Structural Dynamics of Amyloid-β Protofibrils and Actions of Anti-Amyloid-β Antibodies as Observed by High-Speed Atomic Force Microscopy

Abstract

Amyloid-β (Aβ) aggregation intermediates, including oligomers and protofibrils (PFs), have attracted attention as neurotoxic aggregates in Alzheimer's disease. However, due to the complexity of the aggregation pathway, the structural dynamics of aggregation intermediates and how drugs act on them have not been clarified. Here we used highspeed atomic force microscopy to observe the structural dynamics of Aβ42 PF at the single-molecule level and the effect of lecanemab, an anti-Aβ PF antibody with the positive results from Phase 3 Clarity AD. PF was found to be a curved nodal structure with stable binding angle between individual nodes. PF was also a dynamic structure that associates with other PF molecules and undergoes intramolecular cleavage. Lecanemab remained stable in binding to PFs and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Aβ aggregation process.

The Mechanisms of the Roles of α-Synuclein, Amyloid-β, and Tau Protein in the Lewy Body Diseases: Pathogenesis, Early Detection, and Therapeutics

“…We found that Lecanemab remained stable in binding to protofibrils and to globular oligomers, inhibiting the formation of large aggregates. These results provide direct evidence for a mechanism by which antibody drugs interfere with the Aβ aggregation process [ 109 ]. Another major hallmark of AD is abnormally phosphorylated tau protein.…”

Molecular Dynamics Mappings of the CCT/TRiC Complex-Mediated Protein Folding Cycle Using Diffracted X-ray Tracking

“…The AFM technique was used to visualize the immobilization of the CCT complex on the surface coated with anti-PA tag antibody, which was covalently immobilized on mica, following the procedure described in the literature [54,55]. Briefly, 2 µL of 0.01% APTES (Sigma Aldrich, Burlington, MA, USA) diluted in ultra-pure water was applied to mica and incubated for 3 min, followed by two rounds of washing with ultra-pure water to remove any unbound APTES.…”

Distinct Effects of Aducanumab and Lecanemab on Intraneuronal Endogenous Aβ42 and Phosphorylated Tau in Alzheimer’s Disease Treatment

“…Uniquely designed as a bispecific antibody, LCN also enhances blood-brain barrier (BBB) permeability by recognizing the transferrin receptor 14 . Extensive research has shown that LCN possesses a strong affinity for oligomeric Aβ42 15 . It is distinguished by its dual ability to reduce brain Aβ42 protofibrils and inhibit the proliferation of Aβ42 fibrils 16 , showcasing superior clinical symptom improvement compared to Adu 11,17 .…”