Restoring the balance in the kinetic network of Aβ aggregation as a drug discovery strategy for Alzheimer’s Disease
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University of Cambridge
Chemistry
Clare Hall
Chemistry
Clare Hall
Abstract
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Alzheimer’s disease (AD) is the most prevalent cause of dementia that affects over 50 million
people, and is associated strongly with the aggregation of the amyloid-β peptide (Aβ). Even
though a variety of strategies has been developed towards inhibiting the aggregation of Aβ,
no disease-modifying treatment has so far reached the clinic. This failure is in part due to
i) an incomplete knowledge of the aggregation process of Aβ, especially in the context of
the complex biological environment, and ii) an unclear mechanism of action of potential
inhibitors of this process. In this thesis, we address the above points using a combination
of a chemical kinetics based experimental assay and a theoretical analysis that dissects the
macroscopic reaction observed from experimental measurements into individual rates of
microscopic reaction steps. By coupling these analyses to a range of other biophysical
techniques, we can quantitatively determine the modulation of the complex reaction network
of Aβ using a bottom-up approach.
In this thesis, we begin with an introduction of AD, with a specific emphasis on its
association with the aggregation of the Aβ peptide (Chapter 1). We also discuss the potentials
and limitations of current therapeutic approaches in AD. Subsequently, we describe in detail
the experimental and theoretical methods of the chemical kinetics based approach used in
understanding the aggregation of Aβ and quantitatively determining the effect of modulators
on the kinetic network (Chapter 2). Using this approach, we demonstrate how the aggregation
process of Aβ is modulated by relevant biological factors that have been associated with AD
(Chapter 3). These include cholesterol-containing lipids which accelerate the aggregation,
proteins with potential chaperonic functions which inhibit the aggregation, and metal ions
which promote the formation of polymorphic aggregated structures. These results provide
greater insights into the physiological regulation of the aggregation of Aβ, and how it leads
to the onset of AD when the homeostatic control is progressively compromised, especially
as we age. By harnessing the above knowledge of how homeostatic imbalance fails to
regulate the aggregation of Aβ, we describe the potential use of small molecules to inhibit
aggregation and potentially restore the balance (Chapter 4). We use chemical kinetics to
develop a drug discovery approach, known as SAR by kinetics (SKAR), that is used to
systematically find and optimise the potency of small molecules in reducing the rate of formation of oligomers, which are highly cytotoxic intermediates that form transiently during
the aggregation of Aβ. SKAR allows us to determine the relationship between the chemical
structure of a molecule and its kinetic inhibitory potency, and thus iteratively improve
molecules as potential drug candidates, which was impossible to achieve with conventional
methods. Finally, we summarise the work in this thesis (Chapter 5), and discuss the potential
opportunities and challenges, as we aim towards a more complete understanding of how the
kinetic network of Aβ is regulated in the brain, dysregulated in disease, and how we can
restore the balance as a means of drug discovery against AD.
Centre for Misfolding Diseases Agency for Science, Technology and Research Singapore (A*STAR)
Centre for Misfolding Diseases Agency for Science, Technology and Research Singapore (A*STAR)