Abstract
Following the discovery that the amyloid precursor protein (APP) is the source of β-amyloid peptides (Aβ) that accumulate in Alzheimer’s disease (AD), structural analyses suggested that the holoprotein resembles a transmembrane receptor. Initial studies using reconstituted membranes demonstrated that APP can directly interact with the heterotrimeric G protein Gαo (but not other G proteins) via an evolutionarily G protein-binding motif in its cytoplasmic domain. Subsequent investigations in cell culture showed that antibodies against the extracellular domain of APP could stimulate Gαo activity, presumably mimicking endogenous APP ligands. In addition, chronically activating wild type APP or overexpressing mutant APP isoforms linked with familial AD could provoke Go-dependent neurotoxic responses, while biochemical assays using human brain samples suggested that the endogenous APP-Go interactions are perturbed in AD patients. More recently, several G protein-dependent pathways have been implicated in the physiological roles of APP, coupled with evidence that APP interacts both physically and functionally with Gαo in a variety of contexts. Work in insect models has demonstrated that the APP ortholog APPL directly interacts with Gαo in motile neurons, whereby APPL-Gαo signaling regulates the response of migratory neurons to ligands encountered in the developing nervous system. Concurrent studies using cultured mammalian neurons and organotypic hippocampal slice preparations have shown that APP signaling transduces the neuroprotective effects of soluble sAPPα fragments via modulation of the PI3K/Akt pathway, providing a mechanism for integrating the stress and survival responses regulated by APP. Notably, this effect was also inhibited by pertussis toxin, indicating an essential role for Gαo/i proteins. Unexpectedly, C-terminal fragments (CTFs) derived from APP have also been found to interact with Gαs, whereby CTF-Gαs signaling can promote neurite outgrowth via adenylyl cyclase/PKA-dependent pathways. These reports offer the intriguing perspective that G protein switching might modulate APP-dependent responses in a context-dependent manner. In this review, we provide an up-to-date perspective on the model that APP plays a variety of roles as an atypical G protein-coupled receptor in both the developing and adult nervous system, and we discuss the hypothesis that disruption of these normal functions might contribute to the progressive neuropathologies that typify AD.
Highlights
Argument that the aberrant amyloid precursor protein (APP)-Go signaling might contribute to both late-onset Alzheimer’s disease (AD) and some forms of familial AD (FAD)
Since pertussis toxin (PTX) selectively inhibits members of the Gαo/i family, while APP only interacts with Gαo and potentially Gαs, these results argue that APP/sAPPα interactions induce the PI3K/target of PI3K (Akt) pathway via Gαo
Most studies support the model that transmembrane APP normally binds and activates Gαo in response to a variety of ligands, suggesting that APP cleavage is likely to terminate APPGαo signaling rather than activating it. In support of this model, we recently showed that blocking α-secretase activity in the migratory neurons of cultured Manduca embryos significantly increased membrane-associated APPL levels, while inducing the same collapse/stall responses caused by hyperactivating APPLGαo signaling with Contactin fusion proteins (Ramaker et al, 2016a,b)
Summary
Argument that the aberrant APP-Go signaling might contribute to both late-onset AD and some forms of FAD. In a more physiological context, the Kögel group recently demonstrated the importance of the Go domain in mediating APP-dependent neuroprotective responses to sAPPα: a deletion that removed the conserved PEERH motif within this domain (Figure 1B9) prevented APPdependent signaling that was blocked by PTX (implicating Gαo/i proteins), whereas two different deletions targeting the YENPTY motif (Figure 1B10,11) had no effect (as summarized below).
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
