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Cited by 52Alzheimer's disease research and treatmentsIon channel regulation and functionNeuroscience and Neuropharmacology Research

Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Aβ generation in Alzheimer’s disease

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Saito, Yuhki, Inoue, Tsuyoshi, Zhu, Gang, Kimura, Naoki, Okada, Motohiro, Nishimura, Masaki, Kimura, Nobuyuki, Murayama, Shigeo +4 more·2012·Molecular Neurodegeneration
DOI 10.1186/1750-1326-7-50PMC PMC3524764
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Abstract

Background: One of the best-characterized causative factors of Alzheimer’s disease (AD) is the generation of amyloid-β peptide (Aβ). AD subjects are at high risk of epileptic seizures accompanied by aberrant neuronal excitability, which in itself enhances Aβ generation. However, the molecular linkage between epileptic seizures and Aβ generation in AD remains unclear. Results: X11 and X11-like (X11L) gene knockout mice suffered from epileptic seizures, along with a malfunction of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Genetic ablation of HCN1 in mice and HCN1 channel blockage in cultured Neuro2a (N2a) cells enhanced Aβ generation. Interestingly, HCN1 levels dramatically decreased in the temporal lobe of cynomolgus monkeys (Macaca fascicularis) during aging and were significantly diminished in the temporal lobe of sporadic AD patients. Conclusion: Because HCN1 associates with amyloid-β precursor protein (APP) and X11/X11L in the brain, genetic deficiency of X11/X11L may induce aberrant HCN1 distribution along with epilepsy. Moreover, the reduction in HCN1 levels in aged primates may contribute to augmented Aβ generation. Taken together, HCN1 is proposed to play an important role in the molecular linkage between epileptic seizures and Aβ generation, and in the aggravation of sporadic AD.

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  • This is supported by previous observations highlighting an antiepileptic role of Sst+ interneurons, and the observation that susceptible inhibitory interneurons express a high level of the HCN1 channel, whose dysfunction has been linked to several epileptogenesis pathways and the generation of hyperexcitability.

    “This is supported by previous observations highlighting an antiepileptic role of Sst+ interneurons89, and our observation that susceptible inhibitory interneurons express a high level of the HCN1 channel, whose dysfunction has been linked to several epileptogenesis pathways and the generation of hyperexcitability90.”

    From Integrated multimodal cell atlas of Alzheimer’s disease (2024) · cites this paper as [90]

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References 51 · Cited by 52

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Authors
Saito, Y., Inoue, T., Zhu, G., Kimura, N., Okada, M., Nishimura, M., Kimura, N., Murayama, S., Kaneko, S., Shigemoto, R., Imoto, K., & Suzuki, T.
Affiliations
  • Hokkaido University (JP)
  • Okayama University (JP)
  • First Hospital of China Medical University (CN)
  • Mie University (JP)
  • Shiga University of Medical Science (JP)
  • Tokyo Metropolitan Institute of Gerontology (JP)
  • Hirosaki University (JP)
  • National Institute for Physiological Sciences (JP)
Corresponding author
Suzuki, Toshiharu
ORCID
Venue
Molecular Neurodegeneration
Publisher
Springer Science and Business Media LLC
Published
2012-10-03
Volume
7
Issue
1
Pages
50-50
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/1750-1326-7-50
PMC
PMC3524764
OpenAlex
W2134363396
Cited by
52
References
51
Citations by year
2026: 3 · 2025: 6 · 2024: 5 · 2023: 5 · 2022: 5 · 2021: 4 · 2020: 7 · 2019: 3 · 2018: 4 · 2017: 2 · 2016: 4 · 2015: 2 · 2014: 1 · 2013: 1
FWCI
0.86
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Molecular Neurodegeneration (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • Hokkaido University Collection of Scholarly and Academic Papers (Hokkaido University) (submittedVersion, cc-by)
  • Institutional Repositories DataBase (IRDB) (submittedVersion, cc-by)
Funders
  • Akiyama Life Science Foundation
  • Ministry of Education, Culture, Sports, Science and Technology
  • Ministry of Health, Labour and Welfare
  • Japan Society for the Promotion of Science (23390017, 23790069, 22240039, 22300118, 22659011, 21890002)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
HCN channels, HCN1, X Window System, amyloid-beta production, Alzheimer's disease, epileptic seizures, amyloid precursor protein, neuronal excitability, temporal lobe, Macaca fascicularis, aging, sporadic Alzheimer's disease
MeSH terms
Aged, Aged, 80 and over, Aging, Alzheimer Disease, Animals, Brain, Electroencephalography, Epilepsy, Humans, Immunohistochemistry, Macaca fascicularis, Male, Nerve Tissue Proteins, Seizures, Immunoblotting, Potassium Channels, Amyloid beta-Peptides, Mice, Knockout, Patch-Clamp Techniques, Immunoprecipitation, Adaptor Proteins, Signal Transducing, Mice, Cyclic Nucleotide-Gated Cation Channels, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

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