Navβ2 knockdown improves cognition in APP/PS1 mice by partially inhibiting seizures and APP amyloid processing

Abstract

Voltage-gated sodium channels beta 2 (Navβ2, encoded by SCN2B) is a substrate of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and regulates cell surface expression of channels in neurons. Previous studies reported enhanced Navβ2 processing by BACE1 in Alzheimer’s disease (AD) model and patients. We investigated whether changes in Navβ2 expression affect neuronal seizure and amyloid precursor protein (APP) processing in an AD mouse model. Our study used eight-month-old APP/presenilin 1 (PS1) mice and transgenic Navβ2 knockdown [by 61% vs. wild type (WT)] APP/PS1 mice (APP/PS1/Navβ2-kd), with age-matched WT and Navβ2 knockdown (Navβ2-kd) mice as controls. We found that Navβ2 knockdown in APP/PS1 mice partially reversed the abnormal Navβ2 cleavage and the changes in intracellular and total Nav1.1α expression. It also restored sodium currents density in hippocampal neurons and neuronal activity, as indicated by EEG tracing; improved Morris water maze performance; and shifted APP amyloidogenic metabolism towards non-amyloidogenic processing. There were no differences in these indicators between WT and Navβ2-kd mice. These results suggest Navβ2 knockdown may be a promising strategy for treating AD.

Exercise-Induced Cognitive Improvement Is Associated with Sodium Channel-Mediated Excitability in APP/PS1 Mice

“…The period of the spike wave is usually 83-200 ms, and the amplitude is above 100 μV. The representative EEG recordings in these APP/PS1 9 Neural Plasticity mice exhibited longer durations of high-frequency brain activity, with some obvious spikes, which is consistent with previous reports [7,38].…”

“…The dysregulation of Nav1.1α levels and aberrant cleavage of Navβ2 were contributed to the BACE1 upregulation in cortical neurons, abnormal EEG activity, and cognitive deficits in AD mice [7,46]. Increased SCN2B (encode gene of Navβ2) expression in the hippocampus was associated with cognitive deficits in the senescence-accelerated P8 mice [32], while Navβ2 knockdown reversed the APP/PS1 mutation-induced deficiency in amyloid β (Aβ) degradation by regulating NEP in APP/PS1 mouse-derived neurons [47], preserved neurons, redressed Nav1.1α distributions, and improved spatial cognition by partially decreasing pathological amyloidogenic APP processing in aged APP/PS1 mice [38]. Aβ1-42 treatment of cultured hippocampal neurons induced an upregulation of the Nav and Nav1.6 expression, as well as increasing neural excitability [48].…”

“…For EEG recordings, a high resolution mouse EEG using polyimide-based microelectrode array (PBMarray) was used in the study. The protocols of electrode implantation and EEG recordings were performed according to the literature with some modifications [7,38,39]. Mouse was fixed on the stereotaxic instrument after anesthetized for electrode fixation before EEG recordings.…”

“…The mean DF was calculated for each mouse from each DF in each 30 s epoch. The time in high frequency was calculated by summing the number of 30 s epochs with a DF > 6 Hz and dividing it by the total number of 30 s epochs (total time of the recording) for each mouse [7,38].…”

“…Nav1.1α Cell-Surface Biotinylation Assay. The remaining hippocampal tissues were placed into ice-cold Krebs solution containing components as described previously [7] with modification (in mM): 120 NaCl, 4.5 KCl, 1.5 KH 2 PO 4 , 10 Cell-surface biotinylation and detection of cell-surface Nav1.1α were performed as previously described [7,38]. NeutrAvidin-agarose beads (Pierce, USA) were employed to pull down the biotinylated proteins, which were eluted by incubation with SDS-PAGE sample buffer at 37°C for 60 min and analyzed by SDS-PAGE followed by western blotting as described above.…”