From monomer to fibril: Abeta‐amyloid binding to Aducanumab antibody studied by molecular dynamics simulation

Abstract

Alzheimer's disease is one of the most common causes of dementia. It is believed that the aggregation of short Aβ-peptides to form oligomeric and protofibrillar amyloid assemblies plays a central role for disease-relevant neurotoxicity. In recent years, passive immunotherapy has been introduced as a potential treatment strategy with anti-amyloid antibodies binding to Aβ-amyloids and inducing their subsequent degradation by the immune system. Although so far mostly unsuccessful in clinical studies, the high-dosed application of the monoclonal antibody Aducanumab has shown therapeutic potential that might be attributed to its much greater affinity to Aβ-aggregates vs monomeric Aβ-peptides. In order to better understand how Aducanumab interacts with aggregated Aβ-forms compared to monomers, we have generated structural model complexes based on the known structure of Aducanumab in complex with an Aβ 2 − 7-eptitope. Structural models of Aducanumab bound to full-sequence Aβ 1 − 40-monomers, oligomers, protofilaments and mature fibrils were generated and investigated using extensive molecular dynamics simulations to characterize the flexibility and possible additional interactions. Indeed, an aggregate-specific N-terminal binding motif was found in case of Aducanumab binding to oligomers, protofilaments and fibrils that is located next to but not overlapping with the epitope binding site found in the crystal structure with Aβ 2 − 7. Analysis of binding energetics indicates that this motif binds weaker than the epitope but likely contributes to Aducanumab's preference for aggregated Aβspecies. The predicted aggregate-specific binding motif could potentially serve as a basis to reengineer Aducanumab for further enhanced preference to bind Aβaggregates vs monomers.

Aducanumab Therapy to Treat Alzheimer’s Disease: A Narrative Review

“…Aducanumab has been shown to selectively bind to parenchymal amyloid over vascular amyloid [18,19]. The initial package insert of aducanumab generally states that the drug is indicated to treat AD even though the drug is only tested in early-onset AD patients.…”

Aducanumab, a Novel Anti-Amyloid Monoclonal Antibody, for the Treatment of Alzheimer’s Disease: A Comprehensive Review

“…38 Researchers have further investigated the binding mechanisms of aducanumab using molecular dynamics simulation technology in hopes to further optimize selectivity, which may lead to smaller therapeutic doses and greater efficacy. 39…”

“…Several other variables may influence the lag period including the amount of time needed to remove amyloid plaques, individual amyloid burden, APOE ε4 genotype, age, and disease severity. [39][40][41] This may explain why the high-dose group in the Emerge trial resulted in the most significant decrease in the rate of cognitive decline; this group could have had relatively more patients achieve a sustained steady state in the brain. 41…”

An Overview of Several Inhibitors for Alzheimer’s Disease: Characterization and Failure

“…In this structure, aducanumab binds to 3–7 residues of Aβ in an extended conformation. Furthermore, Frost and Zacharias [ 153 ] have performed MD simulation to explore the interaction between AduFab and Aβ1-40 peptide in the form of monomers, dimers, oligomers, and fibrils. The result suggested that AduFab binding affinity is increased in oligomers and fibrils compared to monomers.…”