The authors are well known for their sound experimental procedures. In this study, they crossbred Tg mice that overexpress APP and NEP. The transgene expression was driven by PDGF and CamKII promoters, respectively.

This overexpression paradigm employed is very much artificial: unphysiological overproduction of APP, APPs, AICD in PDGF-expressing cells and unwanted genomic disruption in the case of APP Tg mice, any of which can affect the cognitive phenotypes. In addition, the Tg mice by definition are not perfect models for AD because they fail to reconstitute two indispensable pathologies, i.e., tauopathy and neurodegeneration. Something is still missing.

Under normal conditions, APP and NEP colocalize well in the brain. It is therefore of particular interest to examine their colocalization in the double-Tg mice, for which distinct promoters were used. No proteases can degrade their substrates unless they come across each other in vivo. For the catabolism of Aβ, secretary vesicles and synapses are the important locations. Generally speaking, single Tg mice are already...  Read more

The authors are well known for their sound experimental procedures. In this study, they crossbred Tg mice that overexpress APP and NEP. The transgene expression was driven by PDGF and CamKII promoters, respectively.

This overexpression paradigm employed is very much artificial: unphysiological overproduction of APP, APPs, AICD in PDGF-expressing cells and unwanted genomic disruption in the case of APP Tg mice, any of which can affect the cognitive phenotypes. In addition, the Tg mice by definition are not perfect models for AD because they fail to reconstitute two indispensable pathologies, i.e., tauopathy and neurodegeneration. Something is still missing.

Under normal conditions, APP and NEP colocalize well in the brain. It is therefore of particular interest to examine their colocalization in the double-Tg mice, for which distinct promoters were used. No proteases can degrade their substrates unless they come across each other in vivo. For the catabolism of Aβ, secretary vesicles and synapses are the important locations. Generally speaking, single Tg mice are already artificial, so double Tg mice can be superartificial. This is why we crossed APP-Tg mice with NEP-KO mice and obtained essentially opposite results (Huang et al., 2006).

Do the Aβ trimer and Aβ* that the authors observed represent relevant primary pathogenic agents in AD brains? Is Aβ* really Aβ homo-oligomer? I guess there is some discrepancy between this paper and the 2008 Nat Med paper by the Selkoe group (Shankar et al., 2008).

Unfortunately, some references are cited in a misleading manner, for instance, Kanemitsu et al., 2003.

View all comments by Takaomi Saido