This manuscript adds to the growing list of reports that gamma-secretase activating protein (GSAP) is unlikely to play a role as a genetic modifier of gamma-secretase. In this report, the authors have demonstrated that GSAP down-regulation not only reduces Abeta but also full-length APP protein. The data presented are convincing and suggest that the reviously reported inhibition of Abeta generation is not due to an effect of GSAP on gamma-secretase activity but rather due to APP down-regulation. However, there is one major concern with respect to the present study: The authors did not prove that GSAP is in fact down-regulated in their experiments. This claim must be substantiated and verified by demonstrating down-regulation of GSAP gene expression and GSAP on the protein level. Without this control, potential off-target effects are not excluded. Ideally, rescue experiments with RNAi-resistant GSAP should be performed to provide further evidence for GSAP-specificity.
The authors stated that they could not obtain antibodies used in the original He et al. Nature paper from the Greengard lab. However, antibodies against GSAP (aka as PION) are also commercially available.
Supplementary Table 1 is missing