Amyloid formation via supramolecular peptide assemblies.

Area of Science:

• Biochemistry
• Structural Biology
• Neuroscience

Background:

• Amyloid fibrils are protein aggregates classically defined by linear, non-branched structures and cross beta-sheet conformation.
• Soluble oligomeric peptide assemblies (2-20 nm) are considered critical intermediates in amyloid formation.
• The role of larger intermediates and environmental influence on fibril ultrastructure remains under investigation.

Purpose of the Study:

• To investigate the in vitro formation of amyloid fibrils from pathogenic prion protein peptide (residues 23-144) and Abeta1-40.
• To characterize the size and morphology of intermediate species during fibrillization under varying conditions.
• To explore the impact of the physical microenvironment on amyloid fibril ultrastructure.

Main Methods:

• Utilized pathogenic prion protein peptide (residues 23-144) and Abeta1-40 peptide.
• Induced fibrillization under quiescent and agitated conditions.
• Characterized intermediate assemblies and final fibril structures using microscopy and biophysical techniques.

Main Results:

• Under quiescent conditions, large globular assemblies (up to 1 µm) were observed preceding fibril formation.
• These large globules directly interacted with growing fibril bundles.
• Fibrils formed via these large intermediates exhibited diverse ultrastructural features.
• Similar results were obtained with Abeta1-40 peptide, suggesting a general mechanism.

Conclusions:

• Amyloid formation can proceed through significantly larger globular intermediates than previously described.
• The physical microenvironment profoundly influences amyloid formation mechanisms and resulting fibril properties.
• This challenges the classical view and highlights the importance of environmental factors in amyloid diseases.