$AVXL Inflammation as Cause of Ultimate Destruction in Alzheimer, and ANAVEX 2-73 as Close as it Gets to Cure at The Source of AD.

I have a rather preordained idea what inflammation is all about, and this comes from the multiple descriptions of suspected etiologies and connections with chronic diseases for which there is great, mostly unmet, need.  Being a creature of habit and digging only to the depth of buzzwords I will quote Wikipedia on inflammation:

Inflammation (from Latin: inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants,[1] and is a protective response involving immune cells, blood vessels, and molecular mediators. The function of inflammation is to eliminate the initial cause of cell injury, clear out necrotic cells and tissues damaged from the original insult and the inflammatory process, and initiate tissue repair.

The take away here is that inflammation is a response to irritants or harmful stimuli as well as infection.  In itself it should be precursor of healing but might be connected to harm as in chronic inflammation.  In some sense it is a general immune reaction aimed at making it hard to survive (by creating toxic environment?) by foreign organisms but if not wound down quickly enough leads to destruction of tissues.  Circumstantial evidence is piling up at an alarming rate. See Reference 1.

To just review the neuroinflammation as the process of destruction one would look for trigger for the “toxic environment” cascading into the telltale of Alzheimer disease as it is defined right now and reasons for not wounding down its apparent toxicity.

Reference 1: 

A 3D human triculture system modeling neurodegeneration and neuroinflammation in Alzheimer’s disease

Joseph Park1,2,3,4,5, Isaac Wetzel1,2,3,4, Ian Marriott2,3, Didier Dréau2,3, Carla D’Avanzo5, Doo Yeon Kim 5*, Rudolph E. Tanzi 5* and Hansang Cho 1,2,3,4*

This paper describes devising model of Alzheimer disease including the inflammation process entailing destruction of the neurons by the CNS innate immune system.  The question of the trigger is not solved.  In previous models Aβ and Tau were alone the trigger in creating functional model of the disease.  These substances are toxic in themselves to mice brains and can bring about primary level effect by their toxicity alone.  For example in murine models plain injection of Aβ and Tau into brains sufficed to bring about Alzheimer like symptoms.  What the model does is to add inflammation by solicitation of astrocytes and microglia to the resultant outright destruction of neurons by them. In this respect the increased  complexity of the model lies in the addition of inflammation to it.

The process where inflammation is triggered by deposits of plaque and tau seems to be just a link in much longer cascade with yet unknown incipient physiological change in the brain of Alzheimer sufferers.

I just pulled from publication on ANAVEX 2-73 information on Tg2576 model performance ( male-female difference) and looked for description of the model on ALZFORUM website.  The model timeline indicates that changes in hippocampus and cognitive deficits predate in the model onset of detectable plaque and Tau deposits.  Some very basic process might be at play here, and it seems to be caused by the Swedish Mutation making mouse brain to produce plaque as the only known biomarker of Alzheimer. All up the stream effects, those creating deposits of plaque are unknown at this moment. Had this statement been false set of more efficacious therapeutic targets would have been selected long time ago.

The buzzword of “cellular stress” has been used by Dr Missling to describe the context in which one has to look at ANAVEX 2-73 and the evolutionary utility of SIGMAR1.  I am more prone to call it “an improved quality control” at the point of heightened protein synthesis at the site of endoplasmic reticulum where 50% of all protein are synthesized in cell.  The conditions to put the synthesis into higher gear might either be connected to embryonic state or innate immune response, or yet to increased plasticity of the brain which in lay terms is creating new neural connection hence more protein building material needed. The innate immune response can be inferred from reading of lists of certain reaction to infection by the innate immune system on its Wikipedia page. Could the ultimate trigger be genetic or epigenetic, slowly accumulated over time is not ascertained yet.

If the cascade resulting in Alzheimer disease, or rather syndrome (set of symptoms), starts with some problems with “cell stress” in basic processes like synthesis of protein (at the region exhibiting most plasticity in brain – hippocampus) (plasticity = synthesis of proteins?) and leads to Aβ and Tau deposits then straight into soliciting action of the innate immune system cells and triggering inflammatory response resulting in massive loss of  neurons at the later stages of the disease can be just stopped at the source of the cascade when dosed soon enough then shouldn’t we talk about cure?

Is the evidence mounting for a source of Alzheimer’s cure or is it not the case?  It seems that if given early enough ANAVEX 2-73 can stop or even reverse progress of the disease.  That much could be indicated from results of Phase 2a after 2 years.  The four patients who up to 2 years into trial consistently beat the disease progression can prove with time that this can be classified as such, yet for time being this is only a signal of efficacy, not statistically significant outcome. If one makes connection between this event and high initial MMSE score for those patients (just the onset of the disease) one can be inclined to believe that indeed ANAVEX 2-73 stops Alzheimer at the source before the plaque and Tau deposits formed sufficiently large to make the inflammation progress to wholesale destruction of neurons. Beyond that point there is no return.

I can’t write any more on this subject, kind of exhausted my thinking at this moment but I would gladly promote my Beer Fund.

 

 

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