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A different view of inflammation in Alzheimer's disease
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.
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.
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.
(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.
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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.
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.
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.
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.
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).
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.