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Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading

Kundel, F; Hong, L; Falcon, B; McEwan, WA; Michaels, TCT; Meisl, G; Esteras, N; ... Klenerman, D; + view all (2018) Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading. ACS Chemical Neuroscience 10.1021/acschemneuro.8b00094. (In press). Green open access

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Abstract

The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimer's and Parkinson's diseases. These diseases share common features with prion diseases, in which misfolded proteins can self-replicate and transmit disease across different hosts. Deciphering the molecular mechanisms that underlie the amplification of aggregates is fundamental for understanding how pathological deposits can spread through the brain and drive disease. Here, we used single-molecule microscopy to study the assembly and replication of tau at the single aggregate level. We found that tau aggregates have an intrinsic ability to amplify by filament fragmentation, and determined the doubling times for this replication process by kinetic modeling. We then simulated the spreading time for aggregates through the brain and found this to be in good agreement with both the observed time frame for spreading of pathological tau deposits in Alzheimer's disease and in experimental models of tauopathies. With this work we begin to understand the physical parameters that govern the spreading rates of tau and other amyloids through the human brain.

Type: Article
Title: Measurement of Tau Filament Fragmentation Provides Insights into Prion-like Spreading
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1021/acschemneuro.8b00094
Publisher version: http://doi.org/10.1021/acschemneuro.8b00094
Language: English
Additional information: Copyright © 2018 American Chemical Society. This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.
Keywords: Alzheimer’s disease, Prion propagation, biophysics, kinetic modeling, single-molecule microscopy, tau
UCL classification: UCL > Provost and Vice Provost Offices
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 Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
URI: http://discovery.ucl.ac.uk/id/eprint/10048704
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