ArticleAging cell2022
Reducing Nav1.6 expression attenuates the pathogenesis of Alzheimer's disease by suppressing BACE1 transcription.
Article in Aging cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 34 citations in OpenAlex.
- mTORC2-NaChannels (Austin, Tex.) · 2026Article
- Targeting Nav1.6: a promising strategy against cognitive impairment in maternal separation-sensitive mice.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2026Article
- Riluzole shifts glial responses to protect synapses and memory in Aβ oligomer-treated rats.Journal of neuroinflammation · 2026Article
- Structure and function of voltage-gated sodium channel Nav1.6: Involvement in the pathological process of neural injury.Neural regeneration research · 2026Article
- AAV Vector-Mediated Modulation of Signaling Pathways in Neurological Disorders: Insights From Cellular, Animal, and Human Studies.Cell biochemistry and function · 2026Review
- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
- Axon Initial Segment: Structure, Biological Functions, Diseases, and Therapeutic Targets.MedComm · 2026Review
- Diamonds for the Mind: Exploring the Potential of Adamantane against Alzheimer's Disease.Mini reviews in medicinal chemistry · 2026Review
- Calcium signaling hypothesis: A non-negligible pathogenesis in Alzheimer's disease.Journal of advanced research · 2025Review
- Cell-specific Nav1.6 knockdown reduced astrocyte-derived Aβ by reverse NaJournal of advanced research · 2025Article
- The potential role and mechanism of Rhizoma Coptidis in prevention of diabetic encephalopathy: targeting sodium ion and channels.Frontiers in pharmacology · 2025Article
- Changes in the Properties of Ethanol-Sensitive Molecular Targets During Maturation and Aging.Advances in experimental medicine and biology · 2025Review
- GR/Ahi1 regulates WDR68-DYRK1A binding and mediates cognitive impairment in prenatally stressed offspring.Cellular and molecular life sciences : CMLS · 2024Article
- Genome-wide association analysis and admixture mapping in a Puerto Rican cohort supports an Alzheimer disease risk locus on chromosome 12.Frontiers in aging neuroscience · 2024Article
- A neural perspective on the treatment of hypertension: the neurological network excitation and inhibition (E/I) imbalance in hypertension.Frontiers in cardiovascular medicine · 2024Review
- Application of Dominant Gut Microbiota Promises to Replace Fecal Microbiota Transplantation as a New Treatment for Alzheimer's Disease.Microorganisms · 2023Article
- Voltage-Gated NaLife (Basel, Switzerland) · 2023Review
- Voltage-Gated Sodium Channel Dysfunctions in Neurological Disorders.Life (Basel, Switzerland) · 2023Review
- AQP4 Aggravates Cognitive Impairment in Sepsis-Associated Encephalopathy through Inhibiting NaAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- Ginsenoside Rg1 treatment protects against cognitive dysfunction via inhibiting PLC-CN-NFAT1 signaling in T2DM mice.Journal of ginseng research · 2023Article
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Aberrant increases in neuronal network excitability may contribute to cognitive deficits in Alzheimer's disease (AD). However, the mechanisms underlying hyperexcitability of neurons are not fully understood. Voltage-gated sodium channels (VGSC or Nav), which are involved in the formation of excitable cell's action potential and can directly influence the excitability of neural networks, have been implicated in AD-related abnormal neuronal hyperactivity and higher incidence of spontaneous non-convulsive seizures. Here, we have shown that the reduction of VGSC α-subunit Nav1.6 (by injecting adeno-associated virus (AAV) with short hairpin RNA (shRNA) into the hippocampus) rescues cognitive impairments and attenuates synaptic deficits in APP/PS1 transgenic mice. Concurrently, amyloid plaques in the hippocampus and levels of soluble Aβ are significantly reduced. Interfering with Nav1.6 reduces the transcription level of β-site APP-cleaving enzyme 1 (BACE1), which is Aβ-dependent. In the presence of Aβ oligomers, knockdown of Nav1.6 reduces intracellular calcium overload by suppressing reverse sodium-calcium exchange channel, consequently increasing inactive NFAT1 (the nuclear factor of activated T cells) levels and thus reducing BACE1 transcription. This mechanism leads to a reduction in the levels of Aβ in APP/PS1 transgenic mice, alleviates synaptic loss, improves learning and memory disorders in APP/PS1 mice after downregulating Nav1.6 in the hippocampus. Our study offers a new potential therapeutic strategy to counteract hippocampal hyperexcitability and subsequently rescue cognitive deficits in AD by selective blockade of Nav1.6 overexpression and/or hyperactivity.
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