Language

English

Publication Date

7-1-2025

Journal

Alzheimer's & Dementia

DOI

10.1002/alz.70507

PMID

40717647

PMCID

PMC12301699

PubMedCentral® Posted Date

7-28-2025

PubMedCentral® Full Text Version

Post-print

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 identifying GSK3β as a modulatory protein binding to the Nav1.6 C-terminal domain (CTD), we identified 1063, a brain-penetrant small molecule that inhibits GSK3β/Nav1.6 complex assembly and reduces NH in AD rodent models.

Discussion: These results demonstrate the potential of the GSK3β/Nav1.6 complex as a therapeutic target for NH in early-stage AD.

Highlights: The glycogen synthase kinase 3-β (GSK3β)/Nav1.6 complex is a potential target for hyperexcitability in early Alzheimer's disease (AD). Compound 1063 dose-dependently decreases GSK3β/Nav1.6 complex assembly. Compound 1063 is functionally specific for Nav1.6 over other central nervous system (CNS) Nav isoforms. Ex vivo functional studies provide evidence for target engagement. 1063 dose-dependently reduces epileptiform activity in AD rodent model.

Keywords

Animals, Alzheimer Disease, Glycogen Synthase Kinase 3 beta, NAV1.6 Voltage-Gated Sodium Channel, Humans, Disease Models, Animal, Neurons, Patch-Clamp Techniques, Mice, Transgenic, Electroencephalography, Mice, Action Potentials, Amyloid beta-Peptides, Male, Alzheimer's disease, amyloid beta‐induced hyperexcitability, glycogen synthase kinase 3β, nav1.6, network hyperactivity, neuronal hyperexcitability, small molecule drug discovery, voltage‐gated sodium channel

Published Open-Access

yes

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