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Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease

Eleanor K Pickett, Abigail G Herrmann, Jamie McQueen, Kimberly Abt, Owen Dando, Jane Tulloch, Pooja Jain, Sophie Dunnett, Sadaf Sohrabi, Maria Fjeldstad, Will Calkin, Leo Murison, Rosemary Jackson, Makis Tzioras, Anna Stevenson, Marie D’Orange, Monique Hooley, Caitlin Davies, Iris Oren, Jamie Rose, Chris-Anne McKenzie, Elizabeth Allison, Colin Smith, Oliver Hardt, Christopher M Henstridge, Giles Hardingham, View ORCID ProfileTara L. Spires-Jones
doi: https://doi.org/10.1101/393405
Eleanor K Pickett
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Abigail G Herrmann
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Jamie McQueen
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Kimberly Abt
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Owen Dando
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Jane Tulloch
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Pooja Jain
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Sophie Dunnett
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Sadaf Sohrabi
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Maria Fjeldstad
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Will Calkin
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Leo Murison
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Rosemary Jackson
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Makis Tzioras
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Anna Stevenson
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Marie D’Orange
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Monique Hooley
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Caitlin Davies
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Iris Oren
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Jamie Rose
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Chris-Anne McKenzie
3Centre for Clinical Brain Sciences and Sudden Death Brain Bank, University of Edinburgh, Edinburgh EH16 4SB UK
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Elizabeth Allison
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Colin Smith
3Centre for Clinical Brain Sciences and Sudden Death Brain Bank, University of Edinburgh, Edinburgh EH16 4SB UK
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Oliver Hardt
2McGill Department of Psychology, Montreal QC H3A 1B1, Canada
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Christopher M Henstridge
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Giles Hardingham
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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Tara L. Spires-Jones
1The University of Edinburgh Centre for Discovery Brain Sciences and UK Dementia Research Institute, 1 George Square, Edinburgh, EH8 9JZ UK
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  • ORCID record for Tara L. Spires-Jones
  • For correspondence: Tara.Spires-Jones@ed.ac.uk
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Abstract

Summary One of the key knowledge gaps blocking development of effective therapeutics for Alzheimer’s disease (AD) is the lack of understanding of how amyloid beta (Aβ) and tau cooperate in causing disease phenotypes. Within a mouse tau deficient background, we probed the molecular, cellular and behavioural disruption triggered by wild-type human tau’s influence on human Aβ-induced pathology. We find that Aβ and tau work cooperatively to cause a hyperactivity phenotype and to cause downregulation of gene transcription including many involved in synaptic function. In both our mouse model and in human post-mortem tissue, we observe accumulation of pathological tau in synapses, supporting the potential importance of synaptic tau. Importantly, tau depletion in the mice, initiated after behavioural deficits emerge, was found to correct behavioural deficits, reduce synaptic tau levels, and substantially reverse transcriptional perturbations, suggesting that lowering tau levels, particularly at the synapse, may be beneficial in AD.

Highlights

  • - Expression of human familial Alzheimer’s associated mutant amyloid precursor protein and presenillin 1 with wild-type human tau in the absence of endogenous tau in a novel MAPT-AD mouse model results in behavioural deficits and downregulation of genes involved in synaptic function.

  • - Tau is present in pre and postsynaptic terminals in MAPT-AD mice and human AD brain. In mice, lowering synaptic tau levels was associated with improved cognition and recovered gene expression.

  • - These data suggest that Aβ and tau act cooperatively in impairing synaptic function and that lowering tau at synapses could be a beneficial therapeutic approach in AD.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted August 16, 2018.
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Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease
Eleanor K Pickett, Abigail G Herrmann, Jamie McQueen, Kimberly Abt, Owen Dando, Jane Tulloch, Pooja Jain, Sophie Dunnett, Sadaf Sohrabi, Maria Fjeldstad, Will Calkin, Leo Murison, Rosemary Jackson, Makis Tzioras, Anna Stevenson, Marie D’Orange, Monique Hooley, Caitlin Davies, Iris Oren, Jamie Rose, Chris-Anne McKenzie, Elizabeth Allison, Colin Smith, Oliver Hardt, Christopher M Henstridge, Giles Hardingham, Tara L. Spires-Jones
bioRxiv 393405; doi: https://doi.org/10.1101/393405
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Reducing tau ameliorates behavioural and transcriptional deficits in a novel model of Alzheimer’s disease
Eleanor K Pickett, Abigail G Herrmann, Jamie McQueen, Kimberly Abt, Owen Dando, Jane Tulloch, Pooja Jain, Sophie Dunnett, Sadaf Sohrabi, Maria Fjeldstad, Will Calkin, Leo Murison, Rosemary Jackson, Makis Tzioras, Anna Stevenson, Marie D’Orange, Monique Hooley, Caitlin Davies, Iris Oren, Jamie Rose, Chris-Anne McKenzie, Elizabeth Allison, Colin Smith, Oliver Hardt, Christopher M Henstridge, Giles Hardingham, Tara L. Spires-Jones
bioRxiv 393405; doi: https://doi.org/10.1101/393405

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