Tau-mediated synaptic dysfunction is coupled with HCN channelopathy

IF 13 1区医学 Q1 CLINICAL NEUROLOGY

Alzheimer's & Dementia Pub Date : 2024-07-12 DOI:10.1002/alz.14074

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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Abstract

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.

Abstract Image

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Tau介导的突触功能障碍与HCN通道病变有关。

简介在锥体病中，锥体加工的改变与突触密度和功能的损害相关。在多种神经退行性疾病中，超极化激活的环核苷酸门控（HCN）通道的变化导致了与疾病相关的异常：为了研究 tau 和 HCN 通道之间的联系，我们对来自阿尔茨海默病（AD）、年龄匹配对照组、Tau35 小鼠和/或 Tau35 原发性海马神经元的海马组织进行了组织学、生物化学、超微结构和功能分析：结果：特定HCN通道的表达在死后AD海马中升高。Tau35小鼠出现进行性异常，包括磷酸化tau增加、HCN通道表达增强、树突分枝减少、突触密度降低和囊泡集群缺陷。Tau35 原发性神经元显示 HCN 通道表达增强，超极化诱导的膜电压 "下陷 "以及自发兴奋性突触后电流的频率和动力学发生了变化：我们的研究结果与一个模型相一致，即陶陶病的病理变化影响 HCN 通道，从而驱动整个网络的结构和功能性突触缺陷：亮点：超极化激活的环核苷酸门控（HCN）通道在功能上与tauopathy的发展有关。特定 HCN 通道在阿尔茨海默病海马和 Tau35 tauopathy 小鼠模型中的表达升高。Tau35小鼠中HCN通道的表达增加伴随着超极化诱导的膜电压 "下陷"，这表明tau异常对HCN通道功能有不利影响。Tau35 的表达改变了突触组织，导致 Tau35 小鼠出现松散的囊泡聚集表型。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Alzheimer's & Dementia 医学-临床神经学

CiteScore

14.50

自引率

5.00%

发文量

299

审稿时长

3 months

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.