期刊
ACS CHEMICAL NEUROSCIENCE
卷 9, 期 6, 页码 1276-1282出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschemneuro.8b00094
关键词
Prion propagation; Alzheimers disease; kinetic modeling; single-molecule microscopy; tau; biophysics
资金
- ERC [669237]
- Royal Society
- Augustus Newman foundation
- ERC
- Tsinghua University Initiative Scientific Research Programme [20151080424]
- China Scholarships Council (CSC)
- Sir Henry Dale Fellowship - Wellcome Trust [206248/Z/17/Z]
- Sir Henry Dale Fellowship - Royal Society [206248/Z/17/Z]
- Peterhouse College Cambridge
- Swiss National Science Foundation
- Sidney Sussex College Cambridge
- UK Medical Research Council [MC_U105184291]
- European Union (Joint Programme-Neurodegeneration Research)
- European Union (JPND-REfrAME)
- European Union (Horizon 2020 IMPRiND)
- Wellcome Trust [206248/Z/17/Z] Funding Source: Wellcome Trust
- MRC [MC_U105184291, UKDRI-2003] Funding Source: UKRI
The ordered assembly of amyloidogenic proteins causes a wide spectrum of common neurodegenerative diseases, including Alzheimers and Parkinsons 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 Alzheimers 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.
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