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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Hong, Liu 
Falcon, Benjamin 
McEwan, William A 
Michaels, Thomas CT 

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.

Description

Keywords

Alzheimer’s disease, Prion propagation, biophysics, kinetic modeling, single-molecule microscopy, tau, Alzheimer Disease, Amyloid, Brain, Cytoskeleton, Humans, Neurofibrillary Tangles, Prions, Tauopathies, tau Proteins

Journal Title

ACS Chem Neurosci

Conference Name

Journal ISSN

1948-7193
1948-7193

Volume Title

9

Publisher

American Chemical Society (ACS)
Sponsorship
European Research Council (669237)
Wellcome Trust (206248/Z/17/Z)