APP Protein Family Signaling at the Synapse: Insights from Intracellular APP-Binding Proteins

Abstract

Understanding the molecular mechanisms underlying amyloid precursor protein family (APP/APP-like proteins, APLP) function in the nervous system can be achieved by studying the APP/APLP interactome. In this review article, we focused on intracellular APP interacting proteins that bind the YENPTY internalization motif located in the last 15 amino acids of the C-terminal region. These proteins, which include X11/Munc-18-interacting proteins (Mints) and FE65/FE65Ls, represent APP cytosolic binding partners exhibiting different neuronal functions. A comparison of FE65 and APP family member mutant mice revealed a shared function for APP/FE65 protein family members in neurogenesis and neuronal positioning. Accumulating evidence also supports a role for membrane-associated APP/APLP proteins in synapse formation and function. Therefore, it is tempting to speculate that APP/APLP C-terminal interacting proteins transmit APP/APLP-dependent signals at the synapse. Herein, we compare our current knowledge of the synaptic phenotypes of APP/APLP mutant mice with those of mice lacking different APP/APLP interaction partners and discuss the possible downstream effects of APP-dependent FE65/FE65L or X11/Mint signaling on synaptic vesicle release, synaptic morphology and function. Given that the role of X11/Mint proteins at the synapse is well-established, we propose a model highlighting the role of FE65 protein family members for transduction of APP/APLP physiological function at the synapse.

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

“…On one hand, these factors might also affect protein dynamics and protein–protein interaction. On the other hand, previous studies ( Guénette et al. , 2017 ; Sosa et al.…”

“…, 2012 ]). This putative specific interaction between cytoskeleton and APLP1 (e.g., via the YENPTY motif; see Guénette et al. [2017] and Sosa et al.…”

Epigenetic modifications by polyphenolic compounds alter gene expression in the hippocampus

“…To screen for metabolites that alter the expression of epigenetic modifying genes and differentially methylated genes, we treated primary embryonic mouse cortico-hippocampal neuron cultures with brain bioavailable polyphenol metabolites and measured mRNA expression of the epigenetic modifiers DNMT1, DNMT3B, TET1, TET2 and selected differentially methylated genes GRB10, ITPKA, CAMK2A, and ABPP2 . The select differentially methylated genes were chosen based on their contribution to synaptic plasticity ( Guénette et al, 2017 ; Kim and Whalen, 2009 ; Shonesy et al, 2014 ; Xie et al, 2014 ).…”

Elevated levels of Secreted-Frizzled-Related-Protein 1 contribute to Alzheimer’s disease pathogenesis

“…In APP;PS1 brains-but also in AD patients-APP expression and processing occurs mostly in neurons 28 , including in the synaptic compartment in which APP and ADAM10 localize 29,30 (Fig. 3M).…”