- The authors only checked KD via PCR. There is not always a linear correlation between mRNA levels and protein levels. Taking into account the delay to KD proteins to a significant level, the dependency on the halflife of each protein (which can be dramatically different between proteins) it is of importance to also show that protien levels are decreased to the same extent.
- The authors limit their study to a murine neuronal model, ignoring the human context of APP processing. The murine APP can be processed but producing very little Abeta. Control experiments should be included with neurons expressing human APP (or a mutant) or alternatively, the authors should consider human differentiated neurons to make their point. I feel this is important as several manuscripts have already shown that altered expression of LOAD risk factors (such as PICALM, BIN1, CD2AP) affect Abeta through altering internalizaiton of g-secretase, or polarizing the processing of APP in dendrites and neurons. One cannot just ignore the literature unless experiments are done on a model that is superior to the published data.