Alzheimer's disease: we designed an antibody to detect toxic particles in the brain

Alzheimer’s disease is the major cause of dementia, which affects more than 50 million people worldwide. This disease is still incurable, as we don’t know yet how to stop it, prevent it, or even slow it down. But our recent research may contribute to changing this. We designed an antibody that is able to detect the toxic brain particles thought to cause Alzheimer’s.

The memory loss and cognitive impairment caused by Alzheimer’s disease can be traced back to to a progressive damage to brain tissue. The origins of this damage are still debated, but many think that it is caused by the aggregation of proteins in the brains of people with the disease.

One type of protein, called amyloid beta, is known to accumulate in large plaques in the brains of Alzheimer’s patients. Although the presence of such large plaques is of great concern, even more menacing is the formation of much smaller clumps of this protein, known as oligomers. These oligomers can be highly toxic to neurons and other brain cells.

According to the prevalent “amyloid hypothesis”, the process of aggregation creates oligomers that trigger the pathological processes which eventually result in the death of neurons, leading to memory loss and decreased cognitive ability.

However, without knowing for certain the the number and location in the brain of these oligomers, it has been difficult to prove or disprove the amyloid hypothesis. So far, clinical trials of drugs targeting amyloid beta have failed, as researchers have been unable to tell whether or not these drugs can specifically reduce the number of oligomers in patients.

Alzheimer’s antibodies

To address this problem, we focused on antibodies. These are proteins used by the immune system which can recognise and neutralise harmful pathogens, including bacteria and viruses. Because they have a phenomenal ability to bind to their targets, we decided to use them to recognise and bind to oligomers.

As the amyloid hypothesis assumes these oligomers are the main pathogens that cause Alzheimer’s disease, being able to detect and quantify the number of them in the brain will allow us to better control and treat Alzheimer’s. The antibody that we have designed is capable of binding specifically to oligomers. This makes it possible to detect them in the brain and count how many are present.

Since these oligomers are short-lived, it’s very challenging to use traditional methods, such as immunisation, to generate antibodies capable of binding to them. We developed a computational approach to design an antibody that binds to a very special region of amyloid beta that is accessible only in the oligomers. We then tested this antibody in worms and mice to verify its ability to bind the oligomers.

The antibody can be used to diagnose Alzheimer’s disease by detecting the presence of an abnormal number of oligomers. This is possible because the antibody that we designed binds specifically to oligomers even in complex samples, such as brain tissues. This means the more times we see an antibody bind to something, the higher the number of oligomers.

This antibody may be able to aid the process of drug discovery by measuring whether a drug candidate can reduce the number of oligomers during pre-clinical trials. It may also be used during clinical trials to detect the number of oligomers in patients who have Alzheimer’s, but aren’t yet showing cognitive impairment. This antibody may also be used to monitor how effective a drug is in reducing the number of oligomers in patients compared to a placebo group.

Although further research is needed, I believe that the amyloid hypothesis is fundamentally correct, and that amyloid beta oligomers are the likely cause of Alzheimer’s disease. I’m optimistic that this new antibody can help validate this hypothesis, thus leading to drug discoveries that can reduce these harmful oligomers in the brain.

This article is republished from The Conversation under a Creative Commons license. Read the original article.

mv245@cam.ac.uk is Chief Scientific Officer of Wren Therapeutics, a drug discovery company focused on protein misfolding diseases. For his academic research, he receives funding from the Research Councils and the Wellcome Trust.