Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1784592069402034176 |
---|---|
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. |
format | Online Article Text |
id | pubmed-8555892 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | American Association for the Advancement of Science |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT meislgeorg invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT hidarieric invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT allinsonkieren invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT rittmantimothy invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT devossarahl invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT sanchezjustins invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT xucatherinek invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT duffkarene invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT johnsonkeitha invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT rowejamesb invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT hymanbradleyt invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT knowlestuomaspj invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease AT klenermandavid invivoratedeterminingstepsoftauseedaccumulationinalzheimersdisease |