Engineering amyloid-like assemblies from unstructured peptides via site-specific lipid conjugation

Area of Science:

• Biochemistry
• Molecular Biology
• Neuroscience

Background:

• Amyloid beta (Aβ) aggregation into oligomers and fibrils is implicated in Alzheimer's disease (AD) pathogenesis.
• Understanding the principles governing Aβ aggregation is critical for developing therapeutic strategies.

Purpose of the Study:

• To investigate the induction of β-sheet secondary conformation in disordered native peptide sequences via lipidation.
• To explore how various parameters influence the aggregation process.

Main Methods:

• Lipidation of peptides in hexafluoroisopropanol (HFIP) and phosphate buffered saline (PBS).
• Characterization using Circular Dichroism (CD), ATR-IR, Thioflavin T (ThT) fluorescence, Dynamic Light Scattering (DLS), ssNMR, and Electron Microscopy (EM).

Main Results:

• Demonstrated the generation of β-sheet aggregates from unstructured peptides under physiological pH.
• Showed sequence independence in aggregate formation.
• Identified amphiphilicity and hydrophobicity as key factors driving assembly into amyloid-like structures.

Conclusions:

• Lipidation is an effective method for inducing β-sheet conformation and amyloid-like aggregate formation in peptides.
• The study provides insights into the fundamental principles of amyloid aggregation relevant to Alzheimer's disease.