Download Full Text (274 KB)

Download Gantenerumab 5CSZ Protein Model (197 KB)

Download Alzheimer's Antibodies Protein Modeling Poster (587 KB)

Download Alzheimer's Antibodies Presentation (909 KB)

Submission Date

Fall 2022


Alzheimer’s disease (AD) is a degenerative neurological disorder that destroys memory and other important cognitive functions. As time progresses, brain cell connections, as well as the brain cells themselves, atrophy and die. AD is caused by a missense mutation in the amyloid-beta peptide within the amyloid precursor protein (APP). The mutation results in glutamine being replaced with glutamic acid. Previously conducted studies showed that mutated forms of the amyloid-beta peptide fragment have a greater tendency to stick together and form protein clumps or aggregates. The abnormal build-up of aggregates in and around the brain cells has been found to be strongly associated with the development of Alzheimer’s disease, therefore, it appeared crucial to study the methods that reduce these build-ups.

Attempts to treat this disease have produced antibodies that bind to the mutated amyloid-beta peptide and clear the aggregated amyloid precursor protein out of the brain. The overall goal of this project is to use 3D printed protein models to show interactions leading to a clearer explanation of the efficacy variations between antibodies. One antibody, Aducanumab, is currently in Phase 3 clinical trials and has been fast-tracked by the U.S. Food and Drug Administration. Aducanumab functions by specifically binding to the mutated amyloid-beta peptide and clearing aggregates out of the brain. This antibody binds to a smaller linear epitope formed by amino acids 3-7 of the amyloid-beta peptide. Using Jmol, protein visualization software, the Aducanumab (6CO3) PDB was manipulated to highlight multiple hydrophobic interactions, shown in a dark salmon color, and 2 hydrogen bonds, shown in white. The small binding location, flexibility provided by fewer strong interactions, and high affinity for aggregates at a high density make the antibody ideal for clearing out large aggregates.

Another antibody, Gantenerumab, is still undergoing testing in order to ensure safety and efficacy. This antibody functions by binding to a longer linear epitope formed by amino acids 3-11 of the amyloid-beta peptide. Unlike Aducanumab, Gantenerumab interacts with peptides through 2 salt bridges in addition to 3 hydrogen bonds and multiple hydrophobic interactions. Along with hydrogen bonds in white and hydrophobic interactions in dark salmon, the Gantenerumab (5CSZ) PDB was manipulated to show negative side chains of the salt bridge, labeled in red, while the positive side chains were labeled in blue. The increased number and strength of interactions reduces the flexibility of this antibody, thus making it difficult to easily bind and clear aggregated peptides. While both antibodies bind to a similar region of the amyloid-beta peptide and function to remove aggregates, they vary in the amount and type of interactions made with the amyloid-beta peptide.

Gantenerumab 5CSZ Finalized Model.jpg (197 kB)
Gantenerumab 5CSZ Protein Model

Alzheimer's Antibodies Poster.pdf (587 kB)
Alzheimer's Antibodies Protein Modeling Poster

Alzheimer's Antibodies Presentation.pdf (909 kB)
Alzheimer's Antibodies Presentation

Comparing Effectiveness of Two Antibodies (Aducanumab and Gantenerumab) on Reducing Amyloid-Beta Plaques