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

Yuhki Saito, Tsuyoshi Inoue, Gang Zhu, Naoki Kimura, Motohiro Okada, Masaki Nishimura, Nobuyuki Kimura, Shigeo Murayama, Sunao Kaneko, Ryuichi Shigemoto, Keiji Imoto, Toshiharu Suzuki

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number50
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
Publication statusPublished - 2012

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
Epilepsy
Alzheimer Disease
Macaca fascicularis
Temporal Lobe
Gene Knockout Techniques
Amyloid beta-Protein Precursor
Amyloid
Knockout Mice
Primates
Cultured Cells
Brain

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Clinical Neurology
  • Molecular Biology

Cite this

Hyperpolarization-activated cyclic nucleotide gated channels : A potential molecular link between epileptic seizures and Aβ generation in Alzheimer's disease. / Saito, Yuhki; Inoue, Tsuyoshi; Zhu, Gang; Kimura, Naoki; Okada, Motohiro; Nishimura, Masaki; Kimura, Nobuyuki; Murayama, Shigeo; Kaneko, Sunao; Shigemoto, Ryuichi; Imoto, Keiji; Suzuki, Toshiharu.

In: Molecular Neurodegeneration, Vol. 7, No. 1, 50, 2012.

Research output: Contribution to journalArticle

Saito, Yuhki ; Inoue, Tsuyoshi ; Zhu, Gang ; Kimura, Naoki ; Okada, Motohiro ; Nishimura, Masaki ; Kimura, Nobuyuki ; Murayama, Shigeo ; Kaneko, Sunao ; Shigemoto, Ryuichi ; Imoto, Keiji ; Suzuki, Toshiharu. / Hyperpolarization-activated cyclic nucleotide gated channels : A potential molecular link between epileptic seizures and Aβ generation in Alzheimer's disease. In: Molecular Neurodegeneration. 2012 ; Vol. 7, No. 1.
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