Abstract

The amyloid precursor protein (APP), a key factor in Alzheimer's disease (AD) pathology, and its two mammalian homologs, amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2), are considered as members of the synaptic adhesion molecule (SAM) family. They are localized to the pre- and postsynapse, form trans-cellular dimers, and have been shown to induce presynaptic differentiation in a heterologous synapse formation assay. We demonstrate that expression of all APP family members in non-neuronal cells also promotes dendritic excitatory postsynaptic differentiation in primary mouse neurons of either sex, similar to Neurexin1β and other SAMs. Synaptogenic activity was decreased by deletion of the E1 domain and increased upon inhibition of soluble APP (sAPP) generation, reinforcing that trans-cellular interaction of APP/APLPs can induce synaptogenesis. Consistent with this, the capacity of heterologously expressed APP to induce postsynaptic specializations in contacting dendrites was reduced by the absence of APP family members at the postsynaptic site and was lost in conditional triple knock-out (cTKO) neurons. Pharmacological analyses revealed that heterologous formation of pre- and postsynapses relies on proper microtubule and actin cytoskeleton dynamics, as well as the MAP kinase pathway, similar to what has been shown for Neurexin1β and Neuroligin1. However, inhibition of the PI3K/Akt pathway selectively impaired APP-induced postsynaptic differentiation, suggesting that distinct APP signaling pathways are required for pre- and postsynaptic differentiation. Collectively, our data highlight the role of all APP family members as SAMs in trans-synaptic signaling, providing key insights into their physiological function and advancing our understanding of AD-related synaptopathies.