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Cleavage of the Amyloid Precursor Protein (APP) generates amyloid peptides that accumulate in Alzheimer Disease (AD), but APP is also upregulated by developing and injured neurons, suggesting that it regulates neuronal motility. APP can also function as a G protein-coupled receptor that signals via the heterotrimeric G protein Gao, but evidence for APP-Gao signaling in vivo has been lacking. Using Manduca as a model system, we showed that insect APP (APPL) regulates neuronal migration in a Gao-dependent manner. Recently, we also demonstrated that Manduca Contactin (expressed by glial cells) induces APPL-Gao retraction responses in migratory neurons, consistent with evidence that mammalian Contactins also interact with APP family members. Preliminary studies using cultured hippocampal neurons suggest that APP-Gao signaling can similarly regulate growth cone motility. Whether Contactins (or other APP ligands) induce this response within the developing nervous system, and how this pathway is disrupted in AD, remains to be explored. [ABSTRACT FROM AUTHOR]