The small, soluble oligomers of amyloid β peptide that have been implicated in Alzheimer’s disease (AD) are elusive things. They’re transient, low in concentration, and present in diverse conformations. To get a handle on amyloid β oligomers, scientists would like to have the benefit of selective antibodies—that is, antibodies that could distinguish amyloid β oligomers not only from other soluble protein complexes, but also from amyloid β that has already become incorporated into larger aggregates such as fibrils.

The lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer’s research. In fact, Alzheimer’s research has even had difficulty substantiating the decades-old amyloid β oligomer hypothesis—the idea that amyloid β oligomers are toxic, brain-cell-destroying particles that help drive Alzheimer’s disease.

Difficulties in detecting and quantifying amyloid β oligomers may be overcome thanks to an antibody development approach that has been applied by scientists at the University of Cambridge. According to these scientists (and their colleagues at University College London and Lund University), their approach may not only resolve uncertainty over the amyloid β oligomer hypothesis, but also hasten the development of effective diagnostic and therapeutic interventions.

The scientists presented their approach in the Proceedings of the National Academy of Sciences, in an article titled, “Rational design of a conformation-specific antibody for the quantification of Aβ oligomers.” The article, which will be posted this week, describes a two-step method.

“The first step consists of an ‘antigen scanning’ phase in which an initial panel of antibodies is designed to bind different epitopes covering the entire sequence of a target protein,” the article’s authors wrote. “This procedure enables the determination through in vitro assays of the regions exposed in the oligomers but not in the fibrillar deposits. The second step involves an ‘epitope mining’ phase, in which a second panel of antibodies is designed to specifically target the regions identified during the scanning step.”

The method is based on an approach for antibody discovery developed over the last 10 years at the Centre for Misfolding Diseases, Department of Chemistry, University of Cambridge. Based on the computational assembly of antibody-antigen assemblies, the method enables the design of antibodies for antigens that are highly challenging, such as those that live only for a very short time.

By using a rational design strategy that enables to target specific regions, or epitopes, of the oligomers, the researchers have designed an antibody with at least three orders of magnitude greater affinity for the oligomers over other forms of amyloid β. This difference is the key feature that enables the antibody to specifically quantify oligomers in both in vitro and in vivo samples.

“We have illustrated the application of this rational design method for the determination of the oligomeric populations formed during the aggregation of Aβ42 both in vitro and in vivo using C. elegans and mouse models of AD,” the article’s authors noted. “We anticipate that this technology will create novel opportunities for the detection and accurate quantification of oligomers of amyloidogenic proteins for diagnostic and therapeutic applications.”

Alzheimer’s disease, the most prevalent form of dementia, leads to the death of nerve cells and tissue loss throughout the brain, resulting in memory failure, personality changes, and problems carrying out daily activities.

Abnormal clumps of proteins called oligomers have been identified by scientists as the most likely cause of dementia. Although proteins are normally responsible for important cell processes, according to the amyloid hypothesis, when people have Alzheimer’s disease these proteins—including specifically amyloid β proteins—become rogue and kill healthy nerve cells.

“While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid β oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer’s disease,” said Michele Vendruscolo, PhD, a researcher at the Centre for Misfolding Diseases and the senior author of the current study. “The discovery of an antibody to accurately target oligomers is, therefore, an important step to monitor the progression of the disease, identify its cause, and eventually keep it under control.”

Proteins need to be closely regulated to function properly. When this quality control process fails, the proteins misfold, starting a chain reaction that leads to the death of brain cells. Misfolded proteins form abnormal clusters called plaques which build up between brain cells, stopping them from signaling properly. Dying brain cells also contain tangles, twisted strands of proteins that destroy a vital cell transport system, meaning nutrients and other essential supplies can no longer move through the cells.

“There is an urgent unmet need for quantitative methods to recognize oligomers—which play a major role in Alzheimer’s disease, but are too elusive for standard antibody discovery strategies,” Vendruscolo added. “Through our innovative design strategy, we have now discovered antibodies to recognize these toxic particles.”

The scientists hope that their approach will enable the discovery of better drug candidates and the design of better clinical trials for people affected by the debilitating disease. They also co-founded Wren Therapeutics, a spin-out biotechnology company based at the Chemistry of Health Incubator, in the recently opened Chemistry of Health building, whose mission it is to take the ideas developed at the University of Cambridge and translate them into finding new drugs to treat Alzheimer’s disease and other protein misfolding disorders. The antibody has been patented by Cambridge Enterprise, the University’s commercialization arm.

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