Presynaptic and Postsynaptic Interaction of the Amyloid Precursor Protein Promotes Peripheral and Central Synaptogenesis

TLDR

APP is a key protein in Alzheimer’s disease, yet its normal physiological role remains poorly understood. The study aims to determine whether transsynaptic APP interactions regulate synaptic function and contribute to synaptic dysfunction in AD. Conditional deletion of APP in presynaptic motor neurons or postsynaptic muscle, together with in‑vitro mixed‑culture assays of APP‑expressing HEK293 cells and hippocampal neurons, was used to probe APP’s role. Loss of APP in either compartment caused neuromuscular synapse defects, postsynaptic APP was required for presynaptic choline‑transporter targeting and synaptic transmission, and APP expression in HEK293 cells promoted axonal synaptogenesis via extracellular and intracellular domains that interact with Mint1/Cask and can be substituted by SynCAM sequences, establishing APP as a novel synaptic adhesion molecule.

Abstract

A critical role of the amyloid precursor protein (APP) in Alzheimer's disease (AD) pathogenesis has been well established. However, the physiological function of APP remains elusive and much debated. We reported previously that the APP family of proteins is essential in mediating the developing neuromuscular synapse. In the current study, we created a conditional allele of APP and deleted APP in presynaptic motor neuron or postsynaptic muscle. Crossing these alleles onto the APP-like protein 2-null background reveals that, unexpectedly, inactivating APP in either compartment results in neuromuscular synapse defects similar to the germline deletion and that postsynaptic APP is obligatory for presynaptic targeting of the high-affinity choline transporter and synaptic transmission. Using a HEK293 and primary hippocampus mixed-culture assay, we report that expression of APP in HEK293 cells potently promotes synaptogenesis in contacting axons. This activity is dependent on neuronal APP and requires both the extracellular and intracellular domains; the latter forms a complex with Mint1 and Cask and is replaceable by the corresponding SynCAM (synaptic cell adhesion molecule) sequences. These in vitro and in vivo studies identify APP as a novel synaptic adhesion molecule. We postulate that transsynaptic APP interaction modulates its synaptic function and that perturbed APP synaptic adhesion activity may contribute to synaptic dysfunction and AD pathogenesis.