Tau depletion in human neurons mitigates Aβ-driven toxicity.

Autor: Ng B; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Vowles J; James and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK., Bertherat F; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Abey A; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Kilfeather P; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Beccano-Kelly D; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Stefana MI; JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK., O'Brien DP; Target Discovery Institute, Centres for Medicines Discovery, Nuffield Department of Medicine, University of Oxford, NDM Research Building, Old Road Campus, Oxford, OX3 7FZ, UK., Bengoa-Vergniory N; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Carling PJ; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK.; Oxford Drug Discovery Institute, Target Discovery Institute, University of Oxford, NDM Research Building, Old Road Campus, Oxford, OX3 7FZ, UK., Todd JA; JDRF/Wellcome Diabetes and Inflammation Laboratory, Wellcome Centre for Human Genetics, Nuffield Department of Medicine, NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, OX3 7BN, UK., Caffrey TM; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Connor-Robson N; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK., Cowley SA; James and Lillian Martin Centre for Stem Cell Research, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, OX1 3RE, Oxford, UK. sally.cowley@path.ox.ac.uk., Wade-Martins R; Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK. richard.wade-martins@dpag.ox.ac.uk.; Kavli Institute for Nanoscience Discovery, Dorothy Crowfoot Hodgkin Building, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK. richard.wade-martins@dpag.ox.ac.uk.
Jazyk: angličtina
Zdroj: Molecular psychiatry [Mol Psychiatry] 2024 Jul; Vol. 29 (7), pp. 2009-2020. Date of Electronic Publication: 2024 Feb 15.
DOI: 10.1038/s41380-024-02463-2
Abstrakt: Alzheimer's disease (AD) is an age-related neurodegenerative condition and the most common type of dementia, characterised by pathological accumulation of extracellular plaques and intracellular neurofibrillary tangles that mainly consist of amyloid-β (Aβ) and hyperphosphorylated tau aggregates, respectively. Previous studies in mouse models with a targeted knock-out of the microtubule-associated protein tau (Mapt) gene demonstrated that Aβ-driven toxicity is tau-dependent. However, human cellular models with chronic tau lowering remain unexplored. In this study, we generated stable tau-depleted human induced pluripotent stem cell (iPSC) isogenic panels from two healthy individuals using CRISPR-Cas9 technology. We then differentiated these iPSCs into cortical neurons in vitro in co-culture with primary rat cortical astrocytes before conducting electrophysiological and imaging experiments for a wide range of disease-relevant phenotypes. Both AD brain derived and recombinant Aβ were used in this study to elicit toxic responses from the iPSC-derived cortical neurons. We showed that tau depletion in human iPSC-derived cortical neurons caused considerable reductions in neuronal activity without affecting synaptic density. We also observed neurite outgrowth impairments in two of the tau-depleted lines used. Finally, tau depletion protected neurons from adverse effects by mitigating the impact of exogenous Aβ-induced hyperactivity, deficits in retrograde axonal transport of mitochondria, and neurodegeneration. Our study established stable human iPSC isogenic panels with chronic tau depletion from two healthy individuals. Cortical neurons derived from these iPSC lines showed that tau is essential in Aβ-driven hyperactivity, axonal transport deficits, and neurodegeneration, consistent with studies conducted in Mapt-/- mouse models. These findings highlight the protective effects of chronic tau lowering strategies in AD pathogenesis and reinforce the potential in clinical settings. The tau-depleted human iPSC models can now be applied at scale to investigate the involvement of tau in disease-relevant pathways and cell types.
(© 2024. The Author(s).)
Databáze: MEDLINE
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