Watamura, Naoto;
Foiani, Martha S;
Bez, Sumi;
Bourdenx, Mathieu;
Santambrogio, Alessia;
Frodsham, Claire;
Camporesi, Elena;
... Saido, Takaomi C; + view all
(2024)
In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds.
Nature Neuroscience
, 28
pp. 293-307.
10.1038/s41593-024-01829-7.
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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. MAPTInt10+3G>A and MAPTS305N;Int10+3G>A 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.
| Type: | Article |
|---|---|
| Title: | In vivo hyperphosphorylation of tau is associated with synaptic loss and behavioral abnormalities in the absence of tau seeds |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1038/s41593-024-01829-7 |
| Publisher version: | https://doi.org/10.1038/s41593-024-01829-7 |
| Language: | English |
| Additional information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
| Keywords: | Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, FRONTOTEMPORAL DEMENTIA, ALZHEIMERS-DISEASE, MISSENSE MUTATION, SITE MUTATION, MOUSE MODEL, PROTEIN-TAU, GENE, TAUOPATHY, TANGLES, GENOME |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > The Sainsbury Wellcome Centre UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > UK Dementia Research Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10204676 |
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