Structural Assessment of Fibrillated Beta Amyloid to Reveal the Potential Epitopes for Alzheimer's Disease

초록

Alzheimer's disease is the most common form of dementia accounting for 60% of the cases. On the molecular mechanism of Alzheimer's disease, abnormal accumulation of multimerized amyloid-beta known as amyloid cascade hypothesis have been widely accepted. According to the hypothesis, treating the accumulated amyloid-beta can be considered as a prime target. In this background, several antibody-drug such as aducanumab, lecanemab and donanemab succeed in taking FDA approval or at near-stage. However, even those drugs have side-effects such as ARIA (Amyloid-related imaging abnormalities) or the effect on cognitive function was shown to be inconsecutive. Thus, understanding the detailed structural aspects could enhance the efforts to develop the antibody drugs targeting amyloid-beta. To reveal the structural aspects and identify the targetable epitope region or amino acids, we adapted Alphafold3 model to build multimer series of amyloid-beta. Alphafold3 was able to make comparable structure models with experimentally determined 3D structures. With these simulated models, we determined the structurally opened region and highly potent epitope area using structure-based AI models. Then, we revealed four amino acids in a specific subunit of 12-mer to be targeted by analyzing the structure stability of those regions through molecular dynamics. Our analysis revealed four promising amino acid residues to be targeted which might treat the dementia through targeting multimerized amyloid-beta with at least 70% of their populations.

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