APLP1 Is a Synaptic Cell Adhesion Molecule, Supporting Maintenance of Dendritic Spines and Basal Synaptic Transmission

Abstract

The amyloid precursor protein (APP), a key player in Alzheimer's disease, belongs to the family of synaptic adhesion molecules (SAMs) due to its impact on synapse formation and synaptic plasticity. These functions are mediated by both the secreted APP ectodomain that acts as a neurotrophic factor and full-length APP forming trans-cellular dimers. Two homologs of APP exist in mammals: the APP like proteins APLP1 and APLP2, exhibiting functions that partly overlap with those of APP. Here we tested whether APLP1 and APLP2 also show features of SAMs. We found that all three family members were upregulated during postnatal development coinciding with synaptogenesis. We observed presynaptic and postsynaptic localization of all APP family members and could show that heterologous expression of APLP1 or APLP2 in non-neuronal cells induces presynaptic differentiation in contacting axons of cocultured neurons, similar to APP and other SAMs. Moreover, APP/APLPs all bind to synaptic-signaling molecules, such as MINT/X11. Furthermore, we report that aged APLP1 knock-out mice show impaired basal transmission and a reduced mEPSC frequency, likely resulting from reduced spine density. This demonstrates an essential nonredundant function of APLP1 at the synapse. Compared to APP, APLP1 exhibits increased trans-cellular binding and elevated cell-surface levels due to reduced endocytosis. In conclusion, our results establish that APLPs show typical features of SAMs and indicate that increased surface expression, as observed for APLP1, is essential for proper synapse formation in vitro and synapse maintenance in vivo.

Direct evidence of amyloid precursor–like protein 1 trans interactions in cell–cell adhesion platforms investigated via fluorescence fluctuation spectroscopy

“…, 2009 ; Mayer et al. , 2016 ; Schilling et al. , 2017 ) although, until now, little evidence of protein–protein trans interactions (i.e., among proteins from two different cells at a junction) has been provided in living cells ( Soba et al.…”

“…, 2012 ; Shariati and De Strooper, 2013 ). All three proteins are pre- and postsynaptically expressed and up-regulated during postnatal development ( Schilling et al. , 2017 ).…”

“…, 2009 ). Recent results from coculture assays suggested that APLP1 expression has synaptogenic activity on primary cortical neurons ( Schilling et al. , 2017 ).…”

Copper and zinc ions govern the trans‐directed dimerization of APP family members in multiple ways

“…In previous studies we could show that cis-directed dimerization of APP alters its subcellular localization and lowers amyloid b production (Eggert et al 2009(Eggert et al , 2018, while trans-directed dimerization of APP and APLP1 impacts intercellular contacts (Soba et al 2005;Kaden et al 2008;Wang et al 2009;Isbert et al 2012;Baumkotter et al 2014;Stahl et al 2014;Decock et al 2015;Mayer et al 2016;Schilling et al 2017). For cis-directed dimerization of APP and its paralogues it was shown that zinc decreases sAPP/ APLP levels (Mayer et al 2016) and favor trans-directed dimerization (Dunsing et al 2017).…”

“…; Schilling et al . ). For cis‐directed dimerization of APP and its paralogues it was shown that zinc decreases sAPP/APLP levels (Mayer et al .…”