Establishing the physiological function of APP in vivo has been difficult, in part because of likely redundant functions of APLP1 and APLP2 and in part because some of the previous approaches used to assess synaptic structure may have been insensitive to small changes. In this study, we combined neuronal cell filling with Lucifer Yellow coupled with a sensitive, quantitative, and 3-dimensional, automated system to examine dendritic spine numbers and dendritic morphology in vivo in APP−/− mice. Further, electrophysiology from acute hippocampal slices and in vitro analyses of cultured primary hippocampal neurons were performed to complement these studies. Unexpectedly, we observed that dendritic spine densities were significantly reduced in cultured primary hippocampal neurons deficient in APP and this was confirmed in apical dendrites of CA1 hippocampal neurons in vivo, albeit to a much lesser extent. Importantly, the reduction in spines and marked reduction in dendritic length and branching were seen only in older (12-14 months) but not in young (2-4 months) APP−/− animals. Furthermore, consistent with changes in altered neuronal morphology in older animals, synaptic plasticity as measured by LTP was
