The longstanding “amyloid hypothesis” suggests that Alzheimer’s hallmark beta-amyloid plaques and smaller clumps of beta-amyloid oligomers — proteins highly toxic to brain cells — can lead to cognitive impairment and eventually Alzheimer’s disease. But failed drug trials and conflicting findings have emboldened critics of the amyloid hypothesis. In a study published in the Proceedings of the National Academy of Sciences this month, researchers have designed a new antibody that may hold the key to detecting the oligomers. Michele Vendruscolo, an author of the study and professor of biophysics at University of Cambridge, is optimistic that finding a way to count and measure oligomers could lead to new progress in Alzheimer’s research.
“I really think that a large component of the failures [to date] has been the inability to measure the oligomers,” Vendruscolo said. “Once we are finally able to measure them reliably, then the clinical trials — I believe — will start working.”
While scientists can detect beta-amyloid plaques with PET scans, it’s been difficult to prove or disprove the amyloid hypothesis as scientists have not been able to count the number and location of the oligomers, which are much smaller and short-lived than the beta-amyloid plaques.
There is growing evidence to suggest that the oligomers of beta-amyloid may play a major role in Alzheimer’s: Scientists found that oligomers are linked to cognitive impairment even in the absence of beta-amyloid plaques. They interact with the cell membrane, forming pores and disrupting its permeability.
Meanwhile, the immune system produces antibodies in response to invading organisms as they bind onto specific toxins. While some antibodies can destroy the invading substance, others make it easier for white blood cells to kill them.
Vendruscolo and fellow researchers designed a nanobody — a smaller version of an antibody — and tested it on mice and worms. The nanobodies are capable of differentiating between beta-amyloid plaques and oligomers, binding onto the oligomers and enabling the scientists to observe and count them.
“You really need to be able to quantify the stage of the disease,” Vendruscolo said. “These are very difficult problems and people have made lots of progress in the last 30 years.”
Researchers hope that the antibody can be used not only to measure the effectiveness of drugs in knocking down the oligomers, but also to identify people with early stages of Alzheimer’s for clinical trials.
Oligomers are also linked to inflammatory responses, one of the earliest signs of Alzheimer’s that begin before beta-amyloid plaques are formed.
Still, it is unclear which comes first in Alzheimer’s: Oligomer or inflammation.
Further research lies ahead for Vendruscolo and the team. It will take about one to three years for the team to develop the antibody into a diagnostic tool for humans.