Abstract
Amyloid precursor protein (APP), commonly associated with Alzheimer’s disease, also marks axonal degeneration. In the recent studies, we demonstrated that APP aggregated at nodes of Ranvier (NORs) in myelinated central nervous system (CNS) axons and interacted with Nav1.6. However, the physiological function of APP remains unknown. In this study, we described reduced sodium current densities in APP knockout hippocampal neurons. Coexpression of APP or its intracellular domains containing a VTPEER motif with Nav1.6 sodium channels in Xenopus oocytes resulted in an increase in peak sodium currents, which was enhanced by constitutively active Go mutant and blocked by a dominant negative mutant. JNK and CDK5 inhibitor attenuated increases in Nav1.6 sodium currents induced by overexpression of APP. Nav1.6 sodium currents were increased by APPT668E (mutant Thr to Glu) and decreased by T668A (mutant Thr to ALa) mutant, respectively. The cell surface expression of Nav1.6 sodium channels in the white matter of spinal cord and the spinal conduction velocity is decreased in APP, p35 and JNK3 knockout mice. Therefore, APP modulates Nav1.6 sodium channels through a Go-coupled JNK pathway, which is dependent on phosphorylation of APP at Thr668.
Highlights
Amyloid precursor protein (APP) is well known for its function in the pathogenesis of neurodegenerative disorders, such as Alzheimer’s disease (AD)
Sodium current responses elicited by depolarizing voltage steps in a neuron from WT and APP KO mice. (a), Current-voltage relationships of sodium currents density in WT mice and APP KO mice. pF, picofarads. (b) Peak currents density in APP KO and their littermate WT mice. (B) Overexpression of APP enhances sodium currents in HEK293 cells stably expressing α-subunit of human Nav1.6 (HEK293-Nav1.6 cells)
Sodium current responses elicited by depolarizing voltage steps. (a), Current-voltage relationships of sodium currents density in vector-(open squares) and APP-transfected HEK293-Nav1.6 cells. pF, picofarads. (b), Peak currents density in vector- and APP-transfected HEK293-Nav1.6
Summary
Amyloid precursor protein (APP) is well known for its function in the pathogenesis of neurodegenerative disorders, such as Alzheimer’s disease (AD). Our previous study demonstrates that APP aggregates at NORs in myelinated central nervous system (CNS) axons, but not in the peripheral nervous system (PNS)[1]. As Nav1.6 sodium channels, F3/contactin, tenascin-R, and OMgp, at the NORs are critical to ensure rapid saltatory conduction of action potentials along myelinated fibers[7]. Four distinct α-subunits of sodium channels are expressed in mammalian CNS neurons. They are Nav1.1, Nav1.2, Nav1.3, and Nav1.68. The fine modulation of sodium channels, responsible for depolarizing and repolarizing events at the NORs, is essential for precise saltatory conduction along myelinated axons. According to the phenotype of APP KO mice, we hypothesize that APP, which takes on a characteristic distribution along axons, will render it a candidate molecule for ion channel modulation. We show that APP positively modulates sodium currents of Nav1.6 in an APP Thr[668] phosphorylation-dependent manner through a Go-coupled JNK pathway
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