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Important Mechanism Underlying Alzheimer's Disease Discovered
Myriam
Posted: Saturday, September 7, 2013 2:32 PM
Joined: 12/6/2011
Posts: 3326


Alzheimer's disease affects more than 26 million people worldwide. It is predicted to skyrocket as boomers age -- nearly 106 million people are projected to have the disease by 2050. Fortunately, scientists are making progress towards therapies. A collaboration among several research entities, including the Salk Institute and the Sanford-Burnham Medical Research Institute, has defined a key mechanism behind the disease's progress, giving hope that a newly modified Alzheimer's drug will be effective. 


 
 

In a previous study in 2009, Stephen F. Heinemann, a professor in Salk's Molecular Neurobiology Laboratory, found that a nicotinic receptor called Alpha7 may help trigger Alzheimer's disease. "Previous studies exposed a possible interaction between Alpha-7 nicotinic receptors (α7Rs) with amyloid beta, the toxic protein found in the disease's hallmark plaques," says Gustavo Dziewczapolski, a staff researcher in Heinemann's lab. "We showed for the first time, in vivo, that the binding of this two proteins, α7Rs and amyloid beta, provoke detrimental effects in mice similar to the symptoms observed in Alzheimer's disease ." 

 

Their experiments, published in The Journal of Neuroscience, with Dziewczapolski as first author, consisted in testing Alzheimer's disease-induced mice with and without the gene for α7Rs. They found that while both types of mice developed plaques, only the ones with α7Rs showed the impairments associated with Alzheimer's. 

 

But that still left a key question: Why was the pairing deleterious? 

In a recent paper in the Proceedings of the National Academy of Sciences, Heinemann and Dziewczapolski here at Salk with Juan Piña-Crespo, Sara Sanz-Blasco, Stuart A. Lipton of the Sanford-Burnham Medical Research Institute and their collaborators announced they had found the answer in unexpected interactions among neurons and other brain cells. 

 

Neurons communicate by sending electrical and chemical signals to each other across gaps called synapses. The biochemical mix at synapses resembles a major airport on a holiday weekend -- it's crowded, complicated and exquisitely sensitive to increases and decreases in traffic. One of these signaling chemicals is glutamate, an excitatory neurotransmitter, which is essential for learning and storing memories. In the right balance, glutamate is part of the normal functioning of neuronal synapses. But neurons are not the only cells in the brain capable of releasing glutamate. Astrocytes, once thought to be merely cellular glue between neurons, also release this neurotransmitter. 

 

In this new understanding of Alzheimer's disease, there is a cellular signaling cascade, in which amyloid beta stimulates the alpha 7 nicotine receptors, which trigger astrocytes to release additional glutamate into the synapse, overwhelming it with excitatory ("go") signals. 

 

This release in turn activates another set of receptors outside of the synapse, called extrasynaptic-N-methyl-D-aspartate receptors (eNMDARs) that depress synaptic activity. Unfortunately, the eNMDARs seem to overly depress synaptic function, leading to the memory loss and confusion associated with Alzheimer's. 

Now that the team has finally determined the steps in this destructive pathway, the good news is that a drug developed by the Lipton's Laboratory called NitroMemantine, a modification of the earlier Alzheimer's medication, Memantine, may block the entry of eNMDARs into the cascade. 

 

"Thanks to the joint effort of our colleagues and collaborators, we seem to finally have a clear mechanistic link between a key target of the amyloid beta in the brain, the Alpha7 nicotinic receptors, triggering downstream harmful effects associated with the initiation and progression of Alzheimer's disease," says Dziewczapolski. "This is a clear demonstration of the value of basic biomedical research. Drug development cannot proceed without knowing the details of interactions at the molecular and cellular level. Our research revealed two potential targets, α7Rs and eNMDARs, for future disease-modifying therapeutics, which Dr. Heinemann and I both hope will translate in a better treatment for Alzheimer's patients." 

 

Other researchers on the study were Maria Talantova, Xiaofei Zhang, Peng Xia, Mohd Waseem Akhtar, Shu-ichi Okamoto, Tomohiro Nakamura, Gang Cao, Alexander E. Pratt, Yeon-Joo Kang, Shichun Tu, Elena Molokanova, Gary Tong, Scott R. McKercher, James Parker, Emily A. Holland, Traci Fang-Newmeyer, Dongxian Zhang, Nobuki Nakanishi, H.-S. Vincent Chen and Rajesh Ambasudhan of the Sanford-Burnham Medical Research Institute; Samuel Andrew Hires of the Howard Hughes Medical Research Institute; Herman Wolosker and Hagit Sason of the Technion-Israel Institute of Technology in Israel; Yuqiang Wang of Jinan University in China and Panorama Research Institute in California; Loren H. Parsons, David G. Stouffer, Matthew W. Buczynski, Amanda Roberts, James P. Solomon, Evan T. Powers and Jeffery W. Kelly of the Scripps Research Institute; Sarah Michael and Eliezer Masliah of UCSD School of Medicine. 

 

This work was supported by the National Institutes of Health, Department of Defense, National Institute of Neurological Disorders and Stroke, American Heart Association and the Ministry of Education and Science of Spain. 


Lane Simonian
Posted: Saturday, September 7, 2013 4:47 PM
Joined: 12/12/2011
Posts: 5001


I thought about posting this study separately, so I am glad you did so Myriam.  I think that it may be one of the most important findings in regards to Alzheimer's disease this year.  I am not so keen on singling out the acetylcholine nicotine receptor as a culprit, only because many receptors play a role in glutamate release.  However, the need to inhibit NMDA receptor activity is spot on.  The problem with Namenda/memantine is that it does not regulate this receptor in the right spot.  Perhaps, Lipton's new drug will. 

 

Peroxynitrite-mediated nitration of NMDA receptors contributes to their activation in Alzheimer's disease.  The influx of calcium in turn results in the further production of peroxynitrites and the death of brain cells.  Eugenol in various essential oils scavenge peroxynitrites, inhibit and partially reverse the tyrosine nitration of NMDA receptors, and reduce the death of brain cells.  When other peroxynitrite scavengers in various herbs for example are added to the aromatherapy, the effect is magnified so that the disease can be held in check.  If it were (or is) possible to complete scavenge peroxynitrites, then this would likely provide a cure to Alzheimer's disease. 

 

 http://www.nature.com/pr/journal/v43/n4s/full/pr19982061a.html 

 

http://www.ncbi.nlm.nih.gov/pubmed/15941312 

 

http://www.ncbi.nlm.nih.gov/pubmed/9147382 

 

http://www.ingentaconnect.com/content/ben/cbc/2006/00000002/00000001/art00005 


Myriam
Posted: Saturday, September 7, 2013 7:28 PM
Joined: 12/6/2011
Posts: 3326


Thanks, Lane. I can read and understand legalize, but when it comes to scientific/medical terms, I go cross-eyed, so I tend to post articles that have been edited for those of us who tend to be right brained.
Lane Simonian
Posted: Saturday, September 7, 2013 9:14 PM
Joined: 12/12/2011
Posts: 5001


No problem, Myriam.  It took me several years to understand most of the medical jargon in these studies.  Some of the terms continue to baffle me. 

 

It might be useful just to highlight the key points in the above links. 

 

We speculate that peroxynitrite may modify the NMDA receptor either by exposing additional glutamate sites or by nitration of NMDA receptor tyrosine residues and may be a mechanism of regulation of NMDA receptor function.

 

http://www.nature.com/pr/journal/v43/n4s/full/pr19982061a.html 

 

The essential oil [from true cinnamon bark] and eugenol showed very powerful activities, decreasing 3-nitrotyrosine formation...

 

http://www.ncbi.nlm.nih.gov/pubmed/15941312 

 

These results suggest that eugenol may play a protective role against ischemic injury by modulating both NMDA receptor and superoxide radical.

 

http://www.ncbi.nlm.nih.gov/pubmed/9147382 

 

Eugenol inhibits Aβ [amyloid beta]-induced excessive influx of calcium ion into neurons that causes neuronal death [via the activation of NMDA receptors]...Thus, eugenol can be a good medicine for AD and depression.

 

And the one I never get tired of posting: 

 

RESULTS:

All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy. In particular, patients with AD showed significant improvement in total TDAS scores. Result of routine laboratory tests showed no significant changes, suggesting that there were no side-effects associated with the use of aromatherapy. Results from Zarit's score showed no significant changes, suggesting that caregivers had no effect on the improved patient scores seen in the other tests.

CONCLUSIONS:

In conclusion, we found aromatherapy an efficacious non-pharmacological therapy for dementia. Aromatherapy may have some potential for improving cognitive function, especially in AD patients.

 

http://www.ncbi.nlm.nih.gov/pubmed/20377818 

 

I wonder how many people that might value from this clinical trial forum never come here because the terminology is so daunting.  For those who wade through this morass of terms, here is the gist of it.  Essential oils containing eugenol inhibit and partially reverse the nitration of the NMDA receptor and in doing so prevent many brain cells from dying.  Or to put it in broader terms, aromatherapy with essential oils high in eugenol can help improve cognitive function in people with Alzheimer's disease.  Thank you Myriam for being so willing to try it.  It is wonderful to know for you and for others that in part because of aromatherapy you are succeeding. 

 

 


Serenoa
Posted: Saturday, September 7, 2013 10:13 PM
Joined: 4/24/2012
Posts: 484


 

Protecting the Brain from a Glutamate Storm

 

 

The question was how to increase the pumping of glutamate out of the brain and into the bloodstream to protect the brain. Shutting down a cellular pump is easy; making it work faster and better is much more tricky. As is true for many natural processes perfected by eons of evolution, these pumps already work very well, so that enhancing such a process is no mean feat.

Our answer came from exploring the secrets of brain-to-blood pumping. It turned out that two efficient yet disarmingly simple mechanisms are in play. First, glutamate is pumped into the cells that make up the blood vessel wall. This step is performed by the glutamate pumps on the outer side of the brain’s blood vessels, the side that comes into contact with the brain tissue. Because the blood vessel wall cells are very small in size, glutamate concentration inside them quickly builds up to very high levels, much higher than the chemical’s concentration in the blood. That leads to the second step of the process, which stems from basic chemistry: Glutamate naturally flows by diffusion from areas of high concentration (in blood vessel wall cells) through the blood vessel wall into the circulating bloodstream, where the concentration is lower.

This insight led to the idea of accelerating the naturally occurring brain-to-blood pumping by lowering glutamate levels in the circulating blood. The hypothesis was that a larger difference in glutamate concentration would enhance the driving force for the chemical’s removal, and more glutamate would flow out of the brain and into the circulating blood.

 

http://www.dana.org/news/cerebrum/detail.aspx?id=7376&p=4

 

 


Serenoa
Posted: Saturday, September 7, 2013 10:14 PM
Joined: 4/24/2012
Posts: 484


Journal of Cerebral Blood Flow & Metabolism (2012) 32, 177–189; doi:10.1038/jcbfm.2011.121; published online 14 September 2011

Mechanisms of glutamate efflux at the blood–brain barrier: involvement of glial cells

 

 

 At high concentrations, glutamate (Glu) exerts potent neurotoxic properties, leading to irreversible brain damages found in numerous neurological disorders. The accepted notion that Glu homeostasis in brain interstitial fluid is maintained primarily through the activity of Glu transporters present on glial cells does not take into account the possible contribution of endothelial cells constituting the blood–brain barrier (BBB) to this process. Here, we present evidence for the presence of the Glu transporters, excitatory amino-acid transporters (EAATs) 1 to 3, in porcine brain endothelial cells (PBECs) and show their participation in Glu uptake into PBECs. Moreover, transport of Glu across three in vitro models of the BBB is investigated for the first time, and evidence for Glu transport across the BBB in both directions is presented. Our results provide evidence that the BBB can function in the efflux mode to selectively remove Glu, via specific transporters, from the abluminal side (brain) into the luminal compartment (blood). Furthermore, we found that glial cells lining the BBB have an active role in the efflux process by taking up Glu and releasing it, through hemichannels, anion channels, and possibly the reversal of its EAATs, in close proximity to ECs, which in turn take up Glu and release it to the blood.

 

 

http://www.nature.com/jcbfm/journal/v32/n1/abs/jcbfm2011121a.html

 


Lane Simonian
Posted: Saturday, September 7, 2013 10:34 PM
Joined: 12/12/2011
Posts: 5001


In a way, it pleases me that everything seems to come back to peroxynitrites.  In another way, I wish that I had something new to say. 

  

1996 Mar 15;271(11):5976-9.

Peroxynitrite inhibits glutamate transporter subtypes.

Source

Center of Neuropharmacology, Institute of Pharmacological Sciences, University of Milan, Italy.

Abstract

The reuptake of glutamate in neurons and astrocytes terminates excitatory signals and prevents the persistence of excitotoxic levels of glutamate in the synaptic cleft. This process is inhibited by oxygen radicals and hydrogen peroxide (H2O2). Here we show that another biological oxidant, peroxynitrite (ONOO-), formed by combination of superoxide (O2-) and nitric oxide (NO), potently inhibits glutamate uptake by purified or recombinant high affinity glutamate transporters reconstituted in liposomes. ONOO- reduces selectively the Vmax of transport; its action is fast (reaching > or = 90% within 20 s), dose-dependent (50% inhibition at 50 microM), persistent upon ONOO- (or by product) removal, and insensitive to the presence of the lipid antioxidant vitamin E in the liposomal membranes. Therefore, it likely depends on direct interaction of ONOO- with the glutamate transporters. Three distinct recombinant glutamate transporters from the rat brain, GLT1, GLAST, and EAAC1, exhibit identical sensitivity to ONOO . H2O2 also inhibits reconstituted transport, and its action matches that of ONOO- on all respects; however, this is observed only with 5-10 mM H202 and after prolonged exposure (10 min) in highly oxygenated buffer. NO, released from NO donors (up to 10 mM), does not modify reconstituted glutamate uptake, although in parallel conditions it promotes cGMP formation in synaptosomal cytosolic fraction. Overall, our results suggest that the glutamate transporters contain conserved sites in their structures conferring vulnerability to ONOO- and other oxidants.

 

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

 

 

 


Serenoa
Posted: Sunday, September 8, 2013 8:31 AM
Joined: 4/24/2012
Posts: 484


Once again Lane you are giving valid and convincing (not to mention exciting) evidence that scavenging peroxynitries is critical to stopping Alzheimer's. I had to laugh when you said "I wish I had something new to say."

 

 

Ok, let's break this down:

 

 

Amyloid beta causes release of glutamate by coupling with nicotinic receptors on neurons.

 

Excess glutamate is toxic to neurons because it can activate other molecules on the outside of neurons called NMDA receptors which let too much Ca2+ into the neuron causing it to swell (water follows Ca2+).

 

Peroxynitrites also activate the NMDA receptors with the same result. Meaning that amyloid beta is not required to activate NMDA receptors.

 

So, the swelling does two things, restricts adjacent capillaries cutting off blood flow (which kills cells), and it can burst the neuron.Either way, the stored glutamate in the destroyed neurons gets released causing more damage to other neurons.

 

Therefore, both glutamate and peroxynitrite must be addressed to stop neuronal cell death.

 
I think there are excelent ways, as Lane and others have described, of scavenging peroxynitrites and decreasing oxidative damage (i.e. aromatherapy, antioxidant). But, in the above senario that does still leave us with amyloid beta releasing more glutamate. In addition to that, removing causal factors like glutamate, peroxynitrite, even amyloid beta, does not fix the destroyed capillaries and the holes in the brain from years of damage.

 

 We need a two-pronged attack. But, what is the second prong? Leukine (GM-CSF) seems to be the best thing available to remove amyloid beta and regenerate blood vessels and neurons.

 

 


Serenoa
Posted: Sunday, September 8, 2013 8:58 AM
Joined: 4/24/2012
Posts: 484


Granulocyte colony stimulating factor decreases brain amyloid burden and reverses cognitive impairment in Alzheimer's mice.

 

http://www.ncbi.nlm.nih.gov/pubmed/19500657

 

 

Granulocyte-macrophage colony-stimulating factor-induced vessel growth restores cerebral blood supply after bilateral carotid artery occlusion.

 

http://www.ncbi.nlm.nih.gov/pubmed/17332468

 

 

A neuroprotective function for the hematopoietic protein granulocyte-macrophage colony stimulating factor (GM-CSF)

 

 

http://www.nature.com/jcbfm/journal/v28/n1/abs/9600496a.html

 

 


Lane Simonian
Posted: Sunday, September 8, 2013 10:46 AM
Joined: 12/12/2011
Posts: 5001


Thanks to you Serenoa, I think I finally understand the role of granulocyte macrophage colony stimulating factor in Alzheimer's disease.  It helps reverse the damage done by amyloid and peroxynitrites to blood vessels in the brain.  It helps remove amyloid and activate the neuroprotective phosphatidylinositol 3 kinase/Akt pathway. 

 

Of the signaling pathways studied, GM-CSF most prominently induced the PI3K-Akt pathway, and inhibition of Akt strongly decreased antiapoptotic activity.

 

http://www.nature.com/jcbfm/journal/v28/n1/abs/9600496a.html (from the study cited in Serenoa's post).

 

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 

 

http://www.nature.com/srep/2012/120926/srep00697/full/srep00697.html 

 

Now if you combine this with a peroxynitrite scavenger that would reverse the nitration of receptor tyrosine kinases that help activate the phosphatidyinositol 3 kinase/Akt pathway, then the pathway that largely protects the brain against vascular damage and contributes to the regeneration of neurons in the hippocampus would largely be restored. 


Serenoa
Posted: Tuesday, September 10, 2013 10:59 AM
Joined: 4/24/2012
Posts: 484


The Excitotoxicity Hypothesis

  

Based on the research posted so far on this and other threads, it seems we may have established a viable mechanism by which Alzheimer’s destroys the brain (which by the way is by no means a new hypothesis).  However, I would like to see how many aspects of this disease we can connect to this hypothesis. So let’s put it to further tests by comparing it to other aspects of the disease to see if it can account for some of the things that have been shown to contribute to, or cause Alzheimer’s.  We have already shown how peroxynitrites and amyloid beta fit very well with this hypothesis. What about genetics, metals, diabetes, tau tangles, or anything else that may related?  

  

I don’t want people to have to look up technical medical terms in order to understand this. I think the main thing to understand about this hypothesis is that the over activation of these receptors allows the massive influx of positively charged calcium molecules (Ca2+) into the neuron. This abundance of positive electrical charge entering the neuron causes the neuron to swell with water and/or to lose its electrical capabilities that it needs to function. At least that is my understanding of it.   

  

I started with how having the APOE4 gene may be related (see below) and found good evidence that it increases the amount of calcium the NMDA receptor lets into the cell. Another article states that the APOE4 protein binds to the NMDA receptor and results in the decrease of an enzyme that degrades amyloid beta. This seems to support our hypothesis very well. 

  

ApoE isoforms affect neuronal N-methyl-d-aspartate calcium responses and toxicity via receptor-mediated processes

Abstract

Apolipoprotein E (apoE) alters the pathophysiology of Alzheimer's disease, but its mechanism is not fully understood. We examined the effects of recombinant human apoE3 and apoE4 on the neuronal calcium response to N-methyl-d-aspartate (NMDA), and compared them to their toxicity. ApoE4 (100 nM) significantly increased the resting calcium (by 70%) and the calcium response to NMDA (by 185%), whereas similar changes were not obtained in apoE3-treated neurons. ApoE4, but not apoE3, also significantly increased neurotoxicity, as evidenced by enhanced lactate dehydrogenase release (by 53%) and reduced 3-(4,5-dimethylthiazol-2-yl)-2,5,diphenyltetrazolium bromide levels (by 32%). ApoE4-induced changes in the calcium response to NMDA and associated neurotoxicity were blocked by coincubation with MK-801. Both the receptor-associated protein, which inhibits interaction of apoE with members of the LDL receptor family, including the low-density lipoprotein receptor-related protein (LRP), and activated α2-macroglobulin, another LRP ligand, prevented apoE4-induced enhancement of the calcium response to NMDA, resting calcium levels, and neurotoxicity. A tandem apoE peptide (100 nM) containing only the receptor binding region residues also eliminated the enhanced calcium signaling and neurotoxicity by apoE4.

http://www.sciencedirect.com/science/article/pii/S0306452203006511 

 

ApoE 4 reduces the expression of Aβ degrading enzyme IDE by activating the NMDA receptor in hippocampal neurons

 

Abstract

Apolipoprotein E (ApoE) 4 is a potent risk factor for Alzheimer's disease (AD). However, the mechanism underlying ApoE4 function in the pathology of AD is not well understood. We report here that, in comparison with ApoE2 and ApoE3, ApoE4 significantly reduces levels of insulin-degrading enzyme (IDE), which is responsible for the cellular clearance of Aβ in neurons. This differential regulation of IDE by various ApoE isoforms was blocked by coincubation with N-methyl-d-aspartic acid (NMDA) receptor inhibitors and receptor-associated protein (RAP), which blocked the interaction between ApoE and members of the low-density lipoprotein (LDL) receptor family. Moreover, inhibition of the NMDA receptor increased IDE levels in neurons, while activation of the NMDA receptor-reduced IDE expression. Further studies demonstrate that, as a pathway downstream of the NMDA receptor, cAMP-dependent protein kinase (PKA) contributes to the NMDA receptor-reduced IDE expression. These results suggest that ApoE4 down-regulates IDE expression in neurons by binding to its receptor and stimulating the NMDA receptor pathway, which may account for its role in AD pathogenesis.

http://www.sciencedirect.com/science/article/pii/S0304394009009574 

 


Serenoa
Posted: Tuesday, September 10, 2013 12:03 PM
Joined: 4/24/2012
Posts: 484


Here's another one that seems to support the negative interaction of the ApoE4 protein with the NMDA receptors. Keep in mind that these receptors are located on the neuron membrane where it joins to other neurons, the synapse, and outside of the synapse. NMDA receptor activation within the synapse is necsessary, but outside the synapse, over activation leads to damage. That's my simplification of it anyway. 

 

ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling
  • Edited by Thomas C. Südhof, Stanford University School of Medicine, Palo Alto, CA, and approved May 21, 2010 (received for review December 25, 2009) 
  • Abstract

    Apolipoprotein E (ApoE) genotype is a powerful genetic modifier of Alzheimer's disease (AD). The ApoE4 isoform significantly reduces the mean age-of-onset of dementia through unknown mechanisms. Here, we show that ApoE4 selectively impairs synaptic plasticity and NMDA receptor phosphorylation by Reelin, a regulator of brain development and modulator of synaptic strength. ApoE4 reduces neuronal surface expression of Apoer2, a dual function receptor for ApoE and for Reelin, as well as NMDA and AMPA receptors by sequestration in intracellular compartments, thereby critically reducing the ability of Reelin to enhance synaptic glutamate receptor activity. As a result, the ability of Reelin to prevent LTP suppression by extracts from AD-afflicted human brains in hippocampal slices from knockin mice expressing the human ApoE4 isoform is severely impaired. These findings show an isoform-specific role of ApoE in the localization and intracellular trafficking of lipoprotein and glutamate receptors and thereby reveal an alternative mechanism by which ApoE4 may accelerate onset of dementia and neuronal degeneration by differentially impairing the maintenance of synaptic stability.

     


    Lane Simonian
    Posted: Tuesday, September 10, 2013 3:50 PM
    Joined: 12/12/2011
    Posts: 5001


    Thanks, Serenoa, for finding these very important links between APOE4 and the activation of the NMDA receptor and the aggregation of amyloid plaques. 

     

    Here are some additional connections between the APOE4 gene and inducible nitric oxide (although I am not sure if the mechanism discussed in the article is the correct one) and the inhibition of the phosphatidylinositol 3 kinase/Akt pathway. 

     

    http://www.ncbi.nlm.nih.gov/pubmed/12392781 

     

    http://www.ncbi.nlm.nih.gov/pubmed/16973905 

     

    In addition to potential endema, the calcium influx resulting from the activation of NMDA receptors leads to mitochondrial dysfunction (although I don't fully understand exactly how) and to the death of neurons. 

     

    http://www.eurosiva.org/Archive/Vienna/abstracts/Speakers/SUREDA.htm 

     

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3455645/ 

     

    Inhibiting NMDA receptor activation is critical for protecting brain cells.  Unfortunately the drug for this--Namenda/memantine--does not very effectively inhibit the influx of calcium. 

     


    Lane Simonian
    Posted: Tuesday, September 10, 2013 6:27 PM
    Joined: 12/12/2011
    Posts: 5001


    Whether the NMDA receptor plays a negative role or positive role in short-term and long-term memories appears to depend on the presence of magnesium which modulates this receptor. 

     

    Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.

     

    http://www.cell.com/neuron/abstract/S0896-6273(09)01044-7 

     

    Peroxynitrites help remove this magnesium "block".

    http://www.ncbi.nlm.nih.gov/pubmed/19356025

     

     

     

     

     


    Serenoa
    Posted: Wednesday, September 11, 2013 8:35 AM
    Joined: 4/24/2012
    Posts: 484


    Thank you Lane. The magnesium connection is very interesting and I have not considered it until now. You said in another post that we may eventually find something simple that some people who don't get alz are doing. Magnisium (Mg) is simple, and it is related to the excitotoxicity hypothesis. 

     

    It seems that Mg blocks or regulates the NMDA receptor and thus controls excitotoxicity. It is mentioned all over the place in relation to the drug Memantine which is designed to block the NMDA receptor (but apparently doesn't work very well). And one study found Mg to be lacking in Alz brains. Also, I always look for clues in other symptoms and wonder if they are related to the disease. For example, my mother and many people suffer from leg cramp spasms (charley horses) which are fixed by eating a bannana (high in Mg). Could there a connection between lack of Mg in muscles and a lack of it in the brain?  

     

     

    Disturbances of magnesium concentrations in various brain areas in Alzheimer's disease.

    Abstract

    Our first project aimed at the determination of the average values of Mg in normal human brain (20 individuals, mean age 70 years). Ten brain parts were selected from both hemispheres. Determinations were carried out by inductively coupled plasma atomic emission spectrometry, inductively coupled plasma mass spectrometry and instrumental neutron activation analysis methods. In order to investigate the precision and the accuracy of the methods five biological standard reference materials were analyzed. The present results show a non-homogeneous distribution of Mg in normal human brain. Regions corresponding to each other in both hemispheres show almost identical concentration. The second goal was to study the possible Mg concentration changes in Alzheimer's disease (nine patients, ten brain parts). Mg values are found to be significantly decreased in brain regions of diseased patients compared to the controls.

     

    http://www.ncbi.nlm.nih.gov/pubmed/11008926 

     

     

     

     

     This one is from 1990, but very straigt forward as to the benefits of Mg is mice after brain injury. 

     

    Magnesium reduces View the MathML source (NMDA)-mediated brain injury in perinatal rats

    Abstract

    We evaluated the neuroprotective effects of systemically administered magnesium against View the MathML source (NMDA)-mediated brain injury in perinatal rats. Postnatal day (PND) 7 rats received unilateral intrastriatal injections of 25 nmol NMDA followed 15 min later by single or multiple doses of magnesium intraperitoneally (i.p.). Animals were sacrificed five days later and the severity of brain injury was assessed by comparison of the weights of the injected and contralateral cerebral hemispheres. NMDA injection reduced the weight of the injected cerebral hemisphere by 31 ± 3%. Single doses of magnesium reduced the severity of NMDA-induced brain injury in a dose-dependent fashion (2 mmol/kg, 29 ± 11% protection; 3 mmol/kg, 52 ± 12% protection; 4 mmol/kg, 62 ± 7% protection). Multiple doses of magnesium reduced brain injury by 65 ± 4%. These data demonstrate that systemically administered magnesium antagonizes the neurotoxic effects of NMDA in vivo in perinatal rats.

     

     

    http://www.sciencedirect.com/science/article/pii/030439409090569U 

     

     

     

    Also, Lane's above link showing peroxynitites block Mg.


    Serenoa
    Posted: Wednesday, September 11, 2013 10:32 AM
    Joined: 4/24/2012
    Posts: 484


    Holy molly! I've been doing more research, and you all have got to read this article...Wow.

     

     

    High fructose consumption combined with low dietary magnesium intake may increase the incidence of the metabolic syndrome by inducing inflammation.

    Abstract

    The metabolic syndrome is a cluster of common pathologies: abdominal obesity linked to an excess of visceral fat, insulin resistance, dyslipidemia and hypertension. This syndrome is occurring at epidemic rates, with dramatic consequences for human health worldwide, and appears to have emerged largely from changes in our diet and reduced physical activity. An important but not well-appreciated dietary change has been the substantial increase in fructose intake, which appears to be an important causative factor in the metabolic syndrome. There is also experimental and clinical evidence that the amount of magnesium in the western diet is insufficient to meet individual needs and that magnesium deficiency may contribute to insulin resistance. In recent years, several studies have been published that implicate subclinical chronic inflammation as an important pathogenic factor in the development of metabolic syndrome. Pro-inflammatory molecules produced by adipose tissue have been implicated in the development of insulin resistance. The present review will discuss experimental evidence showing that the metabolic syndrome, high fructose intake and low magnesium diet may all be linked to the inflammatory response. In many ways, fructose-fed rats display the changes observed in the metabolic syndrome and recent studies indicate that high-fructose feeding is associated with NADPH oxidase and renin-angiotensin activation. The production of reactive oxygen species results in the initiation and development of insulin resistance, hyperlipemia and high blood pressure in this model. In this rat model, a few days of experimental magnesium deficiency produces a clinical inflammatory syndrome characterized by leukocyte and macrophage activation, release of inflammatory cytokines, appearance of the acute phase proteins and excessive production of free radicals. Because magnesium acts as a natural calcium antagonist, the molecular basis for the inflammatory response is probably the result of a modulation of the intracellular calcium concentration. Potential mechanisms include the priming of phagocytic cells, the opening of calcium channels, activation of N-methyl-D-aspartate (NMDA) receptors, the activation of nuclear factor-kappaB (NFkB) and activation of the renin-angiotensin system. Since magnesium deficiency has a pro-inflammatory effect, the expected consequence would be an increased risk of developing insulin resistance when magnesium deficiency is combined with a high-fructose diet. Accordingly, magnesium deficiency combined with a high-fructose diet induces insulin resistance, hypertension, dyslipidemia, endothelial activation and prothrombic changes in combination with the upregulation of markers of inflammation and oxidative stress.

     


    Lane Simonian
    Posted: Wednesday, September 11, 2013 10:48 AM
    Joined: 12/12/2011
    Posts: 5001


    Magnesium deficiency may contribute to Alzheimer's disease.  Magnesium threonate is currently being studied for the treatment of Alzheimer's disease.  It probably is not the entire answer but it may be part of the answer.  Here are some of interesting studies regarding Alzheimer's disease and magnesium. 

     

    Magnesium deficiency in rats leads to an oxidative stress involving an increased production of radical oxygen species...These data are in agreement with previous observations indicating that inflammation occurs during magnesium-deficiency and provide an additional cause of oxidative lesions through formation of peroxynitrite from nitric oxide and superoxide anion.

     

    http://www.ncbi.nlm.nih.gov/pubmed/8845288 

     

    CONCLUSIONS:

    Activation of PI3K/Akt signal pathway results in the reduction of cell apoptosis, which likely accounts for the protective effect of magnesium sulfate against intestinal ischemia-reperfusion injury.

     

    http://www.ncbi.nlm.nih.gov/pubmed/20819605 

     

    http://www.lef.org/news/LefDailyNews.htm?NewsID=19559&Section=DISEASE&utm_source=DailyHealthBulletin&utm_medium=email&utm_term=Disease&utm_content=Body+ContinueReading&utm_campaign=DHB_130629 

     

     

     

     


    Serenoa
    Posted: Wednesday, September 11, 2013 1:44 PM
    Joined: 4/24/2012
    Posts: 484


    And here's another article supporting the role of magnesium:

     

    Magnesium deficiency promotes a proatherogenic phenotype in cultured human endothelial cells via activation of NFkB 

     

    Here we report that endothelial cells cultured in low magnesium rapidly activate NFkB, an event which is prevented by exposure to the anti-oxidant trolox.

     

    http://peer.ccsd.cnrs.fr/peer-00623291/fr/ 

     

     

    Here is some good general info on magnesium:

     

    http://ods.od.nih.gov/factsheets/Magnesium-HealthProfessional/ 

     

     

    It seems that magnesium deficiency is very common in the developed world. Our diet is not providing enough of it. Now, what to do about it? Take supplaments? Eat organic foods high in Mg?

     


    Serenoa
    Posted: Wednesday, September 11, 2013 1:49 PM
    Joined: 4/24/2012
    Posts: 484


     Magnesium deficiency is connected to the APOE4 gene. It appears that ApoE deficient mice (mimics having the APOE4 gene) showed some benefits from Mg supplamentation.   

     

     

    Oral Magnesium Supplementation Induces Favorable Antiatherogenic Changes in ApoE-Deficient Mice

    Abstract

    Abstract—Epidemiological studies indicate that dietary magnesium influences atherogenesis. Magnesium inhibits plaque formation in animals receiving a high cholesterol diet, whereas the effect of magnesium in animals on low-fat diet has not been explored. Magnesium sulfate was given in the drinking water (50 mg/mL) to 7-week-old apolipoprotein E–deficient (apoE−/−) mice (n=30). Control animals (n=30) received tap water. At the age of 19 weeks, the extent of atherosclerosis and the density of macrophages were measured in the aortic root, and blood lipids were analyzed. The median plaque area was significantly smaller in magnesium-treated female apoE−/− mice and reached only 66% of control females (P<0.02). Plaque area was also less extensive in magnesium-treated male mice, although not statistically significant. Macrophage density was similar in both groups. Magnesium significantly reduced cholesterol (P<0.05) and triglyceride (P<0.01) levels, whereas high density lipoprotein cholesterol remained stable. No significant differences in body and heart weight were seen between treatment groups for either sex. In conclusion, in apoE−/− mice receiving a low-fat diet, magnesium supplementation significantly inhibited atherogenesis in females but not males. Plaque composition remained unchanged in terms of macrophage density. This was obtained in association with significantly reduced levels of cholesterol and triglycerides.

     

    http://atvb.ahajournals.org/content/21/5/858.short 

     

     


    Vita99
    Posted: Wednesday, September 11, 2013 2:10 PM
    Joined: 9/4/2012
    Posts: 469


    I was just browsing as I missed my early AM read of this board today.  I really got excited when I saw  "magnesium" in big bold letters at the top of one of the last posts.  I am still in the process of catching up on the reading but   I just had to share this bit of info.

     
     I have been on magnesium supplements in pill form for about 2 years, mostly because I thought I needed it for insulin resistance.   Very recently I switched to the powder that you mix with liquid.  Well, I didnt like it, it doesnt taste good but I was going to use up the bottle I bought.  Well, after the first use I noticed a tremendous improvement in sleep quality.   Please note that I have no sleep issues, no trouble falling asleep.  However, I am able to sleep very deeply if I take about only 1/4 of the recommended dose of 2 rounded teaspoons.  It does not matter what time of day I drink this drink, I get the benefit of extremely deep sleep.  Spouse reports similiar effect.  I gave the drink to my mom, but she takes sleeping pills so did did not notice anything.  Seems that there is a big difference in the absorption of the powder form of magnesium citrate vs the pill or tablet.

    Serenoa
    Posted: Wednesday, September 11, 2013 3:00 PM
    Joined: 4/24/2012
    Posts: 484


    Very interesting Vita99. Can you give us the name or the chemical composition of the form you are taking? I have read that water-soluble form are absorbed better, and that many supplaments don't necsesarily get Mg into the brain very well.
    Serenoa
    Posted: Wednesday, September 11, 2013 3:36 PM
    Joined: 4/24/2012
    Posts: 484


    So far we have found and posted considerable supporting evidence for the excitotoxicity hypothesis. We have connected it to amyloid beta, peroxynitrites, APOE4, and Mg deficiency. Let's keep going. Can we connect it to toxic copper build up, tau phosphorylation, vascular damage, benefits of exercise, etc.? 

     

     

    I found several articles connecting the benefits of exercise to the NMDA receptor, but I can't decipher if it supports our hypothesis or not. It seems to provide benefits by activating the NMDA receptor, which is curious. Can anyone figure this connection out?  

     

     

     

     

    Effects of exercise on NMDA receptor subunit contributions to bidirectional synaptic plasticity in the mouse dentate gyrus 

     

     

    http://onlinelibrary.wiley.com/doi/10.1002/hipo.20349/abstract 

     

     

     

    Exercise affects glutamate receptors in postsynaptic densities from cortical mice brain

    http://www.sciencedirect.com/science/article/pii/S0006899305013648 

     


    Lane Simonian
    Posted: Wednesday, September 11, 2013 7:02 PM
    Joined: 12/12/2011
    Posts: 5001


    Thank you both Serenoa and Vita for the useful information and insights.  I thought it was just the extent of calcium influx that determined whether NMDA receptor activation promoted cellular survival or death, but you are right Serenoa the location of the receptors being activated is also important. 

      

    The ability of Ca2+ influx through the N-methyl D-aspartate subclass of glutamate receptor(NMDA receptor) to both kill neurons and to promote survival under different circumstances is well established. Here we discuss the signal pathways that mediate this dichotomous signalling, and the factors that influence whether an NMDA receptor-dependent Ca2+ signal results in a net pro-survival or pro-death effect. The magnitude of NMDA receptor activation, be it intensity or duration, is of course very important in determining the nature of the response to an episode of NMDA receptor activity, with excitotoxic death pathways requiring higher levels than survival pathways.However, the NMDA receptor is not merely a conduit for Ca2+ influx: the consequences of NMDA receptor activity can be influenced by signalling molecules that physically associate with the NMDA receptor or indeed the location (synaptic versus extrasynaptic) of the receptor. Furthermore, we discuss the possibility that the Ca2+ effectors of survival and death are in different subcellular locations, and thus depend on the spatial characteristics of the Ca2+ transient. A greater understanding of these issues may point to ways of selectively blocking pro-death signalling in neurological disorders such as stroke, where global NMDA receptor antagonists have proved ineffective. 

     

     

     

    The PI3K (phosphoinositide-3-kinase)–Akt kinase cascade is a key signalling pathway responsible for the pro-survival effects of NMDAR activity.

      

    http://jp.physoc.org/content/584/2/381.full.pdf  

     

     

     

    Namenda/memantine appears to inhibt the right kind of NMDA receptors (extrasynaptic) but not particularly effectively. 

      

    http://beaker.sanfordburnham.org/2013/06/reversing-the-loss-of-brain-connections-in-alzheimers-disease/ 

     

    I like eugenol in the essential oils because by scavenging peroxynitrites it inhibits the activation of the bad NMDA receptors without having much effect on the positive ones.  Now if you add effective magnesium supplements (except for those with kidney problems) into the equation perhaps all to the better. 

      

    http://www.ncbi.nlm.nih.gov/pubmed/9147382 

     

    http://www.unboundmedicine.com/medline/citation/16428020/Eugenol_depresses_synaptic_transmission_but_does_not_prevent_the_induction_of_long_term_potentiation_in_the_CA1_region_of_rat_hippocampal_slices_

     

    http://www.sciencedaily.com/releases/2010/02/100222162011.htm 

     

     

     


    Vita99
    Posted: Friday, September 13, 2013 5:26 AM
    Joined: 9/4/2012
    Posts: 469


    Serenoa, regarding the magnesium.  I guess we are allowed to mention brand names on this board.  I am using Vitacost Natural Tranquility 350 per serving of 2 rounded teaspoons.  Ingredients are magnesium, magnesium carbonate and citric acid.   According to the label I am getting about 80 mg of magnesium per day and feeling more energetic and sleeping very deeply.  When I was taking a capsule it was 160mg and no noticeable effect.  I am thinking about also trying the liquid magnesium supplement after I finish this jar,  for even better absorption.   
    Lane Simonian
    Posted: Saturday, September 14, 2013 10:58 AM
    Joined: 12/12/2011
    Posts: 5001


    Thanks Vita for the information on magnesium supplements.  This article contains quite a bit of useful information on natural products that might be useful in the treatment of neurodegenerative diseases.  It has a short section on magnesium. 

     

    One of the vital functions for CNS magnesium is modulation of the NMDA glutamate receptor. Low levels of magnesium significantly enhance excitotoxic sensitivity and may be one of the mechanisms by which magnesium depletion precipitates seizures in otherwise healthy individuals. [216] Furthermore, magnesium deficiency has been demonstrated in neurodegenerative disorders, such as AD, where it was correlated with cognitive scores. Patients with lowest magnesium levels had the lowest Global Deterioration Scale scores and Clinical Dementia Ratings. [52] A review of studies found that magnesium may be useful in improving cognitive function and other symptoms in AD patients. [179]
     

    http://www.surgicalneurologyint.com/article.asp?issn=2152-7806;year=2012;volume=3;issue=1;spage=19;epage=19;aulast=Blaylock
     


    Lane Simonian
    Posted: Saturday, September 14, 2013 11:11 AM
    Joined: 12/12/2011
    Posts: 5001


    Ferulic acid in lemon balm essential oil, heat-processed ginseng, and coconut oil is another peroxynitrite scavenger and inhibitor of the NMDA receptor. 

     

    The results suggest that ferulic acid is a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist and neuroprotector.

     

    http://www.ncbi.nlm.nih.gov/pubmed/16257184 

     

    http://online.liebertpub.com/doi/abs/10.1089/jmf.2013.1602.com?journalCode=jmf 

     

    http://www.ncbi.nlm.nih.gov/pubmed/23075678 

     

    http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0055774 

     

    http://www.ncbi.nlm.nih.gov/pubmed/23493505 

     

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

     

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

     

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1738567/