The insect homologue of the amyloid precursor protein interacts with the heterotrimeric G protein Goα in an identified population of migratory neurons

Abstract

The amyloid precursor protein (APP) is the source of Abeta fragments implicated in the formation of senile plaques in Alzheimer's disease (AD). APP-related proteins are also expressed at high levels in the embryonic nervous system and may serve a variety of developmental functions, including the regulation of neuronal migration. To investigate this issue, we have cloned an orthologue of APP (msAPPL) from the moth, Manduca sexta, a preparation that permits in vivo manipulations of an identified set of migratory neurons (EP cells) within the developing enteric nervous system. Previously, we found that EP cell migration is regulated by the heterotrimeric G protein Goalpha: when activated by unknown receptors, Goalpha induces the onset of Ca2+ spiking in these neurons, which in turn down-regulates neuronal motility. We have now shown that msAPPL is first expressed by the EP cells shortly before the onset of migration and that this protein undergoes a sequence of trafficking, processing, and glycosylation events that correspond to discrete phases of neuronal migration and differentiation. We also show that msAPPL interacts with Goalpha in the EP cells, suggesting that msAPPL may serve as a novel G-protein-coupled receptor capable of modulating specific aspects of migration via Goalpha-dependent signal transduction.

Eph receptor expression defines midline boundaries for ephrin‐positive migratory neurons in the enteric nervous system of Manduca sexta

“…Although each migratory EP cell extends an array of exploratory filopodia in advance of its leading process (Horgan and Copenhaver, 1998;Swanson et al, 2005), the neurons remain confined to their muscle band pathways while avoiding adjacent interband regions. In particular, the neurons never cross the midline interband regions of the midgut ("ml"; Fig.…”

Amyloid precursor protein and neural development

“…The divergence in these results might indicate different roles for APPs and APLPs in regulating distinct processes in different regions of the cortex. In line with this, studies from the Copenhaver laboratory suggest that mouse APP and fly APPL regulate neural migration through interactions with heterotrimeric G proteins (Swanson et al, 2005;Ramaker et al, 2013).…”

Analysis of amyloid precursor protein function in Drosophila melanogaster

“…During embryonic development of Manduca sexta, the neurons in the enteric plexus (EP cells) align with the muscle bands on the midgut and foregut and subsequently migrate along these pathways (Copenhaver and Taghert, 1989). APPL expression is detectable in the EP cells starting shortly before the onset of migration (Swanson et al, 2005) and knocking down APPL caused the EP neurons to ectopically migrate onto the interband regions (Ramaker et al, 2013). In Drosophila, the enteric neurons do not migrate along the gut and therefore this function of APPL does not play a role in flies.…”

“…However, insects also express an ortholog of APP which was named APP-like or APPL. APPL is about 30% overall identical to human APP 695 but a much higher degree of conservation is found in the extracellular E1 and E2 domains and especially in the C-terminal intracellular domain or AICD (Rosen et al, 1989;Swanson et al, 2005; Figure 1). Five isoforms of APPL are described in Drosophila that range from 830aa to 890aa (Attrill et al, 2016), however it is unknown whether these isoforms are functionally different.…”