Researchers have designed an antibody that can identify toxic particles that destroy healthy brain cells. A collaboration of scientists from the University of Cambridge, University College London, and Lund University published their findings in an article titled “Rational design of a conformation-specific antibody for the quantification of amyloid beta oligomers” in Proceedings of the National Academy of Sciences. The method they developed is able to recognize and quantify amyloid beta oligomers, toxic particles that are a hallmark of Alzheimer’s Disease (AD), with high accuracy.
The Need for Oligomer Detection
Alzheimer’s Disease leads to the death of nerve cells and consequently brain tissue loss, and the disease is the most prevalent form of dementia. Symptoms include memory failure, personality changes, and difficulty performing daily activities. Approximately 44 million people worldwide live with AD or a related form of dementia, and estimates put the current annual cost to the global economy at $1.25 trillion.
Although there have been more than 400 clinical trials for AD drugs, nothing has been found that can alter the course of the disease. It is the only condition in the top 10 causes of death with no treatment to prevent it, stop it, or slow its progression.
This discovery of a new diagnostic method could be an important step in the fight against AD. “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,” said Professor Michele Vendruscolo from the University of Cambridge’s Centre for Misfolding Diseases, who led the research. “Through our innovative design strategy, we have now discovered antibodies to recognize these toxic particles.”
The Amyloid Hypothesis
Proteins are responsible for important cell processes, and they need to be regulated closely within the delicate ecosystem of the brain in order to function properly. Oligomers, which can form abnormal clumps of proteins, have been identified as the most likely cause of dementia.
According to the amyloid hypothesis of dementia, when someone has AD, these proteins (including amyloid beta proteins) go rogue and kill healthy cells. The proteins misfold and start a chain reaction that leads to the death of brain cells. These misfolded proteins form plaques between brain cells, preventing the cells from signaling properly and keeping nutrients from getting to the cells.
The amyloid hypothesis is the prevailing view on AD’s cause, but it has not been proven. This is partially because amyloid beta oligomers are so hard to detect. The lack of ability to detect oligomers has been a major obstacle to AD research, inhibiting the development of diagnostic and therapeutic interventions.
Antibody Targets Oligomer Epitopes
The research group has generated antibody molecules that can target oligomers, which could be a crucial step toward monitoring AD’s progression, identifying its cause, and eventually learning how to control it. Their method is based on an approach for antibody discovery developed at the University of Cambridge’s Centre for Misfolding Diseases — a computational assembly of antibody-antigen aggregates that enables the design of antibodies for highly challenging antigens. The innovative method relies on the team’s approach, which brings together scientists with backgrounds spanning from mathematics and engineering to physics, chemistry, cell/molecular biology, and medicine.
The rational design strategy enables the method to target specific regions (“epitopes”) of the oligomers in a wide variety of in vivo and in vitro experiments. This has supported the design of an antibody with at least three orders of magnitude greater affinity for the oligomers over other forms of amyloid beta. This particular difference is key: it enables the antibody to specifically quantify oligomers in both in vitro and in vivo samples. The team of researchers hopes this will enable the discovery of better drug candidates and the design of improved clinical trials.
June is Alzheimer’s and Brain Awareness Month, and QPS joins the Alzheimer’s Association in raising awareness and inspiring action.
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