Open Access Research article

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

Yuhki Saito1, Tsuyoshi Inoue2, Gang Zhu3, Naoki Kimura1, Motohiro Okada4, Masaki Nishimura5, Nobuyuki Kimura6, Shigeo Murayama78, Sunao Kaneko9, Ryuichi Shigemoto10, Keiji Imoto11 and Toshiharu Suzuki1*

Author Affiliations

1 Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita12-Nishi6, Kita-ku, Sapporo, 060-0812, Japan

2 Laboratory of Neurobiophysics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, 700-8530, Japan

3 Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, 110001, China

4 Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, 514-8507, Japan

5 Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, 520-2192, Japan

6 Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, 305-0843, Japan

7 Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, 173-0015, Japan

8 Brain Bank for Aging Research, Tokyo Metropolitan Institute of Gerontology, Itabashi-ku, Tokyo, 173-0015, Japan

9 Departments of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, 036-8562, Japan

10 Division of Cerebral Structure, National Institute for Physiological Sciences, Okazaki, 444-8585, Japan

11 Department of Information Physiology, National Institute for Physiological Sciences, Okazaki, 444-8787, Japan

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Molecular Neurodegeneration 2012, 7:50  doi:10.1186/1750-1326-7-50

Published: 3 October 2012

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.