In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds

Tau pathology is a hallmark of several neurodegenerative diseases, including frontotemporal dementia and Alzheimer's disease. However, the sequence of events and the form of tau that confers toxicity are still unclear, due in large part to the lack of physiological models of tauopathy initiation and progression in which to test hypotheses. We have developed a series of targeted mice expressing frontotemporal-dementia-causing mutations in the humanized MAPT gene to investigate the earliest stages of tauopathy. MAPT<sup>Int10+3G>A</sup> and MAPT<sup>S305N;Int10+3G>A</sup> lines show abundant hyperphosphorylated tau in the hippocampus and entorhinal cortex, but they do not develop seed-competent fibrillar structures. Accumulation of hyperphosphorylated tau was accompanied by neurite degeneration, loss of viable synapses and indicators of behavioral abnormalities. Our results demonstrate that neuronal toxicity can occur in the absence of fibrillar, higher-order structures and that tau hyperphosphorylation is probably involved in the earliest etiological events in tauopathies showing isoform ratio imbalance.

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Publication Details

Journal
Nature Neuroscience
Published
2024-12-24
DOI
https://doi.org/10.1038/s41593-024-01829-7
Citations
36
Primary Topic
Alzheimer's disease research and treatments
Type
article
Field-Weighted Citation Impact
11.76

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article

In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds

Emir Turkes, Martha Foiani, Karen Duff, Javier Rueda‐Carrasco et al.
36 citations
Nature Neuroscience
Alzheimer's disease research and treatments
11.76
article

In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds

Emir Turkes, Martha Foiani, Karen Duff, Javier Rueda‐Carrasco, Gunnar Brinkmalm, Takashi Saito, Saisha Patel, Aditi Islam, Sumi Bez, Takaomi C. Saido, Shoko Hashimoto, Michele Vendruscolo, Elena Camporesi, Naoto Watamura, Mika Takahashi, Alessia Santambrogio, Seico Benner, Loukia Katsouri, Mathieu Bourdenx, Stephanie L. Fowler, Henrik Zetterberg, Chiho Ishida, Masahito Yamada, Naoko Kamano, Hiroki Sasaguri, Claire Frodsham, Toshihiro Endo, Katsuji Kobayashi
article en
36 citations

Abstract

Tau pathology is a hallmark of several neurodegenerative diseases, including frontotemporal dementia and Alzheimer's disease. However, the sequence of events and the form of tau that confers toxicity are still unclear, due in large part to the lack of physiological models of tauopathy initiation and progression in which to test hypotheses. We have developed a series of targeted mice expressing frontotemporal-dementia-causing mutations in the humanized MAPT gene to investigate the earliest stages of tauopathy. MAPT<sup>Int10+3G>A</sup> and MAPT<sup>S305N;Int10+3G>A</sup> lines show abundant hyperphosphorylated tau in the hippocampus and entorhinal cortex, but they do not develop seed-competent fibrillar structures. Accumulation of hyperphosphorylated tau was accompanied by neurite degeneration, loss of viable synapses and indicators of behavioral abnormalities. Our results demonstrate that neuronal toxicity can occur in the absence of fibrillar, higher-order structures and that tau hyperphosphorylation is probably involved in the earliest etiological events in tauopathies showing isoform ratio imbalance.

Nature NeuroscienceVol. 28(2)
Kanazawa University (JP), Tokyo Medical and Dental University (JP), Shiga University of Medical Science (JP), Queen Mary University of London (GB), Shiga University (JP), National Institute for Environmental Studies (JP), University of Cambridge (GB), RIKEN Center for Brain Science (JP), Nuffield Orthopaedic Centre (GB), Nagoya City University (JP), Pioneer (Japan) (JP), Kudanzaka Hospital (JP), UK Dementia Research Institute (GB), National Hospital for Neurology and Neurosurgery (GB), University College London (GB), Nagoya University (JP), University of Gothenburg (SE)
Ohio State University, Cure Alzheimer's Fund, Michigan State University, University of Texas Southwestern Medical Center, Japan Agency for Medical Research and Development, Northwell Health, European Commission, Vetenskapsrådet, Göteborgs Universitet, UK Dementia Research Institute, National Institutes of Health, College of Engineering, Michigan State University, HORIZON EUROPE Framework Programme, Medical Research Council, Japan Society for the Promotion of Science, RIKEN, Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology,University College London
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Openalex Percentile: Top 1%
Alzheimer's disease research and treatments
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