# Novel Mechanisms of APP-Go signaling in the control of neuronal motility

> **NIH NIH RF1** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $1,885,550

## Abstract

Amyloid Precursor Protein (APP) was originally identified as the source of beta-amyloid (Aβ) peptides that
accumulate in Alzheimer's disease (AD) and Down Syndrome. However, APP is normally upregulated in both
the developing and injured nervous system, functioning as a guidance receptor that regulates multiple aspects
of neuronal motility, including migration and outgrowth, synaptic remodeling, and retraction/regrowth
responses. However, the mechanisms by which APP regulates these responses remain poorly understood.
Early studies showed that APP could function as an unconventional G protein-coupled receptor (GPCR),
interacting with the heterotrimeric G protein Goα to control neuronal responses. Mutations in APP linked with
early onset AD also hyperactivated Goα and induced cell death, suggesting that the misregulation of normal
APP-Go signaling might provoke neurodegenerative responses. However, subsequent studies produced
contradictory results, and until recently, proof that APP acts as a Goα-coupled receptor in vivo remained
lacking. Defining the normal functions of APP has been complicated by two close orthologs in mammals
(APLP1 and APLP2) with overlapping activities. As an alternative, we adapted a well-characterized assay of
neuronal migration in the moth Manduca. Notably, Manduca only contains a single APP ortholog (APP-like; or
APPL), which also functionally interacts with Goα in migrating neurons. Moreover, inhibiting APPL-Goα
signaling in cultured embryos resulted in ectopic migration and outgrowth, similar to the ectopic migration
caused by deleting all APP family members in mice. Using genetic manipulations and split-GFP assays in
Drosophila, we also showed that APPL directly binds Goα via a conserved Go-binding motif, and that this
interaction is regulated by Goα activation. Using affinity screening methods, we found that Manduca Contactin
functions as an authentic ligand for APPL, paralleling recent evidence that mammalian Contactins also bind
APP family proteins. These results demonstrate that Manduca provides a powerful discovery system for
defining the signaling mechanisms that underlie this evolutionarily conserved pathway. Using our protocols for
manipulating protein and gene expression in cultured embryos, we will investigate two novel Goα effectors that
may regulate different aspects of APPL-Goα signaling. Specifically, we will test whether APPL-Goα signaling
restricts ectopic outgrowth via RhoGEF2, an ortholog of mammalian PDZ-RhoGEFs that activate the small
GTPase RhoA (a regulator of actin remodeling). Likewise, we will test whether APP-Goα signaling also
induces APPL cleavage by the α-secretase ADAM10/Kuzbanian, providing a novel mechanism for terminating
signaling. Lastly, to confirm the relevance of these studies in mammalian neurons, we will test the role of each
effector in regulating the APP-Goα signaling using cultured mouse hippocampal neurons.

## Key facts

- **NIH application ID:** 9940616
- **Project number:** 1RF1NS115898-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** PHILIP F COPENHAVER
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,885,550
- **Award type:** 1
- **Project period:** 2020-04-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9940616

## Citation

> US National Institutes of Health, RePORTER application 9940616, Novel Mechanisms of APP-Go signaling in the control of neuronal motility (1RF1NS115898-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/9940616. Licensed CC0.

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