There is a need for novel biomarkers of Alzheimer’s disease (AD) and other neurodegenerative disorders that are minimally invasive and that more broadly serve as accurate indicators of the underlying pathophysiological processes in brain. The Accelerating Medicine Partnership AMP-AD target discovery consortium is performing large scale multi-omics profiling and systems level integration of more than 2,000 postmortem human brains, establishing an unprecedented understanding of the pathophysiological processes driving cognitive decline, pathological burden, and other disease traits. The Emory AMP-AD team has focused on large scale proteomic analyses using unbiased label-free and isobaric tandem mass tag (TMT) based mass spectrometry methods to quantify thousands of proteins in brains from several different cohorts. Systems based network approaches reveal highly conserved modules of co-expressed proteins, many of which correlate strongly with clinical and pathological phenotypes, including those reflecting key mechanisms strongly correlated with impaired neuronal and synaptic function, neuroinflammation, and neurodegeneration. Preliminary studies were also performed to determine whether hub proteins representing these brain-based modules are found in cerebrospinal fluid (CSF). Following albumin depletion, we analyzed CSF samples from well-characterized AD and non-AD control patients and reliably quantified ~4,000 proteins by TMT based mass spectrometry across all samples. Of these, ~70% of the proteins were also identified in brain tissue, including members of phenotype-associated modules. We are now developing targeted mass spectrometry assays (PRM and SRM) in CSF to directly quantify hub proteins from AD brain modules most associated with disease traits. Hence, large-scale proteomics with systems analyses provides a comprehensive dataset of brain-based protein changes linked to AD. This establishes a pipeline for targeting brain-based proteins in CSF as biomarkers for diagnosis, staging and therapeutic responses.
Biography of Nick Seyfried
Dr. Seyfried is an Associate Professor in the Departments of Biochemistry and Neurology at Emory University School of Medicine. He received his D.Phil in Biochemistry at the University of Oxford and training in mass spectrometry and proteomics at the University of Georgia and Emory University. His research focuses on the integration of proteomics, transcriptomics, and systems biology to tackle fundamental questions related to the pathogenesis of Alzheimer’s Disease (AD) and other neurodegenerative disorders. His team utilizes both label-free and isobaric Tandem Mass Tag (TMT) quantitative mass spectrometry to identify and quantify proteins and post-translational modifications in human brain, plasma, and cerebrospinal fluid. As part of the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD) consortium, Dr. Seyfried and his team leverage the strengths of a national team of collaborating investigators to nominate new drug targets and biomarkers for AD.