Secondary Nucleation in Amyloid Formation

Research output: ThesisDoctoral Thesis (compilation)

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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.
Original languageEnglish
QualificationDoctor
Supervisors/Advisors
  • Snogerup-Linse, Sara, Supervisor
  • Cedervall, Tommy, Assistant supervisor
  • Leiding, Thom, Assistant supervisor
Award date2020 Jun 4
Place of PublicationLund
Publisher
ISBN (Print)978-91-7422-740-6
ISBN (electronic) 978-91-7422-747-5
Publication statusPublished - 2020 May 11

Bibliographical note

Defence details
Date: 2020-06-04
Time: 15:00
Place: Lecture Hall A, Kemicentrum, Naturvetarvägen 14, Lund (Live streaming: https://lu-se.zoom.us/j/64932035028)
External reviewer(s)
Name: Eisenberg, David
Title: Professor
Affiliation: UCLA, Los Angeles, USA
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Subject classification (UKÄ)

  • Other Chemistry Topics

Keywords

  • Alzheimer's disease
  • amyloid
  • Ab42
  • aggregation mechanism
  • aggregation kinetics
  • secondary nucleation
  • Protein misfolding

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