Repository logo

Understanding protein misfolding diseases through the development of biophysical methods



Change log


Lessa Cataldi, Rodrigo 


Alzheimer’s disease (AD) is an untreatable neurodegenerative disorder that affects over 50 million people worldwide. This disease is associated with the aberrant misfolding and aggregation of the Aβ peptide into amyloid plaques in the brains of affected individuals. Despite substantial progress in the understanding of the mechanism of aggregation of Aβ, the variety of ways in which imbalances in brain metabolism can influence this process are still poorly understood. In this thesis, we address this problem by using a range of different biophysical techniques applied to ex vivo and in vivo experiments. Our three main goals are: i) to investigate the interactions of brain metabolites with Aβ, and ii) to develop an approach to systematically track the in vitro and in vivo aggregation of Aβ and iii) identify a range of natural compounds to inhibit the aggregation of Ab. We begin with an introduction of AD, with a specific emphasis on its association with Aβ aggregation. We then describe in detail the characterisation of neurotoxic oligomeric species of Aβ stabilised by an endogenous brain metabolite. In the second part, using highly reproducible chemical kinetics and imaging quantification, we describe a novel approach of using the amyloid dye X-34 to track both in vitro and in vivo the aggregation process of Aβ and further explored these findings in the context of a-synuclein, a protein closely associated with Parkinson’s disease. Taken together, these results illustrate the opportunities offered by combining in vitro aggregation assays with in vivo aggregation kinetics. Finally, we explored several natural compounds in their ability to inhibit the aggregation of Ab42, characterising the molecular mechanisms of inhibition and validating our strategy in an animal model of AD. We conclude by discussing the potential impact and expected challenges of our systematic in vitro and in vivo approach, as we aim to achieve a more complete understanding of the role of brain metabolism in the pathogenesis of AD and other protein misfolding diseases.





Vendruscolo, Michele
Dobson, Christopher


Alzheimer's Disease, Protein Aggregation, Protein Biophysics


Doctor of Philosophy (PhD)

Awarding Institution

University of Cambridge