King's College London

Research portal

HCN channelopathy couples disease-associated tau to synaptic dysfunction

Research output: Contribution to journalArticlepeer-review

Despoina Goniotaki, Francesco Tamagnini, Luca Biasetti, Svenja-Lotta Rumpf, Claire Troakes, Saskia J Pollack, Shalom Ukwesa, Haoyue Sun, Louise Serpell, Wendy Noble, Kevin Staras, Diane P Hanger

Original languageEnglish
Article numbere058346
JournalAlzheimer's & dementia : the journal of the Alzheimer's Association
Volume17
Issue numberSuppl 2
Early online date31 Dec 2021
DOIs
E-pub ahead of print31 Dec 2021
PublishedDec 2021

King's Authors

Abstract

Deficits in synaptic function and neurite connectivity are early correlates of tauopathies. Altered tau processing and mis-localization coincide with reductions in synapse density and synaptic function, suggesting a causal role for tau in disease pathogenesis. In parallel, altered activity of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, involved in synaptic integration, is implicated in disease progression in animal models of tauopathy. However, the mechanisms underlying these pathological events are not fully understood. We performed histological and biochemical analyses of hippocampal tissues from Alzheimer's disease (AD), age-matched controls and Tau35 mice, in which a human tauopathy-associated tau fragment is minimally expressed. Image analysis and quantification were performed on antibody-labelled human and mouse hippocampal sections (Visiopharm). Brain tissue from Tau35 and wild-type (WT) mice was also examined on western blots, by Golgi-Cox staining and transmission electron microscopy. Primary hippocampal neurons from Tau35 and WT mice were transfected with a plasmid expressing enhanced green fluorescent protein (eGFP) and imaged up to 14 days in vitro. Three-dimensional digital reconstruction of dendrites and spines enabled morphological analysis of eGFP-expressing neurons. In parallel, patch-clamp recordings were performed to assess functional changes and HCN channel activity in Tau35 neurons. Here we show that HCN channels are functionally linked to tau abnormalities. Alterations in HCN channel expression are detected in both Tau35 mouse and human post-mortem AD brain. Tau35 neurons exhibit altered synaptic cytoarchitecture, including progressive reductions in dendritic branching, pre-synaptic vesicles, spine density and synaptic markers, along with the development of tau pathology. These changes are accompanied by functional abnormalities in network activity, including increased HCN-dependent sag voltage, reduced frequency and slower kinetics of spontaneous excitatory postsynaptic currents. Our findings are consistent with the hypothesis that disease-associated tau species impact on HCN channels to drive network-wide structural and functional synaptic deficits, with significant therapeutic relevance for tauopathies. [Abstract copyright: © 2021 the Alzheimer's Association.]

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454