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Emory Wins $7.2M from NIA for Proteomic Discovery, Validation of Alzheimer's Drug Targets

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NEW YORK (GenomeWeb News) – Emory University said this week that its Alzheimer's Disease Research Center has been awarded a five-year, $7.2 million grant from the National Institute on Aging for research into proteins altered in Alzheimer's disease.

The effort aims to use discovery-based mass spec analysis of brain tissue to identify potential therapeutic targets and then validate these proteins via targeted mass spec, Nicholas Seyfried, an Emory researcher and project participant, told ProteoMonitor.

Emory will lead a team that includes researchers from five additional Alzheimer's Disease Research Centers at Rush University, University of California, Los Angeles, University of Washington, University of Pennsylvania, and Johns Hopkins University.

In addition to the proteomics effort, the NIA is funding three related projects that will tackle genomic and transcriptomic analyses of brain tissue, with researchers able to choose targets identified via these various methods for validation, Seyfried said.

"The idea is that the four different projects will share data and so we can take projects that were cross-validated in two other centers and nominate [markers identified in] those projects to be [validated] by proteomics," he said.

The effort is part of the larger Accelerating Medicines Partnership, a collaboration between the National Institutes of Health; pharma firms including Biogen Idec, GlaxoSmithKline, and Eli Lilly; and several non-profits that aim to identify and validate targets for drug development for diseases including Alzheimer's, type 2 diabetes, rheumatoid arthritis, and lupus. The partnership plans to fund $129.5 million in Alzheimer's research over the next five years.

"Ultimately, what we hope to do as we develop models and work with the drug companies is to nominate proteins to be rational therapeutic targets for drug discovery," Seyfried said.

Much of Alzheimer's research on both the biomarker and therapeutic front has focused on the proteins tau and β-amyloid. However, drug development efforts aimed as these proteins – and Aβ, in particular, have struggled. Recently, anti-amyloid agents from pharma firms including Pfizer, Johnson & Johnson, and Eli Lilly failed in clinical trials. One commonly cited explanation is that these drugs were tested in patient populations too far progressed for the therapies to work, raising the need for better early detection biomarkers.

The failures also potentially suggest a need for new drug targets, though. According to Seyfried, he and his colleagues enter the project with two particular potential targets that they hope to validate – the U1 small nuclear ribonucleoprotein complex, an abnormal splice form of which he and other researchers implicated in Alzheimer's pathogenesis in a study published last year in Proceedings of the National Academy of Sciences; and TyroBP, an inflammatory microglia marker that also has been implicated in the disease.

The groups will also use shotgun mass spec to do global discovery of potential targets, looking for disparities in the protein content of naturally aging versus diseased brain tissue.

Seyfried and his collaborators have obtained roughly 1,000 brain tissue samples from three longitudinal studies of aging – the Baltimore Longitudinal Study of Aging; the Adult Changes in Thought study; and the Religious Orders Study. From these three studies, the researchers have samples running the spectrum from healthy controls to individuals with mild cognitive impairment to late-stage Alzheimer's patients, Seyfried said.

"So the idea is that we can use the proteomic signatures cross-sectionally from these different neuropathologic and cognitive states to see if certain markers correlate with the onset of cognitive decline," he said.

Seyfried said the researchers planned to run around 200 patient samples in their discovery work, and follow that with a larger cohort of around 800 patients for target validation. "In total, about 1,000 brains will be looked at," he said. The researchers hope to have their discovery dataset available within a year, he added.

Alzheimer's protein biomarker work has typically been done in cerebrospinal fluid or, in some cases, plasma, but, given the study's goal of identifying actual therapeutic targets, brain tissue was the most appropriate sample, Seyfried said.

One issue with proteomic studies of brain tissue is its high myelin content, which, he said, can create challenges for mass spec analysis. This can be avoided, though, by being careful to dissect mainly the grey matter, which contains primarily cell bodies and fewer of the heavily myelinated axons.

"We’ve worked out a lot of these techniques over the last several years, and we're not seeing any problems," Seyfried said.

The Emory team plans to use both a Thermo Fisher Scientific Orbitrap Fusion and Q Exactive Plus for the discovery stage of the project. They might also use the Q Exactive for the validation phase, Seyfried said, noting that they are interested in parallel reaction monitoring mass spec, a high-resolution accurate mass approach to targeted quantitation.

As opposed to conventional SRM assays, which focus the mass spec's measurement time on a preselected set of product ions, PRM uses the upfront quadrupole of a Q-TOF or Q Exactive machine to isolate a target precursor ion, and then monitors not just a few, but all of the resulting product ions.

Because of this, researchers don't have to determine upfront what the best transitions to monitor will be, significantly reducing assay development time. The larger number of product ions monitored via PRM can also improve the specificity of the analysis, since more transitions are available to confirm a peptide ID. This can also reduce the effects of co-isolating background peptides.

The researches will likely use standard triple quad-based SRM assays for the project's validation stage, as well, Seyfried said.

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