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ACS Chem Neurosci. 2018 Jun 20;9(6):1276-1282. doi: 10.1021/acschemneuro.8b00094. Epub 2018 Apr 8.

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

Author information

1
Department of Chemistry , University of Cambridge , Lensfield Road , Cambridge CB2 1EW , United Kingdom.
2
MRC Laboratory of Molecular Biology , Francis Crick Avenue , Cambridge CB2 0QH , United Kingdom.
3
Paulson School of Engineering and Applied Sciences , Harvard University , Cambridge , Massachusetts 02138 , United States.
4
Department of Molecular Neuroscience , UCL Institute of Neurology , London WC1N 3BG , United Kingdom.
5
UK Dementia Research Institute , University of Cambridge , Cambridge CB2 0XY , United Kingdom.

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.

KEYWORDS:

Alzheimer’s disease; Prion propagation; biophysics; kinetic modeling; single-molecule microscopy; tau

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