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Norepinephrine, zinc, amyloid, tau
Lane Simonian
Posted: Thursday, January 16, 2020 7:53 PM
Joined: 12/12/2011
Posts: 4854


Amyloid oligomers may be toxic to the brain in part because they bind zinc.  Zinc and norepinephrine activate g protein-coupled receptors that are often the first step to cognitive decline in Alzheimer's disease.  The following thus makes a certain amount of sense:

The study details a cascade of events. Buildup of beta-amyloid activates a receptor that responds to a brain chemical called norepinephrine, which is commonly known for mobilizing the brain and body for action. Activation of this receptor by both beta-amyloid and norepinephrine boosts the activity of an enzyme that activates tau and increases the vulnerability of brain cells to it, according to the study, published in Science Translational Medicine.

Beta-amyloid itself can kill neurons but only in very high doses, Wang says. Add norepinephrine, and it takes only 1 to 2 percent as much beta-amyloid to eliminate brain cells in a lab dish. So with treatments that targeted beta-amyloid but left the norepinephrine pathway intact, there was enough beta-amyloid remaining to do significant damage, she says.

https://www.scientificamerican.com/article/possible-missing-link-in-alzheimers-pathology-identified/

Beta-amyloid itself is rarely enough by itself to kill brain cells.  Some other primary trigger needs to be present and often these triggers work through g protein-coupled receptors.  The trigger may be norepinephrine (often due to stress) or it could be various air pollutants, or it could be pesticides and herbicides, or it could be chronic viral or bacterial infections.  This helps explain why targeting amyloid itself or targeting specific g protein-coupled receptors have failed in the treatment of Alzheimer's disease.

On the other hand, high levels of norepinephrine are closely correlated to psychological and behavioral problems in Alzheimer's disease so targeting these receptors might make sense at least during the early stages of Alzheimer's disease.

https://neuro.psychiatryonline.org/doi/full/10.1176/jnp.16.3.261






Lane Simonian
Posted: Friday, January 17, 2020 9:02 AM
Joined: 12/12/2011
Posts: 4854


This is a better account of the study:

Pathogenic Alzheimer's disease cascade is activated by faulty norepinephrine signaling

"Our study provides translational insights into mechanisms underlying  protein toxicity, which may have strong implications for future drug design," said Qin Wang, M.D., Ph.D. "It identifies an amyloid-beta/G protein-coupled receptor interaction that represents an attractive, disease-specific therapeutic target for Alzheimer's disease."

Interestingly, the pathologic mechanism found may also explain the failure of numerous Alzheimer's clinical trials that targeted reduction of the culprit in Alzheimer's disease—amyloid protein buildup in the brain.

It is widely accepted, Wang says, that buildup of amyloid-beta oligomers in the brain acts as a trigger to induce pathological changes in tau protein, and that altered tau protein is the bullet that targets and kills neurons in Alzheimer's disease. However, the pathway connecting these two was unknown.

Wang and colleagues have found that amyloid-beta oligomers hijack norepinephrine signaling at brain neurons, which falsely redirects this signal to activate a kinase called GSK3-beta. That activated kinase enzyme, in turn, hyper-phosphorylates tau protein, making it toxic for neurons.

This rewiring of the norepinephrine signaling takes place at a  on the surface of neurons called the alpha-2A . This receptor is part of a large family of G protein-coupled receptors that detect molecules outside of a cell and then activate an internal signal that causes a cellular response. While a certain concentration of amyloid-beta oligomers can activate GSK3-beta, the presence of norepinephrine vastly sensitized that activation by up to two orders of magnitude, Wang and colleagues found. 

Thus, the UAB researchers speculate that nanomolar concentrations of amyloid-beta oligomers in human brains induce a pathogenic GSK3-beta/tau cascade at the earliest stages of Alzheimer's disease. This theory suggests why multiple clinical trials to reduce levels of amyloid-beta oligomers in Alzheimer's disease patients have failed—they cannot reduce the amyloid levels to such low concentrations.

https://medicalxpress.com/news/2020-01-pathogenic-alzheimer-disease-cascade-faulty.html

Now for the problems.  Alpha 2A adrenergic receptors are one of many different kinds of g protein-coupled receptors that can lead to the hyperphosphorylation of tau and to Alzheimer's disease.  Blocking amyloid betas binding to these receptors is at best likely to only slightly slow down the progression of Alzheimer's disease.  Second any overactivation of g protein-coupled receptors can lead to the hyperphosphorylation of tau.  Third, hyperphosphorylated tau is not the primary reason for the death of neurons in Alzheimer's disease, peroxynitrite are.  So efforts to reduce their levels in the brain are not likely to work any better than removing amyloid oligomers.

The activation of g protein-coupled receptors via protein kinase C activation leading to peroxynitrite formation is one of the most important pathways that leads to the onset and progression of Alzheimer's disease.  Inhibiting the formation of peroxynitrite, scavenging peroxynitrite, and reversing some of the oxidative and nitrostative damage that is does to the brain is the key to treating Alzheimer's disease as a variety of clinical trials using various herbs (or in one case a compound derived from brown seaweed) has shown.


Lane Simonian
Posted: Friday, January 17, 2020 9:49 AM
Joined: 12/12/2011
Posts: 4854


This caught my attention:

While a certain concentration of amyloid-beta oligomers can activate GSK3-beta [which leads to the hyperphosphorylation of tau], the presence of norepinephrine vastly sensitized that activation by up to two orders of magnitude, Wang and colleagues found. 

The primary trigger (norepinephrine) does more damage than the secondary trigger (amyloid oligomers) and that is likely true of every other primary trigger for Alzheimer's disease (of which there may be 40 or more).  Amyloid oligomers are likely an add on insult.  The problem is not that just a little bit of amyloid can cause damage therefore you have to remove all of the amyloid, the problem is that many other factors besides amyloid do much greater damage to the brain.


HowDoYouDeal
Posted: Sunday, January 19, 2020 9:59 AM
Joined: 2/17/2019
Posts: 347


Lane you never fail to amaze.