Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 430, Issue 17, Pages 2722-2733Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2018.06.005
Keywords
transthyretin; A beta; amyloid; thioflavin-T; surface plasmon resonance
Categories
Funding
- Insamlingsstiftelsen at Umea University
- Alzheimerfonden
- Demensfonden
- Ahlen-stiftelsen
- J.C. Kempes stiftelse
- Swedish Research Council
- Magn. Bergvalls stiftelse
- Parkinsonfonden
- Centre-UCEM
- Torsten Soderbergs stiftelse
- Medical Faculty of Umea University
- Hjamfonden
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The pathological A beta aggregates associated with Alzheimer's disease follow a nucleation-dependent path of formation. A nucleus represents an oligomeric assembly of A beta peptides that acts as a template for subsequent incorporation of monomers to form a fibrillar structure. Nuclei can form de novo or via surface-catalyzed secondary nucleation, and the combined rates of elongation and nucleation control the overall rate of fibril formation. Transthyretin (TTR) obstructs A beta fibril formation in favor of alternative non-fibrillar assemblies, but the mechanism behind this activity is not fully understood. This study shows that TTR does not significantly disturb fibril elongation; rather, it effectively interferes with the formation of oligomeric nuclei. We demonstrate that this interference can be modulated by altering the relative contribution of elongation and nucleation, and we show how TTR's effects can range from being essentially ineffective to almost complete inhibition of fibril formation without changing the concentration of TTR or monomeric A beta. (C) 2018 Published by Elsevier Ltd.
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