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Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons

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Abstract

The major neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid β (Aβ) plaques and neurofibrillary tangles (NFT), accompanied by neuroinflammation and neuronal loss. Increasing evidence is emerging for the activation of the canonical NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome in AD. However, the mechanisms leading to neuronal loss in AD and the involvement of glial cells in these processes are still not clear. The aim of this study was to investigate the contribution of pyroptosis, a pro-inflammatory mechanism of cell death downstream of the inflammasome, to neurodegeneration in AD. Immunohistochemistry and biochemical analysis of protein levels were performed on human post-mortem brain tissue. We investigated the presence of cleaved gasdermin D (GSDMD), the pyroptosis effector protein, as well as the NLRP3 inflammasome-forming proteins, in the medial temporal lobe of 23 symptomatic AD, 25 pathologically defined preclinical AD (p-preAD) and 21 non-demented control cases. Cleaved GSDMD was detected in microglia, but also in astrocytes and in few pyramidal neurons in the first sector of the cornu ammonis (CA1) of the hippocampus and the temporal cortex of Brodmann area 36. Only microglia expressed all NLRP3 inflammasome-forming proteins (i.e., ASC, NLRP3, caspase-1). Cleaved GSDMD-positive astrocytes and neurons exhibited caspase-8 and non-canonical inflammasome protein caspase-4, respectively, potentially indicating alternative pathways for GSDMD cleavage. Brains of AD patients exhibited increased numbers of cleaved GSDMD-positive cells. Cleaved GSDMD-positive microglia and astrocytes were found in close proximity to Aβ plaques, while cleaved GSDMD-positive neurons were devoid of NFTs. In CA1, NLRP3-positive microglia and cleaved GSDMD-positive neurons were associated with local neuronal loss, indicating a possible contribution of NLRP3 inflammasome and pyroptosis activation to AD-related neurodegeneration. Taken together, our results suggest cell type-specific activation of pyroptosis in AD and extend the current knowledge about the contribution of neuroinflammation to the neurodegenerative process in AD via a direct link to neuron death by pyroptosis.

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All relevant data generated and analyzed in this study are available in this manuscript, online supplementary information or upon reasonable request.

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Acknowledgements

This study was supported by funding from FWO-Vlaanderen (G0F8516N and G065721N, DRT). SM received a Doctoral mandate from KU Leuven internal funds (DB/20/007/BM). An SB PhD Fellowship from FWO-Vlaanderen was given to EVS (1S46219N). JMS is a junior postdoctoral fellow of the Fonds Wetenschappelijk Onderzoek (FWO/Belgium) (12Y1620N) and received funding from Stichting Alzheimer association (#SAO-FRA 2021/00022). We gratefully acknowledge the support of Ms. Simona Ospitalieri and Mrs. Alicja Ronisz, and the VIB Bio Imaging Core for their support & assistance in this study.

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  1. Laboratory for Neuropathology, Department of Imaging and Pathology, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), O&N IV Herestraat 49, Bus 1032, 3000, Leuven, Belgium

    Sebastiaan Moonen, Marta J. Koper, Evelien Van Schoor, Jolien M. Schaeverbeke & Dietmar Rudolf Thal

  2. Laboratory for the Research of Neurodegenerative Diseases, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium

    Sebastiaan Moonen, Marta J. Koper & Bart De Strooper

  3. Vlaams Instituut voor Biotechnologie (VIB) Center for Brain and Disease Research, VIB, Leuven, Belgium

    Sebastiaan Moonen, Marta J. Koper, Evelien Van Schoor & Bart De Strooper

  4. Laboratory for Neurobiology, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium

    Evelien Van Schoor

  5. Laboratory for Cognitive Neurology, Department of Neurosciences, Leuven Brain Institute (LBI), KU Leuven (University of Leuven), Leuven, Belgium

    Jolien M. Schaeverbeke & Rik Vandenberghe

  6. Department of Neurology, University Hospital Leuven, Leuven, Belgium

    Rik Vandenberghe

  7. Department of Neurology, University of Ulm, Ulm, Germany

    Christine A. F. von Arnim

  8. Department of Geriatrics, University Medical Center Göttingen, Göttingen, Germany

    Christine A. F. von Arnim

  9. Department of Pathology, University Hospital Leuven, Leuven, Belgium

    Thomas Tousseyn & Dietmar Rudolf Thal

  10. UK Dementia Research Institute, Institute of Neurology, University College London, London, UK

    Bart De Strooper

Authors
  1. Sebastiaan Moonen
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  2. Marta J. Koper
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  3. Evelien Van Schoor
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  4. Jolien M. Schaeverbeke
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  5. Rik Vandenberghe
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  6. Christine A. F. von Arnim
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  7. Thomas Tousseyn
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  8. Bart De Strooper
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  9. Dietmar Rudolf Thal
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Contributions

SM: study design, neuropathology, immunohistochemistry, microscopic assessments, statistical analysis, manuscript drafting and preparation. MK: study design, immunohistochemistry, microscopic assessments, critical review of the manuscript. EVS: immunohistochemistry, critical review of the manuscript. JMS: statistical analysis, critical review of the manuscript. RV, CAFvA: clinical neurology, recruitment, critical review of the manuscript. TT: neuropathology and critical review of the manuscript. BDS: study design, critical review of the manuscript. DRT: study design and coordination, neuropathology, microscopic assessments, supplementary statistical analysis, and manuscript preparation. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Sebastiaan Moonen or Dietmar Rudolf Thal.

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Conflict of interest

DRT is a member of the Acta Neuropathologica Editorial Board. He was not involved in the assessment or decision-making process for this manuscript. DRT received speaker honorary or travel reimbursement from UCB (Brussels, Belgium) and Biogen (USA), and collaborated with Novartis Pharma AG (Basel, Switzerland), Probiodrug (Halle (Saale), Germany), GE Healthcare (Amersham, UK), and Janssen Pharmaceutical Companies (Beerse, Belgium). RV’s institution has a clinical trial agreement (RV as PI) with Alector, Biogen, J&J, NovoNordisk, Prevail, Roche and UCB. RV’s institution has a consultancy agreement for participation in Data Safety Monitoring Board (RV as provider) with AC Immune and Novartis. RV’s institution has a material transfer agreement (RV as PI) with ADx Neurosciences. CAFvA received honoraria from serving on the scientific advisory board of Biogen, Roche, Novo Nordisk, and Dr. Willmar Schwabe GmbH &Co. KG and has received funding for travel and speaker honoraria from Biogen, Roche diagnostics AG, Medical Tribune Verlagsgesellschaft mbH, and Dr. Willmar Schwabe GmbH &Co. KG and has received research support from Roche diagnostics AG. Bart De Strooper is occasionally consulting for different companies. He is founding scientist of Augustin TX and of Muna TX. He is also shareholder of Muna TX. Funders were not involved in the design of this study, in the collection, analysis or interpretation of data, in the decision to publish the results, or in the preparation of the manuscript.

Ethical approval

Human post-mortem brain tissue was collected in accordance with the applicable laws in Belgium (UZ Leuven) and Germany (Ulm). The recruitment protocols for the collection of human brains were approved by the ethical committees of the UZ Leuven (Belgium; S-59292, S-52791) and the University of Ulm (Germany; 54/08). This study was approved by the UZ Leuven ethical committee (Leuven, Belgium; S-64378).

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Moonen, S., Koper, M.J., Van Schoor, E. et al. Pyroptosis in Alzheimer’s disease: cell type-specific activation in microglia, astrocytes and neurons. Acta Neuropathol 145, 175–195 (2023). https://doi.org/10.1007/s00401-022-02528-y

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  • DOI: https://doi.org/10.1007/s00401-022-02528-y

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