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Putting the last few pieces together
Lane Simonian
Posted: Monday, May 23, 2016 7:24 PM
Joined: 12/12/2011
Posts: 4854


This was the article from years ago that lead me to use aromatherapy with rosemary essential oil for my mother (although it turns out that eugenol not rosmarinic acid is the key compound in rosemary essential oil for treating Alzheimer's disease).

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).

 

I never could figure out how Abeta(25-35) caused the formation of peroxynitrite until I found this article recently.


Enhanced G-protein activation by a mixture of Abeta(25-35), Abeta(1-40/42) and zinc.

 

Beta-amyloid peptides (Abetas) bind to several G-protein coupled receptor proteins and stimulate GTPase activity in neurons.

 

G protein-coupled receptors along with several other receptors leads to the activation of protein kinase C, NMDA receptors, and to the production of peroxynitrite (ON00-).

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

 

http://web.pkusz.edu.cn/ouyang/files/2013/04/Signaling-pathways.jpg


 And a critical recent finding:

"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."



If you have amyloid beta oligomers, but protein kinase C is not activated, a person does not get Alzheimer's disease because peroxynitrite does not form.  If one removes amyloid beta oligomers with some drug, a person still gets Alzheimer's disease because the environmental toxin, chronic bacterial or viral infection, gene, medication, poor diet, smoking, etc. that lead to the initial activation of protein kinase C is still activating the enzyme whether amyloid beta oligomers are present or not.  At the very best, removing amyloid oligomers will only slow down the disease early on, by slowing down the activation of protein kinase C.  On the other hand even with beta amyloid oligomers and protein kinase C activation, a person is not likely to get Alzheimer's disease if peroxynitrite is being scavenged in sufficient amounts.  

http://www.ncbi.nlm.nih.gov/pubmed/20152881

And if one has Alzheimer's disease, powerful peroxynitrite scavengers such as CBD oil, panax ginseng, and aromatherapy will partially reverse some forms of memory loss (name recall, object recognition, facial recognition, place memory, repetitive memory, for instance).


Lane Simonian
Posted: Monday, June 6, 2016 6:23 PM
Joined: 12/12/2011
Posts: 4854


Put together in a slightly different manner:

"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."

The data indicate that... PKC activation mediates ONOO- [peroxynitrite] generation, which results in the oxidation and depletion of glutathione...

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 [glutathione] levels plummet in the hippocampi of patients with Alzheimer’s as well as those with MCI.

A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Abeta(25-35).



Serenoa
Posted: Tuesday, June 7, 2016 10:05 AM
Joined: 4/24/2012
Posts: 484


I've been looking at the role of iron accumulation in the brain. Ran accross this in relation to PKC.

Ferroptosis, a newly characterized form of cell death in Parkinson's disease that is regulated by PKC

http://www.sciencedirect.com/science/article/pii/S096999611630105X


Lane Simonian
Posted: Tuesday, June 7, 2016 11:15 AM
Joined: 12/12/2011
Posts: 4854


Thanks, Serenoa.  This is a new form of cell death for me, so I will need to read more about it, but this is what I have found so far.

 

Ferroptosis: process and function

http://www.nature.com/cdd/journal/v23/n3/full/cdd2015158a.html

 

The recently described form of programmed cell death, ferroptosis can be induced by agents causing GSH depletion or the inhibition of GPX4 (glutathione peroxidase).

http://www.pubfacts.com/detail/25962350/Ferroptosis-is-Involved-in-Acetaminophen-Induced-Cell-Death

 

 

 


Lane Simonian
Posted: Tuesday, June 7, 2016 11:05 PM
Joined: 12/12/2011
Posts: 4854


Amyloid oligomers increase the production of hydrogen peroxide and peroxynitrite which leads to the intracellular release of copper, zinc, and iron.  Copper and zinc stimulate the enzyme superoxide dismutase which converts superoxide anions into hydrogen peroxide and when hydrogen peroxide reacts with ferrous iron (Fe2+) they produce dangerous free radicals.  But here is another key to the Alzheimer's disease, amyloid plaques by absorbing copper and zinc stop the production of hydrogen peroxide.


Hydrogen peroxide is generated during the very early stages of aggregation of the amyloid peptides implicated in Alzheimer disease and familial British dementia.

 

Mature amyloid fibrils derived from Abeta-(1-40) did not generate hydrogen peroxide. We conclude that hydrogen peroxide formation during the early stages of protein aggregation may be a common mechanism of cell death in these (and possibly other) neurodegenerative diseases.


Serenoa
Posted: Thursday, June 9, 2016 5:49 PM
Joined: 4/24/2012
Posts: 484


Lane, I have a new hypothesis that connects everything and is supported by the clinical research. So much evidence to post that I don't know where to begin. I will work on a summary for a new post.
Lane Simonian
Posted: Thursday, June 9, 2016 7:51 PM
Joined: 12/12/2011
Posts: 4854


I will be excited to read all your research and new hypothesis when you have a chance to post it, Serenoa.  Your insights are always invaluable.