New Antibody Discovery Platform Can Inform Alzheimer’s and Parkinson’s

ROCKVILLE, MD – In diseases like Parkinson’s and Alzheimer’s, specific proteins misfold and clump together, forming toxic aggregates that damage brain cells. The process of proteins spontaneously clumping is called protein aggregation and researchers have developed novel methods to generate aggregate-specific antibodies as specific probes or modulators of the aggregation process.

This new method overcomes significant challenges in characterizing these complex and often transient protein structures. The work will be presented at the 69th Biophysical Society Annual Meeting, to be held February 15 – 19, 2025 in Los Angeles.

Most pathological aggregates, called oligomers, are difficult to study with traditional methods, due to their fleeting nature and structural variability. Antibodies, known for their precise target binding, offer a powerful tool for investigating these structures, but generating antibodies against such transitory targets has been a major hurdle.

This new platform integrates computational design and directed evolution to develop new antibodies, which are then screened for their ability to bind to target aggregates or inhibit aggregation process. “We can substantially speed up the process of discovery and production, which can save time and resources,” said Francesco Aprile, PhD, Associate Professor in Biological Chemistry at Imperial College London, who led the study.

Using this platform, Aprile and colleagues successfully generated single-domain antibodies (nanobodies) targeting intrinsically disordered proteins, or proteins that are not defined by one specific three-dimensional structure, but that are constantly changing. “What these intrinsically disordered proteins do is they start to self-assemble and form oligomers and aggregates such as amyloid fibrils, which are a hallmark of Alzheimer’s,” Aprile said.

The nanobodies the researchers developed can target different assemblies of amyloid-beta and alpha-synuclein, proteins associated with Alzheimer’s and Parkinson’s diseases, respectively. These nanobodies can provide valuable insights into what makes these proteins form toxic oligomers.

“Our platform represents a significant advance in our ability to study protein self-assembly,” said Aprile. “By efficiently generating nanobodies against these challenging targets, we can now delve deeper into the mechanisms underlying these processes and their role in disease.”

Importantly, the research has identified specific regions within amyloid-beta and alpha-synuclein that could be promising therapeutic targets. This discovery opens new avenues for drug development aimed at treating Alzheimer’s and Parkinson’s.

Aprile noted, “By targeting these key protein assemblies, we may be able to slow or even prevent disease progression.” 

Image Caption:

This new platform integrates computational design and directed evolution to develop new antibodies, which are screened for their ability to bind to toxic aggregates that form in diseases like Parkinson’s and Alzheimer’s. Courtesy of Francesco Aprile.

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The Biophysical Society, founded in 1958, is a professional, scientific Society established to lead development and dissemination of knowledge in biophysics. The Society promotes growth in this expanding field through its annual meeting, publications, and committee and outreach activities. Its 7,000 members are located throughout the United States and the world, where they teach and conduct research in colleges, universities, laboratories, government agencies, and industry.