Ion mobility spectrometry combined with multivariate statistical analysis: revealing the effects of a drug candidate for Alzheimer's disease on A?1-40 peptide early assembly

Inhibition of the initial stages of amyloid-? peptide self-assembly is a key approach in drug development for Alzheimer's disease, in which soluble and highly neurotoxic low molecular weight oligomers are produced and aggregate in the brain over time. Here we report a high-throughput method based on ion mobility mass spectrometry and multivariate statistical analysis to rapidly select statistically significant early-stage species of amyloid-?1-40 whose formation is inhibited by a candidate theranostic agent. Using this method, we have confirmed the inhibition of a Zn-porphyrin-peptide conjugate in the early self-assembly of A?40 peptide. The MS/MS fragmentation patterns of the species detected in the samples containing the Zn-porphyrin-peptide conjugate suggested a porphyrin-catalyzed oxidation at Met-35(O) of A?40. We introduce ion mobility MS combined with multivariate statistics as a systematic approach to perform data analytics in drug discovery/amyloid research that aims at the evaluation of the inhibitory effect on the A? early assembly in vitro models at very low concentration levels of A? peptides.