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

Timothy John Baumgartner; Manuel Silva-Pérez; Zahra Haghighijoo; Nolan Michael Dvorak; Aditya Kumar Singh; Nana Aboadwe Goode; Jully Singh; Berenice Gutierrez Grebenkova; Mate Marosi; Jessica Di Re; Leandra Koff; Wissarut Wijitrmektong; Manu Bala; Hanyue Liao; Marijn Lijffijt; Adam Thomas Szafran; Michael James Bolt; Michael A Mancini; Gregory D Cuny; Diana Shu-Lian Chow; Agenor Limon; Jeannie Chin; Fernanda Laezza

doi:10.1002/alz.70507

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

Timothy John Baumgartner
, Manuel Silva-Pérez
, Zahra Haghighijoo
, Nolan Michael Dvorak
, Aditya Kumar Singh
, Nana Aboadwe Goode
, Jully Singh
, Berenice Gutierrez Grebenkova
, Mate Marosi
, Jessica Di Re
, Leandra Koff
, Wissarut Wijitrmektong
, Manu Bala
, Hanyue Liao
, Marijn Lijffijt
, Adam Thomas Szafran
, Michael James Bolt
, Michael A Mancini
, Gregory D Cuny
, Diana Shu-Lian Chow

Agenor Limon, Jeannie Chin, Fernanda Laezza

University of Texas Medical Branch

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

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.

Original language	English (US)
Pages (from-to)	e70507
Journal	Alzheimer's and Dementia
Volume	21
Issue number	7
DOIs	https://doi.org/10.1002/alz.70507
State	Published - Jul 2025

Keywords

Animals
Alzheimer Disease/drug therapy
Glycogen Synthase Kinase 3 beta/metabolism
NAV1.6 Voltage-Gated Sodium Channel/metabolism
Humans
Disease Models, Animal
Neurons/drug effects
Patch-Clamp Techniques
Mice, Transgenic
Electroencephalography
Mice
Action Potentials/drug effects
Amyloid beta-Peptides
Male

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Baumgartner, T. J., Silva-Pérez, M., Haghighijoo, Z., Dvorak, N. M., Singh, A. K., Goode, N. A., Singh, J., Grebenkova, B. G., Marosi, M., Di Re, J., Koff, L., Wijitrmektong, W., Bala, M., Liao, H., Lijffijt, M., Szafran, A. T., Bolt, M. J., Mancini, M. A., Cuny, G. D., ... Laezza, F. (2025). Inhibition of the GSK3β/Nav1.6 complex suppresses early-stage Alzheimer's hyperexcitability. Alzheimer's and Dementia, 21(7), e70507. https://doi.org/10.1002/alz.70507

Baumgartner, TJ, Silva-Pérez, M, Haghighijoo, Z, Dvorak, NM, Singh, AK, Goode, NA, Singh, J, Grebenkova, BG, Marosi, M, Di Re, J, Koff, L, Wijitrmektong, W, Bala, M, Liao, H, Lijffijt, M, Szafran, AT, Bolt, MJ, Mancini, MA, Cuny, GD, Chow, DS-L, Limon, A, Chin, J & Laezza, F 2025, 'Inhibition of the GSK3β/Nav1.6 complex suppresses early-stage Alzheimer's hyperexcitability', Alzheimer's and Dementia, vol. 21, no. 7, pp. e70507. https://doi.org/10.1002/alz.70507

@article{b8dcdf5e580045e1912aefadc0cacc04,

title = "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 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/drug therapy, Glycogen Synthase Kinase 3 beta/metabolism, NAV1.6 Voltage-Gated Sodium Channel/metabolism, Humans, Disease Models, Animal, Neurons/drug effects, Patch-Clamp Techniques, Mice, Transgenic, Electroencephalography, Mice, Action Potentials/drug effects, Amyloid beta-Peptides, Male",

author = "Baumgartner, \{Timothy John\} and Manuel Silva-P{\'e}rez and Zahra Haghighijoo and Dvorak, \{Nolan Michael\} and Singh, \{Aditya Kumar\} and Goode, \{Nana Aboadwe\} and Jully Singh and Grebenkova, \{Berenice Gutierrez\} and Mate Marosi and \{Di Re\}, Jessica and Leandra Koff and Wissarut Wijitrmektong and Manu Bala and Hanyue Liao and Marijn Lijffijt and Szafran, \{Adam Thomas\} and Bolt, \{Michael James\} and Mancini, \{Michael A\} and Cuny, \{Gregory D\} and Chow, \{Diana Shu-Lian\} and Agenor Limon and Jeannie Chin and Fernanda Laezza",

note = "{\textcopyright} 2025 The Author(s). Alzheimer's \& Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.",

year = "2025",

month = jul,

doi = "10.1002/alz.70507",

language = "English (US)",

volume = "21",

pages = "e70507",

journal = "Alzheimer's and Dementia",

issn = "1552-5260",

publisher = "John Wiley and Sons Inc.",

number = "7",

}

TY - JOUR

T1 - Inhibition of the GSK3β/Nav1.6 complex suppresses early-stage Alzheimer's hyperexcitability

AU - Baumgartner, Timothy John

AU - Silva-Pérez, Manuel

AU - Haghighijoo, Zahra

AU - Dvorak, Nolan Michael

AU - Singh, Aditya Kumar

AU - Goode, Nana Aboadwe

AU - Singh, Jully

AU - Grebenkova, Berenice Gutierrez

AU - Marosi, Mate

AU - Di Re, Jessica

AU - Koff, Leandra

AU - Wijitrmektong, Wissarut

AU - Bala, Manu

AU - Liao, Hanyue

AU - Lijffijt, Marijn

AU - Szafran, Adam Thomas

AU - Bolt, Michael James

AU - Mancini, Michael A

AU - Cuny, Gregory D

AU - Chow, Diana Shu-Lian

AU - Limon, Agenor

AU - Chin, Jeannie

AU - Laezza, Fernanda

PY - 2025/7

Y1 - 2025/7

N2 - 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.

AB - 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.

KW - Animals

KW - Alzheimer Disease/drug therapy

KW - Glycogen Synthase Kinase 3 beta/metabolism

KW - NAV1.6 Voltage-Gated Sodium Channel/metabolism

KW - Humans

KW - Disease Models, Animal

KW - Neurons/drug effects

KW - Patch-Clamp Techniques

KW - Mice, Transgenic

KW - Electroencephalography

KW - Mice

KW - Action Potentials/drug effects

KW - Amyloid beta-Peptides

KW - Male

U2 - 10.1002/alz.70507

DO - 10.1002/alz.70507

M3 - Article

C2 - 40717647

SN - 1552-5260

VL - 21

SP - e70507

JO - Alzheimer's and Dementia

JF - Alzheimer's and Dementia

IS - 7

ER -

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

Abstract

Keywords

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