Antiamyloid Antibody Effects on Aβ-42 Protein Aggregates Profiled Using Nanospectroscopy

Area of Science:

• Biochemistry
• Neuroscience
• Materials Science

Background:

• Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) protein aggregates.
• Anti-Aβ monoclonal antibodies are developed to target these aggregates for clearance.
• The precise mechanisms by which these antibodies interact with Aβ aggregates require further elucidation.

Purpose of the Study:

• To investigate the morphological and secondary structural changes in Aβ-42 aggregates after treatment with aducanumab and lecanemab.
• To characterize the interfacial interactions between antibodies and Aβ aggregates at the nanoscale.
• To differentiate the modes of action of aducanumab and lecanemab on Aβ-42.

Main Methods:

• Utilized nanospectroscopy, combining atomic force microscopy (AFM) with infrared spectroscopy (IR).
• Analyzed Aβ-42 peptide aggregates before and after treatment with aducanumab and lecanemab.
• Performed label-free chemical imaging at nanometer-scale spatial resolution.

Main Results:

• Aducanumab treatment reduced Aβ-42 oligomers and promoted larger fibril bundles, as shown by AFM and IR.
• Lecanemab treatment did not reduce oligomers but bound to protofibril surfaces.
• Neither antibody induced disassembly of Aβ-42 protofibrils or mature fibrils.

Conclusions:

• Nanospectroscopy provides direct characterization of antibody-amyloid interactions.
• Aducanumab and lecanemab exhibit distinct mechanisms of action against Aβ-42 aggregates.
• These findings offer valuable insights into the development of anti-Aβ therapeutics for Alzheimer's disease.