Inhibition of the GSK3β/Nav1.6 complex suppresses early-stage Alzheimer's hyperexcitability.

ABSTRACT:

Introduction

Network hyperexcitability (NH) is observed in patients with early-stage Alzheimer's disease (AD), emerging decades before cognitive decline. A key molecular determinant of NH is voltage-gated Na+ channel 1.6 (Nav1.6), which mediates action potential firing in CA1 hippocampal neurons. Ameliorating NH through inhibition of the glycogen-synthase kinase 3β (GSK3β/Nav1.6 complex may provide immediate benefits to cognition and memory and slow AD progression.

Methods

Hight-throughput virtual screening and multiple in vitro biological assays were utilized to identify compound 1063. Patch-clamp electrophysiology and electroencephalogram recordings were utilized to functionally assess 1063 in models of AD neuropathology.

Results

Building on previous studies identif

SUBMITTER: Baumgartner TJ 

PROVIDER: S-EPMC12301699 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature