Numerous physiological functions, including a role as a cell surface receptor, have been ascribed to Alzheimer's disease-associated amyloid precursor protein (APP). However, detailed analysis of intracellular signaling mediated by APP in neurons has been lacking. Here, we characterized intrinsic signaling associated with membrane-bound APP C-terminal fragments, which are generated following APP ectodomain release by α- or β-secretase cleavage. We found that accumulation of APP C-terminal fragments or expression of membrane-tethered APP intracellular domain results in adenylate cyclase-dependent activation of PKA (protein kinase A) and inhibition of GSK3β signaling cascades, and enhancement of axodendritic arborization in rat immortalized hippocampal neurons, mouse primary cortical neurons, and mouse neuroblastoma. We discovered an interaction between BBXXB motif of APP intracellular domain and the heterotrimeric G-protein subunit GαS, and demonstrate that GαScoupling to adenylate cyclase mediates membrane-tethered APP intracellular domain-induced neurite outgrowth. Our study provides clear evidence that APP intracellular domain can have a nontranscriptional role in regulating neurite outgrowth through its membrane association. The novel functional coupling of membrane-bound APP C-terminal fragments with GαSsignaling identified in this study could impact several brain functions such as synaptic plasticity and memory formation.