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Secondary Nucleation in Amyloid Formation

Törnquist, Mattias LU (2020)
Abstract
Research into Alzheimer's disease is still hampered by a lack of fundamental understanding of the underlying mechanisms. While the aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is highly implicated as a key factor in the disease, the molecular nature of its involvement has proven complex and elusive. This thesis and the work herein is part of an ongoing effort to map out the aggregation mechanism of Aβ in vitro in as much detail as possible, in the hope to provide a better basis for understanding its role in disease. In particular, the mechanism of secondary nucleation, whereby the fibril surface catalyses the formation of new fibrils is of interest due to its capacity to generate large numbers of toxic oligomers. In this... (More)
Research into Alzheimer's disease is still hampered by a lack of fundamental understanding of the underlying mechanisms. While the aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is highly implicated as a key factor in the disease, the molecular nature of its involvement has proven complex and elusive. This thesis and the work herein is part of an ongoing effort to map out the aggregation mechanism of Aβ in vitro in as much detail as possible, in the hope to provide a better basis for understanding its role in disease. In particular, the mechanism of secondary nucleation, whereby the fibril surface catalyses the formation of new fibrils is of interest due to its capacity to generate large numbers of toxic oligomers. In this work, we probe the determinants of secondary nucleation by studying its influence in different temperatures and pH and we confirm that it remains an important factor in aggregation in human cerebrospinal fluid. We also report a transient accumulation of pre-fibrillar aggregates, likely to be a result of heavily saturated secondary nucleation, which can form a basis for further structural studies of this phenomenon. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Eisenberg, David, UCLA, Los Angeles, USA
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Alzheimer's disease, amyloid, Ab42, aggregation mechanism, aggregation kinetics, secondary nucleation, Protein misfolding
pages
44 pages
publisher
Lund University, Faculty of Science, Department of Chemistry
defense location
Lecture Hall A, Kemicentrum, Naturvetarvägen 14, Lund (Live streaming: https://lu-se.zoom.us/j/64932035028)
defense date
2020-06-04 15:00:00
ISBN
978-91-7422-747-5
978-91-7422-740-6
language
English
LU publication?
yes
id
3a635994-99d3-46e2-a2cc-6688805089e0
date added to LUP
2020-05-11 09:05:21
date last changed
2020-05-13 22:16:09
@phdthesis{3a635994-99d3-46e2-a2cc-6688805089e0,
  abstract     = {Research into Alzheimer's disease is still hampered by a lack of fundamental understanding of the underlying mechanisms. While the aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is highly implicated as a key factor in the disease, the molecular nature of its involvement has proven complex and elusive. This thesis and the work herein is part of an ongoing effort to map out the aggregation mechanism of Aβ in vitro in as much detail as possible, in the hope to provide a better basis for understanding its role in disease. In particular, the mechanism of secondary nucleation, whereby the fibril surface catalyses the formation of new fibrils is of interest due to its capacity to generate large numbers of toxic oligomers. In this work, we probe the determinants of secondary nucleation by studying its influence in different temperatures and pH and we confirm that it remains an important factor in aggregation in human cerebrospinal fluid. We also report a transient accumulation of pre-fibrillar aggregates, likely to be a result of heavily saturated secondary nucleation, which can form a basis for further structural studies of this phenomenon.},
  author       = {Törnquist, Mattias},
  isbn         = {978-91-7422-747-5},
  language     = {eng},
  month        = {05},
  publisher    = {Lund University, Faculty of Science, Department of Chemistry},
  school       = {Lund University},
  title        = {Secondary Nucleation in Amyloid Formation},
  url          = {https://lup.lub.lu.se/search/ws/files/79431255/Secondary_Nucleation_in_Amyloid_Formation.pdf},
  year         = {2020},
}