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In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease

Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing...

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Autores principales: Meisl, Georg, Hidari, Eric, Allinson, Kieren, Rittman, Timothy, DeVos, Sarah L., Sanchez, Justin S., Xu, Catherine K., Duff, Karen E., Johnson, Keith A., Rowe, James B., Hyman, Bradley T., Knowles, Tuomas P. J., Klenerman, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555892/
https://www.ncbi.nlm.nih.gov/pubmed/34714685
http://dx.doi.org/10.1126/sciadv.abh1448
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author Meisl, Georg
Hidari, Eric
Allinson, Kieren
Rittman, Timothy
DeVos, Sarah L.
Sanchez, Justin S.
Xu, Catherine K.
Duff, Karen E.
Johnson, Keith A.
Rowe, James B.
Hyman, Bradley T.
Knowles, Tuomas P. J.
Klenerman, David
author_facet Meisl, Georg
Hidari, Eric
Allinson, Kieren
Rittman, Timothy
DeVos, Sarah L.
Sanchez, Justin S.
Xu, Catherine K.
Duff, Karen E.
Johnson, Keith A.
Rowe, James B.
Hyman, Bradley T.
Knowles, Tuomas P. J.
Klenerman, David
author_sort Meisl, Georg
collection PubMed
description Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every ∼5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD.
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spelling pubmed-85558922021-11-08 In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease Meisl, Georg Hidari, Eric Allinson, Kieren Rittman, Timothy DeVos, Sarah L. Sanchez, Justin S. Xu, Catherine K. Duff, Karen E. Johnson, Keith A. Rowe, James B. Hyman, Bradley T. Knowles, Tuomas P. J. Klenerman, David Sci Adv Neuroscience Both the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we can quantify their replication rate in human brains. Notably, we obtain comparable rates in several different datasets, with five different methods of tau quantification, from postmortem seed amplification assays to tau PET studies in living individuals. Our results suggest that from Braak stage III onward, local replication, rather than spreading between brain regions, is the main process controlling the overall rate of accumulation of tau in neocortical regions. The number of seeds doubles only every ∼5 years. Thus, limiting local replication likely constitutes the most promising strategy to control tau accumulation during AD. American Association for the Advancement of Science 2021-10-29 /pmc/articles/PMC8555892/ /pubmed/34714685 http://dx.doi.org/10.1126/sciadv.abh1448 Text en Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY). https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Neuroscience
Meisl, Georg
Hidari, Eric
Allinson, Kieren
Rittman, Timothy
DeVos, Sarah L.
Sanchez, Justin S.
Xu, Catherine K.
Duff, Karen E.
Johnson, Keith A.
Rowe, James B.
Hyman, Bradley T.
Knowles, Tuomas P. J.
Klenerman, David
In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease
title In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease
title_full In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease
title_fullStr In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease
title_full_unstemmed In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease
title_short In vivo rate-determining steps of tau seed accumulation in Alzheimer’s disease
title_sort in vivo rate-determining steps of tau seed accumulation in alzheimer’s disease
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8555892/
https://www.ncbi.nlm.nih.gov/pubmed/34714685
http://dx.doi.org/10.1126/sciadv.abh1448
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