Hyperpolarization-activated cyclic nucleotide gated channels: a potential molecular link between epileptic seizures and Aβ generation in Alzheimer’s disease
Year: 2012
Type: article
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.
Source: Molecular Neurodegeneration
Institutions: Hokkaido University, Okayama University, First Hospital of China Medical University, National Institute of Biomedical Innovation, Health and Nutrition, National Institute of Biomedical Innovation, Mie University, Shiga University of Medical Science, Tokyo Metropolitan Institute of Gerontology, Hirosaki University, National Institute for Physiological Sciences
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,090
Awards: Molecular mechanism of sporadic Alzheimer's disease onset, Conformational change of X11L and its physiological functions, Development of primate model of sporadic ALS with overexpression of TDP-43, Study on molecular mechanism underlying brain region-specific Ass deposition, Mechanism of kinesin-1 activation by cargo receptor, Analysis of X11 proteins functions in vivo
OpenAlex ID: W2134363396