Alzheimer's disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons

Samuel S Harris¹, Robert Ellingford², Jana Hartmann², Debanjan Dasgupta², Marten Kehring², Rikesh M Rajani³, David Graykowski², Noé Quittot⁴, Dhanush Sivasankaran⁴, Caitlin Commins⁴, Zhanyun Fan⁴, Suraya A Bond², Fred Wolf⁵, David Dupret⁶, Raymond J Dolan⁷, Arthur Konnerth⁸, Andreas Neef⁵, Bradley T Hyman⁴, Marc Aurel Busche⁹

Affiliations

¹ UK Dementia Research Institute at University College London, London, UK. Electronic address: samuel.harris@ucl.ac.uk.
² UK Dementia Research Institute at University College London, London, UK.
³ UK Dementia Research Institute at University College London, London, UK; British Heart Foundation - UK Dementia Research Institute Centre for Vascular Dementia Research at The University of Edinburgh, Edinburgh, UK.
⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁵ Göttingen Campus Institute for Dynamics of Biological Networks, Göttingen, Germany.
⁶ Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁷ Max Planck UCL Centre for Computational Psychiatry and Ageing Research, London, UK.
⁸ Institute of Neuroscience, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁹ UK Dementia Research Institute at University College London, London, UK; Department of Neurodegenerative Diseases, University Hospital of Geriatric Medicine FELIX PLATTER and University of Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland. Electronic address: m.busche@ucl.ac.uk.

PMID: 40300603
PMCID: PMC12255526 (available on 2026-04-28)
DOI: 10.1016/j.cell.2025.04.006

Alzheimer's disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons

Samuel S Harris et al. Cell. 2025.

. 2025 Jul 10;188(14):3775-3788.e21.

doi: 10.1016/j.cell.2025.04.006. Epub 2025 Apr 28.

Authors

Affiliations

¹ UK Dementia Research Institute at University College London, London, UK. Electronic address: samuel.harris@ucl.ac.uk.
² UK Dementia Research Institute at University College London, London, UK.
³ UK Dementia Research Institute at University College London, London, UK; British Heart Foundation - UK Dementia Research Institute Centre for Vascular Dementia Research at The University of Edinburgh, Edinburgh, UK.
⁴ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA.
⁵ Göttingen Campus Institute for Dynamics of Biological Networks, Göttingen, Germany.
⁶ Medical Research Council Brain Network Dynamics Unit, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁷ Max Planck UCL Centre for Computational Psychiatry and Ageing Research, London, UK.
⁸ Institute of Neuroscience, Technical University of Munich, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
⁹ UK Dementia Research Institute at University College London, London, UK; Department of Neurodegenerative Diseases, University Hospital of Geriatric Medicine FELIX PLATTER and University of Basel, Basel, Switzerland; Department of Biomedicine, University of Basel, Basel, Switzerland. Electronic address: m.busche@ucl.ac.uk.

PMID: 40300603
PMCID: PMC12255526 (available on 2026-04-28)
DOI: 10.1016/j.cell.2025.04.006

Abstract

Tau accumulation is closely related to cognitive symptoms in Alzheimer's disease (AD). However, the cellular drivers of tau-dependent decline of memory-based cognition remain elusive. Here, we employed in vivo Neuropixels and patch-clamp recordings in mouse models and demonstrate that tau, independent of β-amyloid, selectively debilitates complex-spike burst firing of CA1 hippocampal neurons, a fundamental cellular mechanism underpinning learning and memory. Impaired bursting was associated with altered hippocampal network activities that are coupled to burst firing patterns (i.e., theta rhythms and high-frequency ripples) and was concurrent with reduced neuronal expression of CaV2.3 calcium channels, which are essential for burst firing in vivo. We subsequently identify soluble high molecular weight (HMW) tau, isolated from human AD brain, as the tau species responsible for suppression of burst firing. These data provide a cellular mechanism for tau-dependent cognitive decline in AD and implicate a rare species of intracellular HMW tau as a therapeutic target.

Keywords: Alzheimer’s disease; CaV2.3 (R-type) channels; extracellular electrophysiology; high molecular weight tau; hippocampus CA1; human; mouse models; neuronal bursting; patch-clamp electrophysiology.

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Conflict of interest statement

Declaration of interests B.T.H. owns stock in Novartis; he serves on the scientific advisory board of Dewpoint and has an option for stock. He serves on a scientific advisory board or is a consultant for AbbVie, Alexion, Ambagon, Aprinoia Therapeutics, Arvinas, Avrobio, AstraZeneca, Biogen, BMS, Cure Alz Fund, Cell Signalling, Dewpoint, Latus, Novartis, Pfizer, Sanofi, Sofinnova, Vigil, Violet, Voyager, and WaveBreak. His laboratory is in part supported by a sponsored research agreement from AbbVie. C.C. is currently employed at AbbVie.

References

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Alzheimer's disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons

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Alzheimer's disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons

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