Functionalized Mesoporous Silicas Direct Structural Polymorphism of Amyloid-β Fibrils

Area of Science:

• Biochemistry
• Materials Science
• Neuroscience

Background:

• Amyloid-beta (Aβ) aggregation into fibrils is central to Alzheimer's disease (AD) pathogenesis.
• Amyloid fibril structure is polymorphic, complicating structure-function relationship development.
• Controlling fibril structure is crucial for understanding AD and developing therapeutics.

Purpose of the Study:

• To investigate the impact of functionalized mesoporous silicas on Aβ₁-40 aggregation kinetics and fibril structure.
• To determine if mesoporous silicas can be used to generate specific Aβ fibril polymorphs.

Main Methods:

• Utilized SBA-15 mesoporous silicas functionalized with hydrophobic (SBA-PFDTS) and hydrophilic (SBA-PEG) groups.
• Monitored Aβ₁-40 aggregation kinetics in the presence of these materials.
• Analyzed resulting fibril structures using electron microscopy to quantify polymorph populations.

Main Results:

• Hydrophilic SBA-PEG had minimal effect on Aβ aggregation kinetics.
• As-synthesized and hydrophobic SBA-PFDTS accelerated Aβ₁-40 aggregation.
• Aβ₁-40 incubated with SBA-15 or SBA-PFDTS formed fibrils with shorter crossover distances, mimicking AD patient-derived fibrils.

Conclusions:

• Mesoporous silicas, particularly hydrophobic variants, can modulate Aβ aggregation kinetics and structure.
• These materials offer a promising approach for the controlled de novo production of specific amyloid fibril polymorphs.
• This strategy may aid in developing structure-function relationships for amyloidogenic proteins relevant to neurodegenerative diseases.