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

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

doi:10.1186/1750-1326-7-50

Abstract

BackgroundOne 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.ResultsX11 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.ConclusionBecause 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.

Highlights

One of the best-characterized causative factors of Alzheimer’s disease (AD) is the generation of amyloid-β peptide (Aβ)
We report that i) X11 proteins (X11s)-/-/X11L-/- mice suffer from spontaneous epileptic seizures along with malfunction of hyperpolarization-activated cyclic nucleotide gated (HCN) channel activity; ii) HCN1 can form a complex with amyloid-β precursor protein (APP) and X11 or X11L in the murine brain; iii) HCN1-/gene knockout mice show enhanced Aβ generation; iv) overexpression of HCN1 in Neuro2a (N2a) cells decreases Aβ generation, whereas blockage of HCN1 channel activity in N2a cells restores the level of Aβ production; v) the level of HCN1 diminishes significantly in the temporal cortex of cynomolgus monkeys (Macaca fascicularis) during aging; and vi) HCN1 levels are significantly reduced in the brains of sporadic AD patients compared with the brains of age-matched healthy subjects
Spontaneous epileptic seizures caused by X11 and X11L gene deficiency Electrocorticograms were recorded in X11+/+/X11L+/+, X11+/+/X11L-/, X11-/-/X11L+/+, and X11-/-/ X11L-/- mice

Summary

Introduction

One of the best-characterized causative factors of Alzheimer’s disease (AD) is the generation of amyloid-β peptide (Aβ). Factors linking seizure activity to Aβ generation in AD patients remain unclear, epilepsy is believed to result from abnormal regulation. Hyperpolarization-activated cyclic nucleotide gated HCN channels 1–4 (HCN1–4) conduct inward, depolarizing mixed Na+/K+ currents and thereby control resting membrane potential, dendritic integration, synaptic transmission, and rhythmic activity in cardiac pacemaker cells and spontaneous firing neurons [11]. Dysregulation of these channels and their hyperpolarization-activated (Ih) currents is strongly implicated in various experimental animal models of epilepsy, as well as in human epilepsy patients [12]. HCN2 co-assembles with the X11-like (X11L) protein [13], which is a metabolic regulator of APP processing [14]

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