(Alvarez and Sabatini, 2007), we hypothesize that the reduction in spine density in the older animals is the result of increased spine elimination. In this context, it is noteworthy that the reduction in dendritic complexity is of greater magnitude than the small but significant reduction in spine density. Whether all of these changes are due to the putative trophic properties of APP, or the lack thereof, is unclear. In a previous report, disruption of immunostaining for the postsynaptic marker MAP-2 and the presynaptic marker synaptophysin had been observed. However, there was no detectable decrease in these protein levels at 12 month of age in APP−/− mice (Seabrook et al., 1999), which is probably due to only a minimal reduction of spine number. Not surprisingly, PSD-95 and synaptophysin levels by Western blotting were not reduced in APP−/− brains as compared to wild type mice (Fig. S4). More interesting is why these changes were only evident when the mice were aged. Perhaps the compensatory effects of APLP1 and APLP2 diminish with age, an explanation frequently invoked when the mild phenotype of the APP-deficient mice was first described. Although no compensatory changes in APLP1 or APLP2 expression were detected in 14 weeks old
