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

Springer Science and Business Media LLC - Tập 7 - Trang 1-15 - 2012
Yuhki Saito1, Tsuyoshi Inoue2, Gang Zhu3, Naoki Kimura1, Motohiro Okada4, Masaki Nishimura5, Nobuyuki Kimura6, Shigeo Murayama7,8, Sunao Kaneko9, Ryuichi Shigemoto10, Keiji Imoto11, Toshiharu Suzuki1
1Laboratory of Neuroscience, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
2Laboratory of Neurobiophysics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
3Department of Psychiatry, The First Affiliated Hospital of China Medical University, Shenyang, China
4Division of Neuroscience, Graduate School of Medicine, Mie University, Tsu, Japan
5Molecular Neuroscience Research Center, Shiga University of Medical Science, Otsu, Japan
6Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Tsukuba, Japan
7Department of Neuropathology, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
8Brain Bank for Aging Research, Tokyo Metropolitan Institute of Gerontology, Tokyo, Japan
9Departments of Neuropsychiatry, Graduate School of Medicine, Hirosaki University, Hirosaki, Japan
10Division of Cerebral Structure, National Institute for Physiological Sciences, Okazaki, Japan
11Department of Information Physiology, National Institute for Physiological Sciences, Okazaki, Japan

Tóm tắt

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. 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. 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.

Tài liệu tham khảo

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