Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

Abstract

The aggregation of Amyloid-{beta} (A{beta}) is associated with the onset of Alzheimers Disease (AD) and involves a complex kinetic pathway as monomers self-assemble into fibrils. A central feature of amyloid fibrils is the existence of multiple structural polymorphs, which complicates the development of disease-relevant structure-function relationships. Developing these relationships requires new methods to control fibril structure. In this work, we demonstrate that mesoporous silicas (SBA-15) functionalized with hydrophobic (SBA-PFDTS) and hydrophilic groups (SBA-PEG) direct the aggregation kinetics and resulting structure of A{beta}1-40 fibrils. The hydrophilic SBA-PEG had little effect on amyloid kinetics while as-synthesized and hydrophobic SBA-PFDTS accelerated aggregation kinetics. Subsequently, we quantified the relative population of fibril structures formed in the presence of each material using electron microscopy. Fibrils formed from A{beta}1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, A{beta}1-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter cross-over distances that were more structurally representative of fibrils found in AD patient-derived samples. Overall, these results suggest that mesoporous silicas and other exogenous materials are promising scaffolds for the de novo production of specific fibril polymorphs of A{beta}1-40 and other amyloidogenic proteins. Significance StatementA major challenge in understanding the progression of Alzheimers Disease lies in the various fibril structures, or polymorphs, adopted by Amyloid-{beta} (A{beta}). Heterogenous fibril populations may be responsible for different disease phenotypes and growing evidence suggests that A{beta} fibrils formed in vitro are structurally distinct from patient-derived fibrils. To help bridge this gap, we used surface-functionalized mesoporous silicas to influence the formation of A{beta}1-40 fibrils and evaluated the distribution of resulting fibril polymorphs using electron microscopy (EM). We found that silicas modified with hydrophobic surfaces resulted in fibril populations with shorter cross-over distances that are more representative of A{beta} fibrils observed ex vivo. Overall, our results indicate that mesoporous silicas may be leveraged for the production of specific A{beta} polymorphs.