This story originally ran on July 13.

By Tony Fong

Name: Tony Wyss-Coray
Postion: Associate professor, department of neurology and neurological sciences, Stanford University School of Medicine, 2005 to present; research career scientist, Veterans Affairs Palo Alto Health Care System, 2007 to present
Background: Assistant professor, department of neurology and neurological sciences, Stanford University School of Medicine, 2002 to 2005; health scientist, GRECC, Veterans Affiars Palo Alto Health Care System, 2002 to 2007

The protein breakdown product beta-amyloid has long been implicated in Alzheimer's disease, and clinical trials are currently being conducted to test whether immunization with beta-amyloid antibodies can reduce amyloid plaque in the brain.

But more than the plaques themselves, it may be smaller aggregations of beta-amyloid molecules called oligomers that are more toxic to neurons, and so, of greater interest in Alzheimer's research. In a study published online July 6 in the Proceedings of the National Academy of Sciences, researchers used peptide microarrays to demonstrate the presence of antibodies naturally occurring in humans against known toxic beta-amyloids and amyloidogenic non-beta-amyloid species in blood and cerebrospinal fluid samples of 250 AD patients and healthy controls.

The antibodies targeted multiple forms and aggregation states of beta-amyloids in both healthy and diseased samples with antibodies against oligomers showing the most immunoreactivity. The researchers also showed, for the first time, that these overall levels of antibodies decline with increasing age.

"Our findings support the concept of conformation-specific, cross-reactive antibodies that may protect against amyloidogenic toxic peptides," the authors said in the PNAS study. "If a therapeutic benefit of beta-amyloids can be confirmed in AD patients, stimulating the production of such neuroprotective antibodies or passively administering them to the elderly population may provide a preventive measure toward AD."

ProteoMonitor spoke with Tony Wyss-Coray, the senior author on the study and an associate professor of neurology and neurological sciences at the Stanford University School of Medicine, last week about the research. Below is an edited transcript of the conversation.

Describe the microarrays that you used for your research.

These are standard epoxy glass slides that we used, and printed different types of peptides that are involved in neurodegenerative diseases, specifically Alzheimer's disease.

We printed peptides on these slides and incubated them with plasma from patients with disease or control. The array is a pretty standard proteomic array, [but] instead of printing antibodies like some people do, we print peptides and then try to find antibodies that bind to these peptides in plasma.

When you customized these arrays, was it more in the content than the actual array itself?

Yes, the customization was the peptides themselves, and … some of them we purchased, some we synthesized, and a lot of them were from one of our collaborators who is an expert in amyloid peptides, so we had a lot of these various different peptides.

And then we either spotted them unmodified, or we incubated them first in certain buffers, so that they would form aggregates. By using different types of buffers, you can steer them toward making more oligomer-type aggregates, or to make fibrils, which are longer or higher order magnitude aggregates.

These different types of preparations were then spotted in an array fashion on the slides.

You have a provisional patent on the technology. What does this cover?

It's actually just an invention disclosure. …This is really [for] the approach of using the different conformations and different types of peptides to monitor disease and monitor maybe efficiency of a vaccine.

The interesting aspect of this work is that one of the most promising treatments for Alzheimer's in the pipeline is a vaccine, or monoclonal antibody that binds to amyloid. So you immunize with amyloid peptides, or you use monoclonal antibodies, humanized antibodies. However, if you use the monoclonal antibody, then of course you know what the specificity is.