Characterizing Alzheimer’s disease using quantitative proteomics

Abstract

Alzheimer’s disease is characterized by the accumulation of neuropathologic amyloid-β and tau peptides in the brain. Bottom-up mass spectrometry proteomics methods were used to understand the protein landscape in the brains with different causes of Alzheimer’s. Correlating peptide abundances with amyloid-β tryptic peptides reveals additional subgroups of disease in sporadic Alzheimer’s cases, with differences across the four brain regions sampled. A cerebrospinal fluid targeted mass spectrometry assay for Alzheimer’s disease related proteins was developed as a proof-of-concept of an updated assay development workflow. This work demonstrates the feasibility of using peptide performance on high-resolution instruments to inform assay targets on a unit-resolution instrument. Both projects with Alzheimer’s disease demonstrate the importance of proteoforms in human disease, a fact that we argue should be considered more carefully when interpreting or developing bottom-up proteomics experiments.