Do not trade this blog as 4 billion years of evolution is against me and possibly even God laughs at it, He has a great sense of humor!
I have a sleepless night so……
The 3xTg (Tg for transgenic) murine model of Alzheimer’s disease uses the same gene, PSEN1 (actually, a trasngenic version of the mutation prevalent in familial AD) and two others are connected to amyloid plaque and Tau deposits. The same mutation was used in the experiments described in paper linked in this post: https://piotrpeterblog.com/2021/03/05/novel-etiology-of-alzheimers-linked-to-neuronal-loss-of-function-due-to-changes-in-cellular-transcription-mechanism-and-dna-chromatin-complex-avxl-sava-atha-biib/
Having made this connection let us turn to this slide from SavaDx presentation by Cassava Sciences $SAVA:
An explanation first, PTI-125 is an old moniker for ATH-1017 called now Simufilam. I have been touting in my blog that the 3xTg mouse model at about 4 month old develops mental disability, 2 months before first signs of Amyloid plaque appear. Here, at 4 months alpha7nAChR/FLNA linking apear to rise at 4 months in the model mice but not in the Wild Type mice. 8 months old WT mice do have elevated level of the complex but in the 3xTg mice it is even higher. In 8 months 3xTg mice one would expect Amyloid plaque to be present. Just to give insight into the timeline 4 months of mice life is about 35 in human terms, 8 months is 70 years, and 6 months is about 50. In the paper referred in the post I presented link to, the degenerating neurons set off a cascade of chemicals calling on the immune systen to removed them. Inflammation is then intrinsically linked to ever increasing degeneraton of neurons under conditions described in the experiment.
What the linkage of alpha7nAChR/FLNA mean in context of Alzheimer’s. Again a slide from $SAVA presentation:
- 3xTg Murine model of AD mimics familial Alzheimer’s
- By the same mechanism by 4 months of age mice develope mild inflammation leading to mental decline all due to increasing degeneration of neurons.
- The occurance of inflammation during this time is in line with the novel etilogy of the disease described in my previously published post (link above). Degeneration of neurons leads to inflammation.
- Simufilam addresses just one mechanism out of many affecting the brain under this new etiology: a misfolded protein FLNA.
- With age the brain is assaulted by inflammation but in 3xTg model it appears way sooner and is much greater in magnitude.
- In responce to prolonged inflammation Amyloid plaque is produced as the deep brain defence mechanism.
- Simufilam regulates the mechanism of Amyloid plaque production but does nothing to stop neurodegeneration as described in the novel ethiology paper. It acts downstream from neuronal degeneration and misfolded protein.
- Neuroinflammation is so essential to the destructive power of AD that simufilam can improve cognition but in very limited way.
- Simufilam can be used to rescue the Amyloid Plaque Theory of AD but for all the wrong reasons. It has to do more with inflammation than anything else!
- Simufilam beats drugs like Donanemab and Aducanumab which just remove the Amyloid plaque but do not address inflammation.
- Yet Simufilam is inferior to Blarcamesine ($AVXL), drug which might be affecting the degeneration of neurons and the inflammation source.
- The evidence supporting the last point can be seen in the latest communique from Anavex Life Sciences. See the link below for my recent post.
This sums up my train of thoughts on Cassava Sciences ($SAVA). The performance of Blarcamesine can be seen in my recent post, link : https://piotrpeterblog.com/2021/03/20/can-blarcamesine-rescue-those-above-mmse-20-with-alzheimers-avxl-blarcamesine/
Indeed, there has never been a better time to be an investor in Alzheimer’s drug, or in general CNS neurodevelopmental and neurodegenrative drugs, as with the advent of genetics and the stem cell field of research, the focus now statrs to be clearly on the root causes of those diseases, leading to therapetics targets with real good prospects of success.
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