Influencing amyloid formation : biasing nucleation of amyloid-[beta] with functionalized materials

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2021-04-02

Authors

Lucas, Michael John

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Abstract

Molecular self-assembly is a ubiquitous phenomenon found in living systems that can either be functional, such as microtubule polymerization, or toxic, such as the aggregation of amyloidogenic peptides from monomers to higher order assemblies of oligomers, fibrils, and plaques. This aggregation of amyloids is associated with a variety of neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease, and amyotrophic lateral sclerosis (ALS). In this work, we focus on the aggregation of Aβ, which is implicated in AD. The fibrilization process of Aβ is extremely complex, in large part due to the structural heterogeneity, or polymorphism, found in amyloid aggregates. Structural polymorphism combined with the struggle to replicate in vivo conditions in vitro has largely hindered the successful development of therapeutics and diagnostics. Therefore, in this work, we develop methods to direct the nucleation of Aβ with the ultimate goal to control fibril polymorphism. In Chapter 2, we demonstrate that ion-exchanged zeolites can be used to modulate the kinetics of fibrilization of Aβ and to direct the formation of off-pathway intermediates, largely depending on the metal cation coordinated to the zeolite framework. In Chapter 3, we show that functionalized mesoporous silicas can also be used to not only influence the kinetics of aggregation but also the resulting fibril polymorph distribution of Aβ. Notably, we found that through a hydrophobic functionalization, a fibril population is formed that mimics the structure of ex vivo fibrils. We then analyze the polymorph phenotypes and reveal the presence of a polymorph observed to have neuroprotective effects, establishing structure-function relationships. In Chapter 4, we use Aβ mutant fibril seeds and faithfully replicate their structure into wild-type monomer to ultimately prepare in vitro fibril populations that recapitulate the structure of their in vivo counterparts. Taken together, these results demonstrate substantial advancements in the control of Aβ aggregation through the methods developed to bias amyloid polymorphism and the resulting fibril phenotypes. Overall, this work offers promise in the de novo production of Aβ fibril populations, ultimately helping to establish structure-function relationships and enabling the development of effective therapeutics.

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