The most consistent finding of neuronal function of APP is perhaps its role as a neurotrophic factor and in synaptogenesis, a neuronal function potentially related to its cell adhesion activity. APP has been shown to be localized to the tips of growing nerve fibers while changes in APP processing from full-length to sAPP have also been shown to be tightly regulated in this process, implicating APP in synapse formation (Moya et al., 1994). The obvious explanation for the mechanism of abnormal dendritic morphology developing in APP−/− mice is the concomitant loss of APPs secretion in the absence of APP in primary cultures, the fact that the reduction in dendritic spines can be restored simply by culturing the APP-deficient neurons in media conditioned from wild type neurons implied that the loss of soluble factors are causative of these alterations. Furthermore, we 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
