Tau-mediated synaptic dysfunction is coupled with HCN channelopathy

Goniotaki, D., Tamagnini, F. ORCID: https://orcid.org/0000-0002-8741-5094, Biasetti, L., Rumpf, S.-L., Troakes, C., Pollack, S. J., Ukwesa, S., Sun, H., Kraev, I., Serpell, L. C., Noble, W., Staras, K. and Hanger, D. P. (2024) Tau-mediated synaptic dysfunction is coupled with HCN channelopathy. Alzheimer's and Dementia: Translational Research and Clinical Interventions, 20 (8). pp. 5629-5646. ISSN 2352-8737 doi: 10.1002/alz.14074

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/119102
Identification Number/DOI	10.1002/alz.14074
Refereed	Yes
Divisions	Life Sciences > School of Chemistry, Food and Pharmacy > School of Pharmacy > Division of Pharmacology
Publisher	Alzheimer's Association
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