Despoina Goniotaki, Francesco Tamagnini, Luca Biasetti, Svenja-Lotta Rumpf, Claire Troakes, Saskia J. Pollack, Shalom Ukwesa, Haoyue Sun, Igor Kraev, Louise C. Serpell, Wendy Noble, Kevin Staras, Diane P. Hanger
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Changes in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to disease-associated abnormalities in multiple neurodegenerative diseases.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age-matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons.</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>Expression of specific HCN channels is elevated in <i>post mortem</i> AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization-induced membrane voltage “sag” and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents.</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network-wide structural and functional synaptic deficits.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are functionally linked to the development of tauopathy.</li>\n \n <li>Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy.</li>\n \n <li>Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization-induced membrane voltage “sag” demonstrating a detrimental effect of tau abnormalities on HCN channel function.</li>\n \n <li>Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":7471,"journal":{"name":"Alzheimer's & Dementia","volume":null,"pages":null},"PeriodicalIF":13.0000,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11350046/pdf/","citationCount":"0","resultStr":"{\"title\":\"Tau-mediated synaptic dysfunction is coupled with HCN channelopathy\",\"authors\":\"Despoina Goniotaki, Francesco Tamagnini, Luca Biasetti, Svenja-Lotta Rumpf, Claire Troakes, Saskia J. Pollack, Shalom Ukwesa, Haoyue Sun, Igor Kraev, Louise C. Serpell, Wendy Noble, Kevin Staras, Diane P. Hanger\",\"doi\":\"10.1002/alz.14074\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> INTRODUCTION</h3>\\n \\n <p>In tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to disease-associated abnormalities in multiple neurodegenerative diseases.</p>\\n </section>\\n \\n <section>\\n \\n <h3> METHODS</h3>\\n \\n <p>To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age-matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons.</p>\\n </section>\\n \\n <section>\\n \\n <h3> RESULTS</h3>\\n \\n <p>Expression of specific HCN channels is elevated in <i>post mortem</i> AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. 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Tau-mediated synaptic dysfunction is coupled with HCN channelopathy
INTRODUCTION
In tauopathies, altered tau processing correlates with impairments in synaptic density and function. Changes in hyperpolarization-activated cyclic nucleotide-gated (HCN) channels contribute to disease-associated abnormalities in multiple neurodegenerative diseases.
METHODS
To investigate the link between tau and HCN channels, we performed histological, biochemical, ultrastructural, and functional analyses of hippocampal tissues from Alzheimer's disease (AD), age-matched controls, Tau35 mice, and/or Tau35 primary hippocampal neurons.
RESULTS
Expression of specific HCN channels is elevated in post mortem AD hippocampus. Tau35 mice develop progressive abnormalities including increased phosphorylated tau, enhanced HCN channel expression, decreased dendritic branching, reduced synapse density, and vesicle clustering defects. Tau35 primary neurons show increased HCN channel expression enhanced hyperpolarization-induced membrane voltage “sag” and changes in the frequency and kinetics of spontaneous excitatory postsynaptic currents.
DISCUSSION
Our findings are consistent with a model in which pathological changes in tauopathies impact HCN channels to drive network-wide structural and functional synaptic deficits.
Highlights
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are functionally linked to the development of tauopathy.
Expression of specific HCN channels is elevated in the hippocampus in Alzheimer's disease and the Tau35 mouse model of tauopathy.
Increased expression of HCN channels in Tau35 mice is accompanied by hyperpolarization-induced membrane voltage “sag” demonstrating a detrimental effect of tau abnormalities on HCN channel function.
Tau35 expression alters synaptic organization, causing a loosened vesicle clustering phenotype in Tau35 mice.
期刊介绍：
Alzheimer's & Dementia is a peer-reviewed journal that aims to bridge knowledge gaps in dementia research by covering the entire spectrum, from basic science to clinical trials to social and behavioral investigations. It provides a platform for rapid communication of new findings and ideas, optimal translation of research into practical applications, increasing knowledge across diverse disciplines for early detection, diagnosis, and intervention, and identifying promising new research directions. In July 2008, Alzheimer's & Dementia was accepted for indexing by MEDLINE, recognizing its scientific merit and contribution to Alzheimer's research.
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