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Imaging Aβ(1–42) fibril elongation reveals strongly polarised growth and growth incompetent states

Accepted version
Peer-reviewed

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Type

Article

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Authors

Young, LJ 
Kaminski Schierle, GS 
Kaminski, CF 

Abstract

The major hallmark of Alzheimer’s disease is the deposition of plaques of amyloid fibrils formed from amyloid-beta (Ab) peptides. Kinetic studies have contributed significantly towards a mechanistic understanding of amyloid fibril self-assembly, however dynamic features of the aggregation process cannot be captured using ensemble methods. Here we present an assay for imaging Ab42 aggregation dynamics at the single fibril level, allowing for the quantitative extraction of concentration and temperature dependent kinetic parameters. From direct observation of elongation using TIRF and superresolution optical microscopy, we find that Ab42 fibril growth is strongly polarized, with fast and slow growing ends arising from different elongation rates, but also from a growth incompetent state, which dominates the process at the slow growing end. Our findings reveal the surprising complexity of the Ab42 fibril elongation reaction at the microscopic level.

Description

Keywords

0299 Other Physical Sciences, Aging, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurodegenerative, Dementia, Brain Disorders, Acquired Cognitive Impairment, Neurosciences, Alzheimer's Disease, 1.1 Normal biological development and functioning

Journal Title

Physical Chemistry Chemical Physics

Conference Name

Journal ISSN

1463-9076
1463-9084

Volume Title

19

Publisher

Royal Society of Chemistry
Sponsorship
Medical Research Council (MR/K02292X/1)
Engineering and Physical Sciences Research Council (EP/L015889/1)
EPSRC (1108165)
Wellcome Trust (203249/Z/16/Z)
Engineering and Physical Sciences Research Council (EP/H018301/1)
Medical Research Council (MR/K015850/1)
Biotechnology and Biological Sciences Research Council (BB/H023917/1)
Medical Research Council (G0902243)
Wellcome Trust (089703/Z/09/Z)
Engineering and Physical Sciences Research Council (EP/G037221/1)
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