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Findings of team led by ASU scientists offer hope for therapies targeting cell loss in the brain
Keep It 100
Posted: Thursday, August 10, 2017 10:48 AM
Joined: 2/26/2017
Posts: 105


 https://asunow.asu.edu/20170724-discoveries-asu-tgen-study-identifies-new-brain-death-pathway-alzheimers-disease

It is an interesting article, and a discovery like this could potentially lead to some targeted therapies to restore cell function.

Of particular note was this paragraph: Furthermore, they also demonstrated that necroptosis activation correlated with the protein tau. Intriguingly, necroptosis did not appear to be linked with the other chief physiological characteristic of Alzheimer’s pathology, beta-amyloid plaque.




Lane Simonian
Posted: Thursday, August 10, 2017 9:00 PM
Joined: 12/12/2011
Posts: 3997


The death pathway begins with activation of protein kinase C (see diagram in link).  Amyloid oligomers and many other factors cause cell death via the activation of protein kinase C.

Malinow’s team found that when mice are missing the PKC alpha gene, neurons functioned normally, even when amyloid beta was present. Then, when they restored PKC alpha, amyloid beta once again impaired neuronal function. In other words, amyloid beta doesn’t inhibit brain function unless PKC alpha is active.

http://www.frontiersin.org/files/Articles/131867/fncel-09-00091-HTML/image_m/fncel-09-00091-g003.jpg

 

Protein kinase C eventually becomes inactivated in Alzheimer's disease by nitrooxidative stress but before it does so it activates NMDA receptors.  NMDA receptor activation leads to nitro-oxidative stress (which results in a scarcity of neurotransmitters needed for the recovery of short-term memory, sleep, balanced mood, social recognition, and alertness, prevents the regeneration of neurons, prevents synpase regeneration, and decreases blood flow and glucose transport into the brain which can lead to delusions), DNA damage, inflammation, depletion of the brain's master antioxidant (glutathione), and to cell death (via caspase 3 activation).  


Many stimuli pull the necrotic trigger, an overview

In addition to oxidative stress, nitrosative stress (e.g. peroxynitrite--ONOO-) has recently been reported to trigger necrosis and HMGB1 release...Stimulation with glutamate- or N-methyl-d-aspartate (NMDA) increases intracellular calcium levels, thereby triggering necrotic cell death, known as excitotoxicity. Similar to oxidative stress-induced necrosis, this form of necrosis also relies on PARP1 and CypD. In addition, studies have shown that NMDA- and glutamate-induced necrosis are inhibited by Nec-1 treatment, indicating a role for RIPK1 kinase activity in excitotoxicity.

The key to treating Alzheimer's disease is to limit excitotoxicity initiated by NMDA receptor activation and scavenge peroxynitrite.  Unfortunately, the one drug that inhibits NMDA receptor activation is not particularly effective at doing so (Namenda/memantine).  Nor have the best peroxynitrite scavengers for the treatment of Alzheimer's disease been studied in the United States.

Two examples of compounds that scavenge peroxynitrite and limit excitotoxicity are eugenol in various essential oils via aromatherapy and ferulic acid in panax ginseng.

Eugenol protects neuronal cells from excitotoxic and oxidative injury in primary cortical cultures.

In Vitro Activity of the Essential Oil of Cinnamomum zeylanicum and Eugenol in Peroxynitrite-Induced Oxidative Processes

Effect of aromatherapy on patients with Alzheimer's disease.

All patients showed significant improvement in personal orientation related to cognitive function on both the GBSS-J and TDAS after therapy.

 

Potent protection of ferulic acid against excitotoxic effects of maternal intragastric administration of monosodium glutamate at a late stage of pregnancy on developing mouse fetal brain.

 

Evaluation of the peroxynitrite scavenging activity of heat-processed ginseng.

 

Heat-processed ginseng enhances the cognitive function in patients with moderately severe Alzheimer's disease.

These results demonstrate the potential efficacy of a heat-processed form of ginseng on cognitive function and behavioral symptoms in patients with moderately severe AD.


Ferulic acid like THC in marijuana has the additional advantage of improving behavior by reducing norepinephrine levels.


For those of you with contacts in the Alzheimer's research world please feel free to share this post.  


Lane Simonian
Posted: Friday, August 11, 2017 10:05 AM
Joined: 12/12/2011
Posts: 3997


Adding to the above post:

Pathophysiological Role of Peroxynitrite Induced DNA Damage in Human Diseases: A Special Focus on Poly(ADP-ribose) Polymerase (PARP)

Over-activation of PARP induced by peroxynitrite consumes NADand consequently ATP decreases, culminating in cell dysfunction, apoptosis or necrosis. This mechanism has been implicated in the pathogenesis of various diseases like diabetes, cardiovascular diseases and neurodegenerative diseases. In this review, we have discussed the cytotoxic effects (apoptosis and necrosis) of peroxynitrite in the etiology of the mentioned diseases, focusing on the role of PARP in DNA repair in presence of peroxynitrite.

Several studies have shown that NO and peroxynitrite either cause acute cell death (necrosis) or delayed cell death (apoptosis) in various cell types . Sustained low level exposure of NO or peroxynitrite cause apoptosis, whereas cell necrosis results from sudden exposure to high concentrations of peroxynitrite or NO. Therefore, necrosis induced by peroxynitrite has been suggested to play an important role in inflammation.

Neuropathological studies have revealed fragmentation of nuclear DNA (by use of in situ end-labelling, ISEL) in a much higher proportion of neurons, oligodendrocytes, astrocytes and microglia in the brains of patients with Alzheimer’s disease than in age-matched controls. This led to the interpretation that the loss of neurons is due to apoptosis, probably initiated by Abeta-protein or other inducers of oxidative stress.

The type of cell death in Alzheimer's disease is likely apoptosis (programmed cell death) and not the more rapid process of necrosis.  Whatever the case, the peroxynitrite-DNA fragmentation--PARP--ATP depletion--caspase 3 pathway is what likely leads to the death of neurons in Alzheimer's disease. 


Keep It 100
Posted: Friday, August 11, 2017 6:05 PM
Joined: 2/26/2017
Posts: 105


Lane, what exactly do your posts mean in response? I am curious. I am sure it is profound...but seriously, I would prefer discussion that is understood....Thank you!!
Lane Simonian
Posted: Friday, August 11, 2017 9:42 PM
Joined: 12/12/2011
Posts: 3997


I might not understand the question, but if the question is what was I trying to show: the answer is to further identify the pathway that leads to apoptosis (or necroptosis) in Alzheimer's disease.  The one part of my response that directly ties back to the article is the following:

Many stimuli pull the necrotic trigger, an overview

In addition to oxidative stress, nitrosative stress (e.g. peroxynitrite--ONOO-) has recently been reported to trigger necrosis and HMGB1 release...Stimulation with glutamate- or N-methyl-d-aspartate (NMDA) increases intracellular calcium levels, thereby triggering necrotic cell death, known as excitotoxicity. Similar to oxidative stress-induced necrosis, this form of necrosis also relies on PARP1 and CypD. In addition, studies have shown that NMDA- and glutamate-induced necrosis are inhibited by Nec-1 treatment, indicating a role for RIPK1 kinase activity in excitotoxicity.


To boil it down to two main points it is this: many factors contribute to cell death in Alzheimer's disease.  Amyloid oligomers are only one of them.  To remove amyloid oligomers only deals with one source of the problem even in early onset cases.

Secondly: the pathway to cell death involves NMDA receptor activation that leads to the formation of peroxynitrite, ATP depletion (depletion of cellular energy), and caspase-3 activation (which leads to mitochondrial failure).  Thus particularly good peroxynitrite scavengers such as eugenol in essential oils via aromatherapy and ferulic acid in panax ginseng have not only stopped the progression of Alzheimer's disease but have partially reversed it in small-scale clinical trials.

"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."

If a scientist understands the pathway that leads to synaptic dysfunction, tau hyperphosphorylation, reduction in neurotransmitter levels, the end to the regeneration of neurons, and neuronal cell death in Alzheimer's disease it opens the door open to much more effective treatments.   




Lane Simonian
Posted: Friday, August 11, 2017 10:02 PM
Joined: 12/12/2011
Posts: 3997


To be more philosophical, let me express some frustration.  Doubt is not necessarily a bad thing as long as one maintains a relatively open mind.  I like this definition of modern skeptics: they doubt want they don't want to believe and they believe what they don't want to doubt.  In the case of Alzheimer's disease, this means believing that the misfolding of amyloid and tau proteins are the cause of Alzheimer's disease.  It means doubting that the disease is caused by nitro-oxidative stress.  It particularly means doubting that natural products can be used to treat the disease.  It means doubting all evidence to the contrary. One of the easiest ways to do this is cite systematic reviews. Nearly every systematic review ends with the word inconclusive and the call for larger-scale clinical trials. Inconclusive does not as many skeptics seem to imply conclusively against.  It just means small trials have to be replicated and better constructed on a larger scale.

Another frequent criticism is that mechanism does not prove results.  But if every factor that leads to Alzheimer's disease leads to the formation of peroxynitrite, if everything that reduces the formation of peroxynitrite reduces the risk of Alzheimer's disease, if peroxynitrite directly or indirectly is responsible for every feature of Alzheimer's disease, and certain strong peroxynitrite scavengers have led to some improvements in memory that were sustained, then mechanism comes very close to proving results.

I don't believe in either the term false hope or alternative medicine.  There is medicine that works and medicine that does not work based in part upon the correct understanding of a disease.  It does not matter to me if that comes in the form of a synthetic pill or a natural product.  There is no true hope or false hope either.  There are treatments that are likely to help and treatments that are unlikely to help.  It just takes time and more importantly the ability to change course to determine what works and what doesn't.


Lane Simonian
Posted: Saturday, August 12, 2017 10:00 AM
Joined: 12/12/2011
Posts: 3997


Regarding the science:


 2017 Jun 24. pii: S0361-9230(17)30274-5. doi: 10.1016/j.brainresbull.2017.05.008. [Epub ahead of print]

Cellular mechanisms of peroxynitrite-induced neuronal death.

Abstract

Peroxynitrite (ONOO-) is a strong biological oxidant formed by the diffusion-limited reaction of nitric oxide (NO-) and superoxide anion (O2-). It has long been theorized that peroxynitrite generation could be the cause in a number of pathological conditions ranging from atherosclerosis to inflammatory, autoimmune, heart and neurodegenerative diseases. Its relatively long biological half-life and high reactivity allows peroxynitrite to oxidize a number of different targets in the cell. In physiologically relevant conditions peroxynitrite can directly react with thiols, or the radical products of peroxynitrite decomposition may indirectly oxidize other cellular components such as lipids, proteins and DNA. Downstream, oxidative modifications caused by peroxynitrite trigger cell death by a variety of mechanisms depending on the concentration of the oxidant. Peroxynitrite stimulates necrosis, apoptosis, autophagy, parthanatos and necroptosis. Here we review the mechanisms activated by peroxynitrite to cause neuronal death.


Regarding the philosophy:


[Clinical trials with over-the-counter supplements have concentrated either on items which suppress inflammation, or on antioxidants which scavenge oxygen derived free radicals. Most of these items have proved to be worthless in the treatment of Alzheimer's disease. Similarly most drugs used to treat Alzheimer's disease do little to slow deterioration, but instead offer a mild temporary symptom relief.  However, evidence has been accumulation that the primary driver of Alzheimer's disease is a nitrogen derived free radical called peroxynitrite, which may mediate both amyloid and tau accumulation as well as their toxicity.  Excellent results have been obtained with peroxynitrite scavengers, with reversals of Alzheimer's disease in human clinical trials being repeatedly demonstrated.  IMHO, the only thing which may be preventing the abolition of Alzheimer's disease is the mental inertia of scientists, as well as bureaucrats who fund them.  Unfortunately, most bureaucrats keep throwing money into repeatedly testing discredited interventions, while ignoring successful ones.  Common sense in anything but...]

 



 
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