Neuroprotection induced by Navβ2‑knockdown in APP/PS1 transgenic neurons is associated with NEP regulation.

Abstract

Voltage‑gated sodium channel β2 (Navβ2), as an unconventional substrate of β‑site amyloid precursor protein cleaving enzyme1, is involved in regulating the neuronal surface expression of sodium channels. A previous study demonstrated that knockdown of Navβ2 protected neurons and induced spatial cognition improvement by partially reducing pathological amyloidogenic processing of amyloid precursor protein (APP) in aged APP/presenilin1 (PS1) transgenic mice. The present study aimed to investigate whether Navβ2 knockdown altered APP metabolism via regulation of the Aβ‑degrading enzyme neprilysin (NEP). APPswe/PS1ΔE9 mice (APP/PS1 transgenic mice with a C57BL/6J genetic background) carrying a Navβ2‑knockdown mutation (APP/PS1/Navβ2‑kd) or without Navβ2 knockdown (APP/PS1) were used for cell culture and further analysis. The present results demonstrated that in APP/PS1 mouse‑derived neurons, Navβ2 knockdown partially reversed the reduction in pathological APP cleavage, and the recovery of neurite extension and neuron area. Additionally, Navβ2 knockdown increased NEP activity and levels, and the levels of intracellular domain fragment binding to the NEP promoter. The present findings suggested that knockdown of Navβ2 reversed the APP/PS1 mutation‑induced deficiency in amyloid β degradation by regulating NEP.