LL-37 and Its Truncated Fragments Modulate Amyloid-β Dynamics, Aggregation and Toxicity Through Hetero-Oligomer and...

Area of Science:

• Biochemistry
• Molecular Biology
• Nanotechnology

Background:

• Amyloid-beta (Aβ) fibril formation is implicated in neurodegenerative diseases.
• The role of amphiphilic peptides like LL-37 in modulating Aβ aggregation is recognized but mechanistically unclear.
• Understanding peptide-Aβ interactions at different scales is crucial for therapeutic development.

Purpose of the Study:

• To investigate the mechanism by which LL-37 and its variants affect amyloid-beta 40 (Aβ40) aggregation.
• To analyze the impact of these peptides on Aβ40 at both nanoscale and microscale levels.
• To elucidate the relationship between peptide-induced clustering and Aβ fibrillation inhibition.

Main Methods:

• Utilized four peptides: LL-37, LL-37_9-32, LL-37_18-29, and LL-37_19-28.
• Employed nanoscale analysis to study hetero-oligomer and nanocluster formation with Aβ40.
• Applied microscale analysis to examine Aβ cluster formation and aggregation dynamics.

Main Results:

• All LL-37 peptides formed hetero-oligomers and nanoclusters with Aβ40.
• LL-37 and LL-37_19-28 showed stronger inhibition, forming more hetero-oligomers and smaller nanoclusters.
• Peptides promoted Aβ cluster formation, with LL-37 and LL-37_19-28 rapidly forming larger clusters, suggesting smaller nanoclusters assemble into toxic aggregates.
• Inhibition of Aβ fibrillation occurred across all peptides, affecting nucleation, while elongation was specifically impacted by LL-37 and LL-37_19-28.

Conclusions:

• LL-37 and its fragments modulate Aβ40 aggregation through distinct nanoscale and microscale mechanisms.
• The formation of hetero-oligomers and small nanoclusters appears to be an off-pathway mechanism inhibiting fibrillation.
• Findings provide a deeper understanding of LL-37's role in Aβ aggregation, relevant for neurodegenerative disease research.