major but not exclusive role in these dendritic defects. Given the findings of the APP-APLP2 deficient mice, it is highly likely that the C-terminus of APP also contribute to normal APP function, an interesting possibility that was not addressed in this study. In addition, our results are quite consistent with other reports describing the reduction in dendritic spine numbers following RNAi-mediated knockdown of APP or after deletion of the E1 and E2 domains of APP, the latter being located in the extracellular region contained within APPs (Lee et al., 2010). However, the precise mechanisms by which APPs functions as a trophic molecule in a paracrine fashion have not been elucidated yet. Lastly, the fact that a bona fide receptor for APPs has not been established adds to the difficulty in understanding how APP is mediating these effects.
