NaV1.6 as a new potential target of Alzheimer's Disease

Alterations of the neuronal excitability and ionic homeostasis are becoming crucial events of Alzheimer's Disease (AD). The voltage-gated sodium (NaV) channels play an essential role in the control of the neuronal excitability. In fact, they trigger the generation and propagation of action potentials suggesting their involvement in AD. However, the NaV channel role has not yet been clarified in AD. The aim of the present study was to investigate the effects of A?1-42 peptide on NaV channels in a transgenic mouse model of AD, Tg2576. The A?1-42-exposure modulated selectively Nav1.6 channel expression and activity in primary hippocampal neurons. In particular, A?1-42-exposure induced a time-dependent modulation of NaV currents with a peak at 24 hrs accompanied by a significant leftward shift in the voltage dependence of activation. Interestingly, the NaV1.6 knockingdown completely counteracted the NaV current increase suggesting a possible NaV1.6 involvement in AD. Similar results were obtained in Tg2576 hippocampal neurons. The anisomycin, a well known selective NaV1.6 current inhibitor through an p38 MAPK activation, induced a significant reduction of the NaV current peak recorded in Tg2576 hippocampal neurons compared to that recorded in absence of anisomycin. Immunocytochemical analysis revealed that NaV1.6-immunoreactivity signal was higher in Tg2576 hippocampal neurons than in wild type whereas in the presence of anisomycin the NaV1.6 signal was lower. These results suggest that NaV1.6 channel hyperactivity could represent a new potential target in AD.