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A different view of inflammation in Alzheimer's disease
Lane Simonian
Posted: Sunday, March 5, 2017 10:31 PM
Joined: 12/12/2011
Posts: 3996


Microglia (the brain's main immune cells) are likely over-activated during the early stages of Alzheimer's disease leading to inflammation but damaged as the disease progresses:

New research suggests that Alzheimer’s disease (AD) could be caused by the degeneration of microglia, the cells in the central nervous system that normally protect neurons...

This new hypothesis challenges the theory that AD is the result of amyloid protein deposits in the brain that trigger an inflammatory reaction. According to this theory, the inflammatory response activates microglial cells to produce toxic substances that in turn cause neurons to degenerate. This inflammation theory has been implicated not only in AD but in other neurological diseases, including Parkinson's disease, amyotrophic lateral sclerosis (ALS), and Huntington's disease.

"If people are claiming that these activated microglia kill neurons by producing toxins of various kinds, then I should expect to see these activated microglia right next to the dying neurons," said lead author and microglia expert Wolfgang J. Streit, PhD, from the department of neuroscience at the McKnight Brain Institute at the University of Florida College of Medicine, in Gainesville.

"But when I looked in those regions, I couldn't find a single activated microglial cell," he told Medscape Neurology. "What I found instead were microglial cells that were breaking apart, fragmenting into many little pieces."

These observations might help explain why anti-inflammatory drugs do not seem to prevent or diminish dementia, he suggests. And if borne out, they could result in a reevaluation of current treatment approaches for AD.

Inflammation may play a role in Alzheimer's disease (activated microglia, for instance, add to oxidative stress), but its role may decline as the disease continues. Furthermore, the damage done to microglia by oxidative stress may prevent them from removing toxins from the brain. 


Larrytherunner
Posted: Sunday, March 12, 2017 1:31 PM
Joined: 2/26/2016
Posts: 52


Thanks Lane for this great find on microglia. I found the 2009 Medscape article about Dr Streit's research very informing, and based on the research by Dr Streit and also by Dr Ludwig Aigner and their teams, I can see the importance of microglia in the the progression of Alzheimer's and other dementias.

According to Wikipedia, microglia are resident macrophage cells, acting as the first and main form of active immune defense in the central nervous system (CNS). Microglia are widely distributed in the CNS and make up 10 to 15% of all cells found in the brain. Microglia are key cells in overall brain maintenance - constantly scavenging the CNS for plaques, damaged or unnecessary neurons and synapses, and infectious agents. Damage to the microglia would result in serious injury to the brain.

In Dr Streit's 2009 research on microglia, he and his colleagues obtained 19 specimens from the brain bank at the Institute for Clinical Neuroanatomy at the University of Frankfurt, Germany. The specimens represented a range of pathologies from no AD to severe AD. 

The hypothesis at the time was that amyloid deposits in the brain trigger an inflammatory reaction. According to this theory, the inflammatory response activates microglial cells to produce toxic substances that in turn cause neurons to degenerate. But when he looked in the areas next to destroyed neurons in the AD specimens, he couldn't find any activated microglial cells. What he found was microglial cells that had broken apart, fragmenting into many small pieces. Therefore he concluded that AD is linked to microglia degeneration. He didn't adequately explain the reason for the degeneration. He also stated that because that he could not find activated microglia, inflammation is not a major factor. I think he was wrong on that interpretation. The microglia could have become activated at an earlier stage, causing inflammation, and then become exhausted and fragmented at a later stage of AD.

He also stated that many studies had failed to show that anti-inflammatory drugs could have a positive affect in the treatment of AD. I believe he was referring to studies of Non-steroidal anti-inflammatory drugs (NSAIDs) during that time period. Numerous studies showed then that they did not work. However there are other classes of anti-inflammatory drugs that were not studied as AD treatments at the time of his research.
Moving on to Dr Ludwig Aigner's research in 2015, he and his team examined the brains of young and old rats treated with montelukast. One group of young rats was untreated. Another group had montelukast  added to its food for 6 weeks. One group of old rats was untreated. Another group of old rats also had montelukast added to their food for 6 weeks. Montelukast (Singulair) is a generic drug approved for the treatment of asthma. Within the brain, the drug blocks cysteinyl leukotrienes, inflammatory substances secreted by microglia, from entering nearby brain cells.
 
The brains of the young rats not treated showed no signs of inflammation or microglia activation. The brains of the old rats not treated showed signs of inflammation, and in particular, microglia activation with soma enlargement (the soma is the bulbous part of the cell containing the nucleus). The brains of the old rats treated with montelukast had microglia with normal size soma and reduced inflammation.

My theory is that microglia can become activated causing chronic inflammation in the earlier stages of dementia and over the years the microglia can become exhausted and break up, leaving the brain unable to keep up with maintenance and defend itself from outside agents. Montelukast appeared to reverse the activation.

So why in Dr Aigner's research did the activated microglia in the old rats not break up. My theory on this is that rats have a short life span compared to humans. Therefore they will never live long enough for the microglia to break up after chronic activation.
(continued in next reply)

Larrytherunner
Posted: Sunday, March 12, 2017 1:54 PM
Joined: 2/26/2016
Posts: 52


(continued from previous reply) From these two research projects, there is evidence that cysteinyl leukotriene blockers, such as montelukast, could prevent chronic microglia activation in earlier stages of AD and dementia and thus prevent the break up of microglia in the later stages.

There is plenty of evidence that montelukast would be effective. But it is only if Intelgenx Pharmaceuticals or some other company or organization can pay for a clinical trial that we can know for sure.

Note: Ludwig Aigner is no longer listed as the lead person in his 2015 research. His name has now dropped to the bottom on the research credits. Possibly, the reason could be a dispute with Paracelsus University over Dr Aigner's pending patents  for montelukast as treatments for Alzheimer's, dementia and Parkinson's. He now works for Intelgenx Pharmaceuticals. 

https://en.m.wikipedia.org/wiki/Microglia

 

Medscape article requires making up password and logging in. It's quick and free.

http://www.medscape.com/viewarticle/705409

http://www.nature.com/articles/ncomms9466

 


Lane Simonian
Posted: Sunday, March 12, 2017 6:09 PM
Joined: 12/12/2011
Posts: 3996


I think that you are right on target on this.  The question is which anti-inflammatory drugs are likely to be the most effective and how early in Alzheimer's disease do they need to be given.

Here are some good connections.  Peroxynitrite leads to the activation of caspase-3. Caspase-3 can contribute to microglia activation (and further oxidation) but also to the death of microglia.  

Regulation of caspase-3 processing by cIAP2 controls the switch between pro-inflammatory activation and cell death in microglia

My guess is that the switch is thrown somewhere along the line in Alzheimer's disease from micorglia activation and subsequent inflammation to the death of microglia.

And this may explain one of the reasons why montelukast can potentially help in the prevention and early treatment of Alzheimer's disease.

Montelukast inhibits caspase-3 activity and ameliorates oxidative damage in the spinal cord and urinary bladder of rats with spinal cord injury.

https://www.ncbi.nlm.nih.gov/pubmed/22986158

  




Lane Simonian
Posted: Sunday, March 12, 2017 8:56 PM
Joined: 12/12/2011
Posts: 3996


This is a bit more precise explanation for micorglia activation and microglia death in Alzheimer's disease.  G protein-coupled receptors activate the src kinase which through tyrosine phosphorylation leads to the activation of microglia.  

c-Src function is necessary and sufficient for triggering microglial cell activation.

 Peroxynitrite through tryosine nitration deactivates and along with caspase-3 kill microglia just as both kill neurons.  The following is for T cells but the same principal applies to microglia.

Peroxynitrite Inhibits T Lymphocyte Activation and Proliferation by Promoting Impairment of Tyrosine Phosphorylation and Peroxynitrite-Driven Apoptotic Death 

Montelukast by inhibiting a specific g protein-coupled receptor (cysteinyl leukotriene receptor 1) inhibits src activation (thus inhibiting initial neuroinflammation in Alzheimer's disease) and the formation of peroxynitrite and caspase-3 (preventing the eventual death of microglia in Alzheimer's disease).  


Larrytherunner
Posted: Tuesday, March 14, 2017 11:07 AM
Joined: 2/26/2016
Posts: 52


Lane, thanks for your scientific explaination regarding microglia and montelukast. I have to admit that I don't have the necessary knowledge of neurochemistry to understand it. But from my experience, montelukast works and I hope this information will reach the people with the influence to bring it to a clinical trial for Alzheimer's and dementia.
Lane Simonian
Posted: Tuesday, March 14, 2017 7:03 PM
Joined: 12/12/2011
Posts: 3996


I certainly agree, Larry.  At the very least, montelukast should help delay and slow down the progression of Alzheimer's disease in those with asthma and it may do more than that. Off patent drugs and/or natural products may be part of the answer to Alzheimer's disease, but no money is to be made by going in that direction, so no progress against the disease is made.
JazzyOne
Posted: Wednesday, March 15, 2017 9:52 AM
Joined: 11/28/2016
Posts: 128


Larry, have you had an opportunity to compare your response using various generic mfg of montelukast? If so, do you track your results based on mfg?

I've personally had the experience with generics from one mfg vs. another (in other meds) where there was a significant difference in performance, and I'd be interested to know your views.  Another unfortunate issue is that generic mfg can change their formulation without any apparent notification, so things can vary even using the same mfg.

Thank you for posting on your experience with montelukast.


Larrytherunner
Posted: Wednesday, March 15, 2017 1:03 PM
Joined: 2/26/2016
Posts: 52


Jazzy, thank you for replying. When I said that montelukast was now generic, I meant that the patent has expired and other companies can now make the drug. Usually the price goes down because of the competition. But you don't have to take the generic version. You can take the brand name version. I am actually taking Singulair, which is the brand name version of the drug developed by Merck, which is the original patent holder. In the country where I am living, I pay about $1.50 per 10 mg tablet and I take 2 a day, so it is not expensive to take the brand name. Singulair is a common drug and easy to find. Where I live, it does not require a prescription but in the US, a prescription is required.
 
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