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

被引：41

作者：

Saito, Yuhki ^{[1
]}

Inoue, Tsuyoshi ^{[2
]}

Zhu, Gang ^{[3
]}

Kimura, Naoki ^{[1
]}

Okada, Motohiro ^{[4
]}

Nishimura, Masaki ^{[5
]}

Kimura, Nobuyuki ^{[6
]}

Murayama, Shigeo ^{[7
,8
]}

Kaneko, Sunao ^{[9
]}

Shigemoto, Ryuichi ^{[10
]}

Imoto, Keiji ^{[11
]}

Suzuki, Toshiharu ^{[1
]}

机构：

[1] Hokkaido Univ, Grad Sch Pharmaceut Sci, Neurosci Lab, Kita Ku, Sapporo, Hokkaido 0600812, Japan

[2] Okayama Univ, Grad Sch Med Dent & Pharmaceut Sci, Lab Neurobiophys, Okayama 7008530, Japan

[3] China Med Univ, Affiliated Hosp 1, Dept Psychiat, Shenyang 110001, Peoples R China

[4] Mie Univ, Grad Sch Med, Div Neurosci, Tsu, Mie 5148507, Japan

[5] Shiga Univ Med Sci, Mol Neurosci Res Ctr, Otsu, Shiga 5202192, Japan

[6] Natl Inst Biomed Innovat, Lab Dis Control, Tsukuba Primate Res Ctr, Tsukuba, Ibaraki 3050843, Japan

[7] Tokyo Metropolitan Inst Gerontol, Dept Neuropathol, Itabashi Ku, Tokyo 1730015, Japan

[8] Tokyo Metropolitan Inst Gerontol, Brain Bank Aging Res, Itabashi Ku, Tokyo 1730015, Japan

[9] Hirosaki Univ, Grad Sch Med, Dept Neuropsychiat, Hirosaki, Aomori 0368562, Japan

[10] Natl Inst Nat Sci, Natl Inst Physiol Sci, Div Cerebral Struct, Okazaki, Aichi 4448585, Japan

[11] Natl Inst Physiol Sci, Dept Informat Physiol, Okazaki, Aichi 4448787, Japan

来源：

MOLECULAR NEURODEGENERATION | 2012年 / 7卷

基金：

日本学术振兴会;

关键词：

TEMPORAL-LOBE EPILEPSY; AMYLOID PRECURSOR PROTEIN; ENTORHINAL CORTEX; ADAPTER PROTEIN; TRANSGENIC MICE; MOUSE-BRAIN; LAYER-II; IN-VIVO; HCN; EXPRESSION;

D O I：

10.1186/1750-1326-7-50

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Background: One of the best-characterized causative factors of Alzheimer's disease (AD) is the generation of amyloid-beta peptide (A beta). AD subjects are at high risk of epileptic seizures accompanied by aberrant neuronal excitability, which in itself enhances A beta generation. However, the molecular linkage between epileptic seizures and A beta 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 A beta 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-beta 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 A beta generation. Taken together, HCN1 is proposed to play an important role in the molecular linkage between epileptic seizures and A beta generation, and in the aggravation of sporadic AD.

引用

页数：15

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