Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
Inhibition of the GSK3β/Nav1.6 complex suppresses early-stage Alzheimer's hyperexcitability.
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Baumgartner Timothy John, Silva-Pérez Manuel, Haghighijoo Zahra, Dvorak Nolan Michael, Singh Aditya Kumar, Goode Nana Aboadwe, Singh Jully, Grebenkova Berenice Gutierrez, Marosi Mate, Di Re Jessica, Koff Leandra, Wijitrmektong Wissarut, Bala Manu, Liao Hanyue, Lijffijt Marijn, Szafran Adam Thomas, Bolt Michael James, Mancini Michael A, Cuny Gregory D, Chow Diana Shu-Lian, Limon Agenor, Chin Jeannie, Laezza Fernanda
Аннотация
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.
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.