Amyloid β-Induced Upregulation of Nav1.6 Underlies Neuronal Hyperactivity in Tg2576 Alzheimer's Disease Mouse Model.

Abstract

Hyperexcitability and alterations in neuronal networks contribute to cognitive impairment in Alzheimer's Disease (AD). Voltage-gated sodium channels (NaV), which are crucial for regulating neuronal excitability, have been implicated in AD-related hippocampal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we show by using primary hippocampal neurons exposed to amyloid-β1-42 (Aβ1-42) oligomers and from Tg2576 mouse embryos, that the selective upregulation of NaV1.6 subtype contributes to membrane depolarization and to the increase of spike frequency, thereby resulting in neuronal hyperexcitability. Interestingly, we also found that NaV1.6 overexpression is responsible for the aberrant neuronal activity observed in hippocampal slices from 3-month-old Tg2576 mice. These findings identify the NaV1.6 channels as a determinant of the hippocampal neuronal hyperexcitability induced by Aβ1-42 oligomers. The selective blockade of NaV1.6 overexpression and/or hyperactivity might therefore offer a new potential therapeutic approach to counteract early hippocampal hyperexcitability and subsequent cognitive deficits in the early stages of AD.

• Authors: Roselia Ciccone, Cristina Franco, Ilaria Piccialli, Francesca Boscia, Antonella Casamassa, Valeria de Rosa, Pasquale Cepparulo, Mauro Cataldi, Lucio Annunziato, Anna Pannaccione
• Journal: Scientific reports (Sci Rep) Vol. 9 Issue 1 Pg. 13592 (09 19 2019) ISSN: 2045-2322 [Electronic] England
• PMID: 31537873 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• NAV1.6 Voltage-Gated Sodium Channel
• Scn8a protein, mouse

Topics

• Alzheimer Disease (chemically induced, metabolism)
• Amyloid beta-Peptides (adverse effects)
• Animals
• Cells, Cultured
• Disease Models, Animal
• Hippocampus (cytology, metabolism)
• Male
• Mice
• Mice, Transgenic
• NAV1.6 Voltage-Gated Sodium Channel (metabolism)
• Neurons (cytology, metabolism)
• Primary Cell Culture
• Up-Regulation