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Inflammation is the new amyloid
Lane Simonian
Posted: Tuesday, April 30, 2019 10:08 AM
Joined: 12/12/2011
Posts: 4550


With one anti-amyloid drug trial failing after another, researchers are casting around for another explanation for Alzheimer's disease.  One of the new favorites is inflammation.

In some ways this is a positive shift--from one specific cause of the disease to multiple causes that lead to the same outcome (in this case inflammation).  The following quote captures this change:

Dr. Carrasco and his team think a clinical trial of anti-fungal drugs is the next logical step. But there is yet another possibility. In the absence of a definitive ultimate cause, it may be that the symptoms of Alzheimer's disease can arise from many different types of insult to the brain. There have been several papers, says Dr. Le Guillou, that have found correlations between various infectious organisms and Alzheimer's. "It could be 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." If Alzheimer's is a general response to all sorts of neurological triggers, then it may be that the fungal infections found by Dr. Carrasco are simply one of a long list of causes.

Inflammation is a problem in Alzheimer's disease.  Activated microglia (the brain's immune cells) produce peroxynitrite (and hydrogen peroxide early in the disease) which through nitration and oxidation reduce the synthesis and release of neurotransmitters needed for the retrieval of short-term memory, sleep, balanced mood, social recognition and alertness.  Via damage to mitochondria, DNA damage, and energy depletion, peroxynitrite sets forth of chain of reactions that leads to the death of neurons.

However, formation of peroxynitrite can occur without infammation and some inflammation occurs due to the formation of peroxynitrite.  The latter explains why most non-steriodal anti-inflammatory drugs do not help someone with Alzheimer's disease.  

Without the production of oxidants, activated micorglia don't harm the brain:

These results suggest a dual-key mechanism, whereby glial iNOS [inducible nitric oxide] or microglial NOX activation [NADPH oxidase/superoxide anions] alone is relatively benign, but if activated simultaneously are synergistic in killing neurons, through generating peroxynitrite. This mechanism may mediate inflammatory neurodegeneration in response to cytokines, bacteria, ATP, arachidonate and pathological prions, in which case neurons may be protected by iNOS or NOX inhibitors, or scavengers of NO, superoxide or peroxynitrite.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1232863/

Herein lies the key to treating Alzheimer's disease: reduce, scavenge, and partially reverse the damage done by peroxynitrite.  It is not accident that the substances which have done this are the only ones that have slowed down and partially reversed some aspects of Alzheimer's disease:

The neuroprotection by THC and CBD was because of attenuation of peroxynitrite.

To ascertain the principal active peroxynitrite (ONOO(-)) scavenging components of heat-processed Panax ginseng C.A. Meyer (sun ginseng [SG]), the ONOO(-) scavenging activities of fractions and components of SG were compared. The results demonstrated that the ONOO(-) scavenging ability of SG was due to its ether fraction containing phenolic compounds. High-performance liquid chromatography analysis and ONOO(-) scavenging activity tests of the phenolic acids contained in SG identified vanillic acid, ferulic acid, p-coumaric acid, syringic acid, and maltol as the main active ONOO(-) scavenging components of SG. The ONOO(-) scavenging activities of phenolic acids and maltol were dependent on the degrees of their proton donating ability.

The essential oils obtained from fifteen relevant and commonly used plants belonging to Cruciferae, Lamiaceae, Lauraceae, Apiaceae, and Zingiberaceae were screened using an in vitro model of peroxynitrite-induced tyrosine nitration. Almost complete inhibition of 3-nitrotyrosine formation (91% at 300 microg/ml) was achieved only with the essential oil obtained from the leaves of Laurus nobilis. 1,8-Cineol, accounting for a 50% of this essential oil, which resulted as inactive in this model, thus evidencing a major role for the minor volatile compounds present in the leaves.

So we are getting closer, but not close enough yet.



Lane Simonian
Posted: Tuesday, May 28, 2019 11:10 PM
Joined: 12/12/2011
Posts: 4550


I over complicated this.  Peroxynitrite leads to caspase-3 activation.  Without caspase-3 activation there is no amyloid and there is no neuroinflammation.  But over time caspase-3 activation leads to the down-regulation and death of microglia which are the brain's main immune cells.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958192/




OrganizerBecky
Posted: Wednesday, June 5, 2019 2:14 PM
Joined: 10/31/2017
Posts: 20


University of Kansas Medical Center is doing a Phase II study for a therapy to prevent brain cell death and inflammation in Alz patients. It's called AMX0035 - combination of two compounds: Sodium Phenylbutyrate (PB) and Tauroursodeoxycholic Acid (TUDCA). Paid for by Amylyx Pharmaceuticals with the support of the Alzheimer's Association and the Alzheimer's Drug Discovery Foundation .
Lane Simonian
Posted: Wednesday, June 5, 2019 4:07 PM
Joined: 12/12/2011
Posts: 4550


This looks like a potentially promising treatment.  Thanks for posting and keep us informed of any future results if possible.
dolor
Posted: Thursday, June 6, 2019 11:14 AM
Joined: 11/9/2017
Posts: 308


Lane,

Along the lines of inflammation, here is another possibility.

Try to overlook pfizer's sickening behavior.

https://www.washingtonpost.com/business/economy/pfizer-had-clues-its-blockbuster-drug-could-prevent-alzheimers-why-didnt-it-tell-the-world/2019/06/04/9092e08a-7a61-11e9-8bb7-0fc796cf2ec0_story.html?noredirectn&utm_source=pocket-newtab&utm_term=.dc328c847039


Lane Simonian
Posted: Thursday, June 6, 2019 3:38 PM
Joined: 12/12/2011
Posts: 4550


Thanks, Dolor.  I am still fuming about Pfizer's hiding of important data, but some of the larger picture is beginning to sink in for me.

First, if Enbrel does reduce the risk of Alzheimer's disease and it does not cross the blood-brain barrier than reducing inflammation and oxidation elsewhere in the body must have a beneficial effect on the brain.  Maybe this is further evidence of how damage to the gut can lead to damage to the brain.

Secondly, the results give further credence to this pathway as the critical one for Alzheimer's disease (Enbrel is a tumor necrosis alpha inhibitor):

The data indicate that TNF-induced PKC activation mediates ONOO- generation, which results in the oxidation and depletion of glutathione... (and protein kinase C activates tumor necrosis factor alpha).

Directly and indirectly peroxynitrite damages receptors, enzymes, and transport systems needed for the retrieval of short-term memory, quality sleep, stable mood, social recognition, and alertness, prevents the regeneration of synapses and neurons in the hippocampus, inhibit blood flow and the transport of glucose in the brain (which can lead to delusions), depletes antioxidants such as glutathione, causes DNA damage, produces inflammation, and the death of neurons.  Tumor necrosis alpha inhibition should at least slow down the progression of the disease.  Scavenging of peroxynitrite with CBD oil, aromatherapy with certain essential oils, and panax ginseng should partially reverse the diseae (because it partially reverses oxidation and nitration). 



Lane Simonian
Posted: Thursday, June 6, 2019 11:34 PM
Joined: 12/12/2011
Posts: 4550


Adding a bit more to the picture:

Not only the inhibition of iNOS [inducible nitric oxide synthase] activity but also TNF-alpha (-/-) prevented the nitration of proteins in the hippocampus and the impairment of recognition memory in mice induced by Abeta(25-35)...These results suggested the practicability of targeting TNF-alpha as a preventive strategy against Abeta-mediated cognitive impairments.

Tumor necrosis factor leads to the production of inducible nitric oxide and superoxide anions which combine to form peroxynitrite.

Thus, iNOS seems to be a major instigator of beta-amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

These results demonstrated that the memory protective effects of RA [rosmarinic acid] in the neurotoxicity of Abeta(25-35) is due to its scavenging of ONOO(-) [peroxynitrite], and that daily consumption of RA [rosmarinic acid] may protect against memory impairments observed in AD.

Now the basic problem with mice is that only amyloid (and perhaps stress) is causing nitro-oxidative damage and inflammation in their brains.  Whereas in human beings, multiple factors are leading to this detrimental outcome.  So things that work for mice almost never work so well in human beings.  But inhibition of tumor necrosis alpha and inducible nitric oxide synthase are two of the more important pressure points for limiting the progression of Alzheimer's disease and when combined with compounds that scavenge and reverse the damage done by peroxynitrite you have a shot at successfully treating Alzheimer's disease (and some plant compounds have the potential to do all three).


amanda424
Posted: Wednesday, June 26, 2019 8:08 PM
Joined: 6/22/2019
Posts: 9


If you were predisposed to this disease, is there anything you would take now?
Larrytherunner
Posted: Thursday, June 27, 2019 8:50 AM
Joined: 2/26/2016
Posts: 172


Amanda, I would say "stay tuned". This coming October, there is expected to be a report at the halfway point for the montelukast (Singulair) clinical trial for mild cognitive impairment (MCI) and early stage Alzheimer's. Montelukast has been available for over 20 years as a treatment for the prevention of asthma attacks and is cheap and very safe for adults. I have been taking it for three years after being diagnosed with age related dementia, and I am back to normal. It works for me.
Lane Simonian
Posted: Friday, June 28, 2019 3:18 PM
Joined: 12/12/2011
Posts: 4550


Amanda, probably the main way to at least delay the onset of Alzheimer's disease is a diet high in polyphenols such as fruits, vegetables, spices, and herbal teas.  Some herbal supplements such as panax ginseng and ashwagandha may potentially help.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705783/


Donr
Posted: Thursday, July 4, 2019 1:41 PM
Joined: 4/6/2014
Posts: 333


https://www.washingtonpost.com/business/economy/alzheimers-research-is-getting-a-reboot-at-small-companies-focused-on-the-immune-system/2019/07/03/974d8854-91e9-11e9-b58a-a6a9afaa0e3e_story.html?utm_term=.db44b6f0b77e

Sorry  for not posting link in click form. It is a Washington Post story, reboot of researching ALZ by small companies and the immune system.


Lane Simonian
Posted: Thursday, July 4, 2019 6:10 PM
Joined: 12/12/2011
Posts: 4550


This was a very interesting article, Don.  Thank you for posting it.  I will repost my response to the article.  A number of the comments were good.

The problem in Alzheimer's disease is not so much inflammation as it is the oxidation and nitration of critical transport systems, enzymes, and receptors in the brain (including those which affect the retrieval of short-term memory, sleep, mood, social recognition, and alertness).  Oxidative and nitrostative stress initially ramp up inflammation in Alzheimer's disease (leading to more oxidation and nitration) before they damage immune cells.  Thus paradoxically, you have researchers arguing the need to use anti-inflammatory medications and others arguing you need to increase immune responses.  

Medications that reduce inflammation prior to oxidation and nitration (tumor necrosis factor-alpha blockers, for instance) may have a role to play in the treatment of Alzheimer's disease but those which act primarily after oxidation and nitration apparently do not (non-steroidal anti-inflammatory drugs).  A perfect example of this is minocycline.

"Minocycline inhibits neurogenic inflammation by blocking the effects of tumor necrosis factor-α."

"Neuroprotection by Minocycline Caused by Direct and Specific Scavenging of Peroxynitrite"

Several compounds scavenge peroxynitrite and partially reverse oxidation and nitration in the brain.  These include panax ginseng and aromatherapy with certain essential oils both of which have largely stabilized the disease in small-scale clinical trials.