From NIH Research Matters
One of the first stages of Alzheimer’s disease involves formation of toxic aggregates, called oligomers, of the protein beta-amyloid. These oligomers can start to form more than a decade before symptoms appear and before other known disease markers form. The ability to detect these oligomers would permit early disease diagnosis. This would make strategies to intervene before irreparable brain damage occurs possible.
An NIH-funded research team led by Valerie Daggett at the University of Washington developed a method to detect toxic beta-amyloid oligomers in patients’ blood. They tested the assay, called the soluble oligomer binding assay (SOBA), on nearly 400 banked human blood plasma samples. Results appeared on Dec. 13, 2022, in the Proceedings of the National Academy of Sciences.
Toxic beta-amyloid oligomers have a structure known as an alpha sheet that isn’t normally found in proteins. Alpha sheets tend to bind to each other. SOBA takes advantage of this distinct structural feature. The researchers designed a synthetic alpha sheet molecule to bind to the alpha sheets in beta-amyloid oligomers. They showed that their designed molecule, called AP193, bound to the subset of beta-amyloid with alpha sheets but not to other, non-toxic forms of beta-amyloid.
Beta-amyloid oligomers normally reduce signaling in cultured neurons. Adding AP193 prevented this reduction in signaling. AP193 might thus form the basis for future therapeutic strategies.
When the team applied SOBA using AP193 to a cerebrospinal fluid sample from a person with Alzheimer’s disease, they detected beta-amyloid oligomers. They did not detect oligomers in cerebrospinal fluid from a person who had no cognitive impairment.
Next, the researchers tested whether SOBA could detect beta-amyloid oligomers in blood samples. The samples came from more than 300 people who were diagnosed as having no cognitive impairment (controls), mild cognitive impairment, Alzheimer’s disease, or other forms of cognitive impairment.
SOBA detected toxic oligomers in 52 out of 53 people with Alzheimer’s disease or mild cognitive impairment. It did not detect oligomers in most of the control samples, although there were 11 controls in which SOBA did detect oligomers. Ten of these positive samples came from people who later developed mild cognitive impairment. This shows that the SOBA test detected the toxic beta-amyloid oligomer before Alzheimer’s symptoms appeared. The team also measured conventional Alzheimer’s disease biomarkers in cerebrospinal fluid samples from the same people. None of these correlated with disease state as well as the SOBA method did.
SOBA distinguished Alzheimer’s disease from other forms of cognitive impairment. The team designed SOBA to detect only oligomers of beta-amyloid and not of other proteins. Consistent with this, samples from people with other forms of cognitive impairment tested negative.
Other neurodegenerative diseases, such as Parkinson’s disease, also involve toxic protein oligomers. The team showed that SOBA could be modified to detect Parkinson’s disease and Lewy body dementia.
These results suggest that SOBA could detect toxic oligomers in the blood even before cognitive impairment occurs. It could thus form the basis for early diagnostic tests of Alzheimer’s disease and other neurodegenerative diseases.
“We believe that SOBA could aid in identifying individuals at risk or incubating the disease,” Daggett says, “as well as serve as a readout of therapeutic efficacy to aid in development of early treatments for Alzheimer’s disease.”
— by Brian Doctrow, Ph.D.
This research was supported in part by NIA grants 1R01AG067476 and P0105136.
Reference: Shea D, et al. SOBA: Development and testing of a soluble oligomer binding assay for detection of amyloidogenic toxic oligomers. Proceedings of the National Academy of Sciences. 2022;119(50):e2213157119. doi: 10.1073/pnas.2213157119. Epub 2022 Dec 9.