Investigating the Phase Behaviour of the Alzheimer’s Amyloid-β Peptide

A wide range of degenerative neurological conditions, including Alzheimer’s Disease (AD), are associated with the misfolding and aggregation of proteins. The aggregation of the amyloid-β peptide (Aβ) into amyloid plaques is a hallmark in the aetiology of AD. However, the exact nature of the association between AD and Aβ aggregation is not fully understood. Quite generally, the aggregation of proteins into amyloid fibrils takes place via a nucleation pathway leading from the reactants (monomers) to the products (amyloid fibrils) through a series of intermediates (oligomers). Recently, an alternative aggregation pathway, named the condensation pathway has emerged, where proteins may transition from the monomeric state into the amyloid state via a dense liquid-like intermediate state. To clarify the origins of this complex phase behaviour, this thesis aims to explore the phase space of Aβ and its potential to self-associate into a condensed liquid phase. We demonstrate that under appropriate conditions Aβ may undergo liquid-liquid phase separation, where a dense liquid phase appears in the presence of a dilute liquid phase. Moreover, we show that the dense liquid phase creates an environment where Aβ may aggregate into amyloid fibrils, since the high local concentration of Aβ within these condensates facilitate the nucleation process. Additionally, we report a droplet-client mechanism where Aβ condensation is driven by the condensation of another protein. To this effect, we show that in a sample of Aβ40 and αSyn, Aβ40 is sequestered into α-synuclein (αSyn) condensates, and enhance the aggregation of αSyn by a heterogeneous primary nucleation pathway. By contrast, we also show that in a sample of Aβ42 and αSyn, Aβ42 forms aggregates, and that these Aβ42 aggregates nucleate the condensation of αSyn. Taken together, our results provide initial evidence about the complex phase behaviour of Aβ, and its dependence on the sequence of the peptide and on the presence of other proteins.

Name dc:type.qualificationname

Doctor of Philosophy (PhD)

Level dc:type.qualificationlevel

Doctoral

Grantor dc:publisher.institution

University of Cambridge

Year dc:date.issued

2024

Author dc:creator

• Morris, Owen

Advisor dc:contributor.advisor

• Vendruscolo, Michele

• alpha-synuclein
• Alzheimer's disease
• Amyloid-β
• Parkinson's disease
• Phase separation
• protein aggregation
• protein misfolding

Licence

• https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/228c4643-382f-4293-a6a9-251c17f853a8/download
• https://www.rioxx.net/licenses/all-rights-reserved/

Language dc:language

eng

DOI dc:identifier.doi

https://doi.org/10.17863/CAM.112332

OAI identifier oai:identifier

oai:www.repository.cam.ac.uk:1810/374160