Anavex Life Sciences Corp (AVXL)

[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