observed partial restoration of dendritic spine numbers in APP-deficient neurons after the addition of media from N2a cells transfected with mouse α-secretase cleaved sAPPα (Fig. 6). As described, the restoration was incomplete but this could be due to incompatibility of media conditioned by N2a cells because we saw a reduction in dendritic spine numbers in neurons cultured with mock transfected media (data not shown). On the other hand, recent studies using APP knock-in mice to rescue the postnatal lethality of APP-APLP2 double knock-out mice suggested that knock-in mice expressing only sAPPα, i.e. truncated after the α-secretase site identical to our sAPPα construct, are hypomorphic with respect to APP function (Weyer et al., 2011). Specifically, in the setting of APLP2 deficiency, sAPPα knock-in mice which survive into adulthood demonstrated abnormal hippocampal and neuromuscular functions. These observations imply that the transmembrane and/or intracellular domains of APP carry out additional essential physiological functions. Consequently, our results are highly suggestive of sAPPα playing a 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
