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.
Highlights
The amyloid precursor protein (APP) can be processed to generate the amyloid β (Aβ) peptides, which aggregate to form senile plaques, one of the major pathological hallmarks found in Alzheimer’s disease (AD; Masters and Selkoe, 2012)
The association of FE65 proteins with receptors such as apolipoprotein E receptor 2 (ApoER2) and Notch/Notch intracellular domain (NICD) is shown in Figure 1 as a possible mechanism by which FE65 may function at the synapse
The cadherin related protein family member, Calsyntenin-3/Alcadein β, which is highly expressed in interneurons, forms a functional complex with α-neurexin that promotes calsyntenin-3 mediated presynaptic differentiation of inhibitory synapses (Pettem et al, 2013; Um et al, 2014)
Summary
The amyloid precursor protein (APP) can be processed to generate the amyloid β (Aβ) peptides, which aggregate to form senile plaques, one of the major pathological hallmarks found in Alzheimer’s disease (AD; Masters and Selkoe, 2012). APP is a ubiquitously expressed type I transmembrane protein with a large ectodomain, a single membrane spanning domain, and a short cytoplasmic tail. The ectodomain comprises two highly conserved E1 and E2 domains, involved in metal (copper and zinc) and heparin binding (Baumkötter et al, 2012; Müller and Zheng, 2012). Aged mice deficient in APP show impairments in behavior (Müller et al, 1994; Phinney et al, 1999; Ring et al, 2007), long-term potentiation (LTP; Seabrook et al, 1999; Ring et al, 2007), dendritic branching and synaptic density (Zheng et al, 1995; Dawson et al, 1999; Phinney et al, 1999; Seabrook et al, 1999; Lee et al, 2010; Tyan et al, 2012; Weyer et al, 2014).
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