APP, commonly associated with Alzheimers disease, marks axonal degeneration.Its physiological distribution and function along myelinated axons remain unknown.We report that APP null and APP overexpressing transgenic (APPtg) mice show minor hypo-and hyper-myelination, respectively.Through axoglial interactions, APP aggregates at nodes of Ranvier (NORs) in the CNS.Notably, coexpression of APP or its intracellular domains containing a VTPEER motif with Nav 1.6 sodium channels in Xenopus oocytes resulted in an increase in peak sodium currents, which was enhanced by APPT668E mutation and blocked by APPT668A mutation and inhibitors of CDK5 and JNKs.The cell surface expression of Navl.6 sodium channels in the white matter of spinal cord is decreased in APP, p35 and JNK3 null mice.Consistently, APP, p35 and JNK3 deficiency significantly reduce spinal conduction velocity.Thus, APP acts as a novel component at CNS NORs, modulating Navl.6 sodium channels in an APPThr668 phosphorylation-dependent manner.