that inhibition of the mitochondrial respiratory chain diminishes aerobic energy metabolism, interferes with microglial inflammatory responses, and compromises mitochondrial function, including KGDHC activity, which is vulnerable to NO. and peroxynitrite that result from microglial activation. Thus, activation of metabolically compromised microglia can further diminish their oxidative capacity, creating a deleterious spiral that may contribute to neurodegeneration.

After awhile it is not the microglia producing oxidation and inflammation, but oxidation continues via NMDA receptor activation.


Serenoa
Posted: Thursday, December 24, 2015 4:37 AM
Joined: 4/24/2012
Posts: 484


Yes, I think you are right. It's amazing how much evidence you have found connecting oxidative stress to this disease and showing the exact mechanisms by which it does its dammage. So there is no doubt of the involvement of ROS, peroxynitrite, etc as both cause and mechanism of AD. But I'm starting to think that we are missing something. That oxidative stress alone is not enough to trigger the dammage required. There is another factor. Oxidative stress may be the gun but what is pulling the trigger?

 For example, another post shows how magnesium deficiency can lead to oxidative stress. But magnesium deficiency alone is not the cause of AD. There has to be other factors in combination. Maybe ApoE plus magnesium deficiency plus insulin resistance or something like that. Maybe a virus (like Herpes) that lies dormant until triggered by some environmental factor plus ApoE or insulin resistance. I don't know.


Lane Simonian
Posted: Thursday, December 24, 2015 9:31 AM
Joined: 12/12/2011
Posts: 4998


This is certainly one of the critical questions regarding Alzheimer's disease: what are the triggers for oxidative stress.  Here is one of my favorite quotes regarding the triggers for Alzheimer's disease:

“It could be a bit like the Mississippi river,” says Dr Hardy. “You can start in all sorts of places, but eventually you’re going to end up in New Orleans.” 

This is not a complete list and some have not been proven, but here are some of the factors that increase oxidative stress and may increase the risk for Alzheimer's disease.

High glucose levels (prediabetic or diabetic)
High sodium levels
High fructose corn syrup
Down syndrome
Magnesium deficiency
Apoe4 gene
Presenilin gene mutations
Amyloid precursor protein mutations
Psychological or physical stress
Air pollutants (particulate matter, diesel fumes, carbon monoxide, nitric oxides)
Mercury
Industrial solvents (benzene, toulene)
Bisphenols in plastics
Pesticides (DDT, dioxin in Agent Orange, polyethoxylated tallow amines in Roundup)
Chronic bacterial and viral infections (Herpes simplex virus 1, lyme disease, oral bacterial infections)
Chronic acetaminophen use
Bisphosphonate osteoporosis drugs
Heavy smoking
Heavy drinking

Some of these alone may be enough to cause Alzheimer's disease and some may not.

The factors that trigger oxidative stress often work by increasing tyrosine phosphorylation and polyphenols inhibit tyrosine phosphorylation.  The damage done to various receptors, enzymes, and transport systems in Alzheimer's disease is often a result of tyrosine nitration and polyphenols partially reverse tyrosine nitration.  This is why a Mediterranean diet high in polyphenols both reduces the risk for Alzheimer's disease and slows its progression.  



Serenoa
Posted: Monday, December 28, 2015 6:12 AM
Joined: 4/24/2012
Posts: 484


One thing that I am going back to is Dr. George Perry's Free Radical theory of Alzheimer's (AD) pathology which you posted Lane some time ago. He states that plaques and tangles are the brains reaction to oxidative stress and not the cause of AD (as you have said many times and other research supports). 

Therefore, when one considers that oxidative damage (peroxynitrite, hydrogen peroxide, NO, inflamation) are the drivers of this disease, it only remains to determine what is triggering the free radicals/oxidative damage. You have suggested many factors above that contribute or cause AD in combination or alone. Let me simplify that to the following statement, which I'm sure you have already done many times in previous posts. Anything that increases levels of free radicals (like peroxynitrite) in the brain, or anything that reduces the body's defences against normal levels of free radicals can cause AD.

This puts things in a different light for me I think. One thing I have been considering lately are triggers of inflamation in the brain which increase levels of free radicals. The immune system is great at creating oxidative damage and we have all sorts of viruses and bacteria floating around in us that may be promoting chronic inflamation. And, the reason it's happening more now than in the past is exposure to multiple viruses in vaccines, breakdown of the gut lining and blood-brain barrier and dysregulation of the immune system by lifestyle (diet, exercise) and environmental factors.

 

 

 


Serenoa
Posted: Monday, December 28, 2015 6:16 AM
Joined: 4/24/2012
Posts: 484


Oh, and I do like the Mississippi River quote. That nails it. I guess oxidative damage would be the main channel flowing into New Orleans.
Lane Simonian
Posted: Tuesday, December 29, 2015 5:38 PM
Joined: 12/12/2011
Posts: 4998


This is it, Serenoa!  Several streams can flow into the main channel of oxidative stress and over time they can contribute to the onset of Alzheimer's disease.
Eden Desjardins
Posted: Monday, January 4, 2016 10:45 AM
Joined: 5/25/2015
Posts: 48


Lane Simonian wrote:
This is certainly one of the critical questions regarding Alzheimer's disease: what are the triggers for oxidative stress.  Here is one of my favorite quotes regarding the triggers for Alzheimer's disease:

“It could be a bit like the Mississippi river,” says Dr Hardy. “You can start in all sorts of places, but eventually you’re going to end up in New Orleans.” 

This is not a complete list and some have not been proven, but here are some of the factors that increase oxidative stress and may increase the risk for Alzheimer's disease.

High glucose levels (prediabetic or diabetic)
High sodium levels
High fructose corn syrup
Down syndrome
Magnesium deficiency
Apoe4 gene
Presenilin gene mutations
Amyloid precursor protein mutations
Psychological or physical stress
Air pollutants (particulate matter, diesel fumes, carbon monoxide, nitric oxides)
Mercury
Industrial solvents (benzene, toulene)
Bisphenols in plastics
Pesticides (DDT, dioxin in Agent Orange, polyethoxylated tallow amines in Roundup)
Chronic bacterial and viral infections (Herpes simplex virus 1, lyme disease, oral bacterial infections)
Chronic acetaminophen use
Bisphosphonate osteoporosis drugs
Heavy smoking
Heavy drinking

Some of these alone may be enough to cause Alzheimer's disease and some may not.

The factors that trigger oxidative stress often work by increasing tyrosine phosphorylation and polyphenols inhibit tyrosine phosphorylation.  The damage done to various receptors, enzymes, and transport systems in Alzheimer's disease is often a result of tyrosine nitration and polyphenols partially reverse tyrosine nitration.  This is why a Mediterranean diet high in polyphenols both reduces the risk for Alzheimer's disease and slows its progression.  

Seems like quite a few things are unavoidable but definitely controllable. I'm amazed at how many people take their bodies for granted by doing heavy smoking/heavy drinking without considering the consequences later on.
Thanks for the list, Lane.  

JaneJ
Posted: Thursday, January 28, 2016 2:13 AM
Joined: 1/28/2016
Posts: 1


"Glutathione (GSH) is an important antioxidant in plants, animals, fungi, and some bacteria and archaea, preventing damage to important cellular components caused by reactive oxygen species such as free radicals, peroxides, lipid peroxides and heavy metals." from which it can be seen that glutathione (http://www.bocsci.com/glutathione-cas-70-18-8-item-5-464855.html)quite commonly exists, and once the main problem that the substance is hard to get into brain cells is addressed, it will be a highly potential drug for ALZ. And the nanotechnology may be possible to assist the process. 
Lane Simonian
Posted: Thursday, January 28, 2016 10:38 AM
Joined: 12/12/2011
Posts: 4998


JaneJ, welcome.  I could not agree with you more.  I just don't know how long it will take scientists to develop a way to get glutathione effectively into brain cells.