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

Affiliations

• 1. UK Dementia Research Institute at University College London, London, 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.

 PMID: 40300603 PMCID: PMC12255526 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.

摘要

Tau蛋白积累与阿尔茨海默病（AD）的认知症状密切相关。然而，tau蛋白依赖的记忆认知功能衰退的细胞驱动机制仍不清楚。本研究通过在小鼠模型中运用在体Neuropixels记录技术和膜片钳记录技术，揭示出tau蛋白（独立于β-淀粉样蛋白的作用）会选择性损害海马CA1神经元的复杂锋电位簇放电（complex-spike burst firing）——这是一种支撑学习与记忆的基础性细胞机制。这种簇放电功能障碍与海马网络活动（即θ节律和高频涟漪波，这些活动与簇放电模式相耦联）的改变相关，并同时伴有神经元CaV2.3钙通道表达的降低，而该通道对于在体条件下的簇放电至关重要。我们进一步鉴定出，分离自人类AD患者脑组织的可溶性高分子量tau蛋白（soluble high molecular weight, HMW tau），正是导致簇放电抑制的特定tau蛋白种类。这些数据为AD中tau蛋白依赖的认知衰退提供了细胞层面的机制解释，并提示细胞内罕见的高分子量tau蛋白可作为潜在的治疗靶点。

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.

关键词：阿尔茨海默病、CaV2.3（R型）通道、细胞外电生理学、高分子量tau、海马CA1、人类、小鼠模型、神经元爆发、贴片钳电生理学、鼠抗、兔单抗、内参抗体、重组蛋白、佰乐博、佰乐博生物