Replies to post #334040 on Anavex Life Sciences Corp (AVXL)

[Amatuer17]

See the 2nd para - does not see good for S1R activators

They showed for the first time that preventing assembly of MAMs, either with gene therapy or a drug that blocked a key protein called the sigma-1 receptor (S1R), dramatically decreased beta secretase cleavage of palAPP in axons and lowered Abeta production.

Conversely, a drug that activated S1R triggered an increase in beta secretase cleavage of palAPP and increased production of amyloid beta in axons.

“Our results suggest that the sigma-1 receptor might be a viable therapeutic target for reducing Abeta production, specifically in axons,” says Tanzi.

[plexrec]

falconer--our board scientist--Alzheimer’s Mystery Solved: care to comment on what this recent finding is saying ???? re:2-73 Thanks !!

[nidan7500]

Thanks RedShoulder

By Massachusetts General Hospital on Oct 15, 2021

“Our results suggest that the sigma-1 receptor might be a viable therapeutic target for reducing Abeta production, specifically in axons,”

https://scitechdaily.com/alzheimers-mystery-solved-how-amyloid-beta-forms-in-brain-nerve-cells/amp/

Thanks Red shoulder. We keep score, not only of nominally positive/MOA supportive research comments, but we keep an eye open for contradictions.

IMO, at some point, well funded and precision research also continuously presents an opportunity to show/rattle any potential AVXL skeletons that might be found. AVXL MOA is out there for the scientific world to review and to use for target practice. BTW-Many, multiple such papers did in past point out the scientific flaws in the Amyloid Thesis (for example) and rightfully so.

So, everyone keep watch on the horizon for any signs of weakness or technical flaws in AVXL MOA thesis. Any such science contradictions must be analyzed and responded to. (belt and suspenders)

[Investor2014]

It is a tough biotechnical read to follow.

The paper does not state conclusions in a manner directly expressed in terms of what is best: agonising or antagonising the S1R.

However, having read though the whole thing (despite Tanzi being involved), increasing S1R expression using an S1R Agonist (PRE-084) is beneficial and significantly reducing S1R expression using an S1R Antagonist (NE-100) is bad. So it would appear this paper supports our plight to demonstrate that A2-73 is beneficial for treating AD.

S1R-agonist PRE-084 and S1R-antagonist NE-100 regulate MAM levels in FAD hNPCs
S1R function can be regulated using the S1R agonist PRE-084 (PRE) and antagonist NE-100 (NE) (Bernard-Marissal et al., 2015). Total IP3R3 levels were increased in the presence of 5.0 or 10.0 µM PRE and decreased following treatment with 5.0 or 10.0 µM in FAD hNPCs (Figure 2F). 10 µM PRE increased total IP3R3 levels by ~43% (1.43- ± 0.2-fold; p < 0.05, n = 3), whereas treatment with 10 µM NE decreased total-IP3R3 levels by ~20% (0.79- ± 0.08-fold; p < 0.05, n = 3) versus vehicle control (veh) cells (Figure 2G).
To confirm regulation of S1R-activity modulated MAM-associated IP3R3 levels, we isolated MAM, ER, mixed ER/mitochondria, and mitochondria fractions from FAD hNPCs following pretreatment with 10 µM PRE or NE. The fractions were probed with antibodies against IP3R3 and cytochrome C (cyto C) to determine the purity of MAMs and of mitochondria (mito), respectively (Figure 2H). MAM-IP3R3 levels were increased (3.73- ± 0.43-fold) following treatment with PRE and significantly reduced (~55%; 0.45- ± 0.13-fold) following treatment with NE compared to veh cells (Figures 2H and 2I). The significant effects of S1R-activation or -inactivation on MAM-IP3R3 levels as opposed to the more modest effects on total-IP3R3 suggest S1R preferentially modulates MAMs in FAD hNPCs