Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils




Lucas, Michael J.
Pan, Henry S.
Verbeke, Eric J.
Webb, Lauren J.
Taylor, David W.
Keitz, Benjamin K.

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The aggregation of Amyloid-b (Ab) is associated with the onset of Alzheimer’s 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 Ab1-40 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 Ab1-40 exposed to SBA-PEG were structurally similar to control fibrils. In contrast, Ab1-40 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 Ab1-40 and other amyloidogenic proteins.


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