Abstract
Alzheimer’s disease (AD) and other tauopathies are characterized by the aggregation of tau into soluble and insoluble forms (including tangles and neuropil threads). In humans, a fraction of both phosphorylated and non-phosphorylated N-terminal to mid-domain tau species, are secreted into cerebrospinal fluid (CSF). Some of these CSF tau species can be measured as diagnostic and prognostic biomarkers, starting from early stages of disease. While in animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, it is unclear whether the tau species present in CSF will modulate neural activity. Here, we have developed and applied a novel approach to examine the electrophysiological effects of CSF from patients with a tau-positive biomarker profile. The method involves incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF, followed by a suite of electrophysiological recording methods to evaluate their effects on neuronal function, from single cells through to the network level. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, has enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We then observed, at the network level, increased input–output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF-tau to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding tau pathology, thus allowing for the development of better targeted treatments for tauopathies in the future.
Graphical Abstract
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Introduction
Tau plays a central role in the neuropathology of Alzheimer's disease (AD) and other tauopathies [69, 113]. Whilst insoluble high-molecular weight tau aggregates, including neurofibrillary tangles are more prominent in late phases of these diseases and can help to stage their pathological and clinical severity [21, 30, 95], the soluble forms of tau, including low-molecular weight aggregated and phosphorylated forms, are thought to be the most toxic species that modulate changes in neuronal function in the early stages of disease. In animal models of AD pathology, soluble tau aggregates have been shown to disrupt neuronal function, alter synaptic plasticity and impair cognitive function [20, 45, 81, 105, 108].
In AD, N-terminal to mid-domain tau fragments, both phosphorylated and non-phosphorylated variants, are released into the cerebrospinal fluid (CSF) early in disease progression, which has enabled the development of biomarkers for disease prognosis, diagnosis, and staging [19, 32, 57, 67, 110, 111]. While the presence of different tau forms in the CSF of AD patients is associated with neurofibrillary tangle pathology and cognitive decline [98, 99, 104, 109, 118, 119].
This leads to the question of what incubation with CSF-tau in this study might be doing to hippocampal neurons to mediate the elevation in the power of theta oscillations. A combination of experimental and simulated data has indicated that the early-stage AD hyperactivity underpinning oscillatory slowing could be due to pyramidal neuron hyperexcitability [25, 27, 49, 97, 117, 138] and/or reduced excitability of GABAergic PV interneurons and thus pyramidal cell disinhibition [4, 31, 59, 89, 97, 103, 121]. Support for the latter hypothesis of disinhibition also comes from the loss of inhibitory synapses in AD along with the pronounced GABAergic dysfunction observed in AD mouse models, including the model of APOE4, the principal genetic disease risk factor [24, 97]. Such findings provide a potential mechanism for the oscillatory disruption induced by CSF-tau incubation in this study and imply such network alterations to represent an element of the core, initial neuropathology of AD. Indeed, recent studies are now evaluating the therapeutic implementation of theta entrainment for AD patients [40, 84, 133, 134].
It has also been demonstrated that changes to theta oscillatory power—similar to what we observed herein—can be used to distinguish between prodromal AD and non-AD cases with cognitive decline [97]. The fact that our effects on oscillations agree with clinical human electrophysiological studies gives confidence that this is a method that could, in the future, be clinically useful in compliment to EEG testing.
Taking all of these changes together, it would be helpful to know whether the changes in membrane potential (4 mV depolarisation), increase in input resistance (~ 1/3) and reduction in rheobase are sufficient to account for the increases in the other parameters measured (e.g., baseline synaptic strength, PPF, LTP and theta oscillations). This question is difficult to answer without several additional experiments. In this proof of principle study, we only recorded from CA1 pyramidal cells. Thus, we do not know if similar effects on excitability also occur with CA3 pyramidal cells and with inhibitory interneurons. With this additional information it would be possible to construct computational models and for example determine whether these changes could account for the increase in theta oscillations and this will be explored further in future studies.
Conclusion
In this study, we have demonstrated that incubation of acutely-isolated wild-type mouse hippocampal brain slices with small volumes of diluted human CSF-tau allowed us to evaluate effects on neuronal function from single cells through to network level effects. Comparison of the toxicity profiles of the same CSF samples, with and without immuno-depletion for tau, enabled a pioneering demonstration that CSF-tau potently modulates neuronal function. We demonstrate that CSF-tau mediates an increase in neuronal excitability in single cells. We observed, at the network level, increased input–output responses and enhanced paired-pulse facilitation as well as an increase in long-term potentiation. Finally, we show that CSF-tau modifies the generation and maintenance of hippocampal theta oscillations, which have important roles in learning and memory and are known to be altered in AD patients. Together, we describe a novel method for screening human CSF to understand functional effects on neuron and network activity, which could have far-reaching benefits in understanding pathological mechanisms of tauopathies, thus allowing the development of better targeted treatments.
Availability of data and materials
The raw data generated and analysed for this manuscript are available from the corresponding author upon reasonable request.
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Acknowledgements
We would like to thank Professor Bruno Frenguelli for providing an interface chamber for the recording of theta oscillations.
Funding
EH holds a Race Against Dementia Fellowship funded by the Barbara Naylor Foundation, in collaboration with ARUK. JB is funded by the Medical Research Council doctoral training partnership at The University of Manchester. AW is funded by the Medical Research Council doctoral training partnership at the University of Warwick. TKK is funded by the Swedish Research Council (Vetenskapsrådet #2021-03244), the Alzheimer’s Association Research Fellowship (#AARF-21-850325), the Aina (Ann) Wallströms and Mary-Ann Sjöbloms stiftelsen, and the Emil och Wera Cornells stiftelsen. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2022-01018), the European Union’s Horizon Europe research and innovation programme under grant agreement No 101053962, Swedish State Support for Clinical Research (#ALFGBG-71320), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809-2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21-831376-C, #ADSF-21-831381-C, and #ADSF-21-831377-C), the Bluefield Project, the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2022-0270), the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), the European Union Joint Programme—Neurodegenerative Disease Research (JPND2021-00694), and the UK Dementia Research Institute at UCL (UKDRI-1003). KB is supported by the Swedish Research Council (#2017-00915 and #2022-00732), the Swedish Alzheimer Foundation (#AF-930351, #AF-939721 and #AF-968270), Hjärnfonden, Sweden (#FO2017-0243 and #ALZ2022-0006), the Swedish state under the agreement between the Swedish government and the County Councils, the ALF-agreement (#ALFGBG-715986 and #ALFGBG-965240), the European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236), the Alzheimer’s Association 2021 Zenith Award (ZEN-21-848495), and the Alzheimer’s Association 2022-2025 Grant (SG-23-1038904 QC).
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Conceptualization: EH, MJW, TKK, JB, Methodology: EH, MJW, TKK, JB, Formal analysis, and Investigation: EH, MJW, JB, EC, JLR, MO, AW, BM, Writing—original draft preparation: EH, Writing—review and editing: EH, MJW, TKK, JB, EC, JLR, MO, AW, BM, HZ, KB, Resources: EH, MJW, TKK, EC, JLR, MO, HZ, KB, Supervision: EH, MJW, TKK.
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CSF collection and processing were performed at the University of Gothenburg, Sweden, with local ethical approval, and the samples sent to the University of Warwick, UK, where all experiments were done as approved by the local Human Tissue Authority and Biomedical & Scientific Research Ethics Committees. All animal care and experimental procedures were reviewed and approved by the institutional animal welfare and ethical review body (AWERB) at the University of Warwick.
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Additional file 1. Figure 1. Dose response for the effect of CSF-tau on neuronal function. Figure 2. Protocol for analysis of hippocampal CA3 theta oscillations. Figure 3. Validation of tau effects using CSF-mock-depleted.
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Brown, J., Camporesi, E., Lantero-Rodriguez, J. et al. Tau in cerebrospinal fluid induces neuronal hyperexcitability and alters hippocampal theta oscillations. acta neuropathol commun 11, 67 (2023). https://doi.org/10.1186/s40478-023-01562-5
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DOI: https://doi.org/10.1186/s40478-023-01562-5