One possible expansion of present immunotherapies for Alzheimer’s disease is to more specifically track and target oligomeric forms of amyloid-β. Efforts to reduce amyloid-β in the brain have, after many years of failure, started to succeed in that goal in human trials, but patients are not exhibiting benefits as a result. It remains to be seen whether or not this is because amyloid-β is a trigger for other self-sustaining pathological mechanisms, such as cellular senescence of supporting cells in the brain, and thus removing it does little good once Alzheimer’s is underway. An alternative view is that perhaps the wrong forms of amyloid-β are being targeted by existing approaches, and a more specific therapy would achieve better results.
Researchers have designed an antibody which is highly accurate at detecting toxic amyloid-beta oligomers and quantifying their numbers. “There is an urgent unmet need for quantitative methods to recognise oligomers – which play a major role in Alzheimer’s disease, but are too elusive for standard antibody discovery strategies. Through our innovative design strategy, we have now discovered antibodies to recognise these toxic particles.”
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-beta proteins – become rogue and kill healthy nerve cells.
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 signalling 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.
“While the amyloid hypothesis is a prevalent view, it has not been fully validated in part because amyloid-beta oligomers are so difficult to detect, so there are differing opinions on what causes Alzheimer’s disease. 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.” The lack of methods to detect oligomers has been a major obstacle in the progress of Alzheimer’s research. This has hampered the development of effective diagnostic and therapeutic interventions and led to uncertainty about the amyloid hypothesis.
Link: https://www.cam.ac.uk/research/news/antibody-designed-to-recognise-pathogens-of-alzheimers-disease