Ion mobility spectrometry combined with multivariate statistical analysis: revealing the effects of a drug candidate for Alzheimer’s disease on Aβ1-40 peptide early assembly: revealing the effects of a drug candidate for Alzheimer's disease on A beta 1-40 peptide early assembly

Serena Lazzaro, Nina Ogrinc, Lieke Lamont, Graziella Vecchio, Giuseppe Pappalardo, Ron M. A. Heeren*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Inhibition of the initial stages of amyloid-beta 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-beta 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 beta 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 beta 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 beta early assembly in vitro models at very low concentration levels of A beta peptides.

Original languageEnglish
Pages (from-to)6353-6363
Number of pages11
JournalAnalytical and Bioanalytical Chemistry
Volume411
Issue number24
DOIs
Publication statusPublished - Sept 2019

Keywords

  • Alzheimer's disease (AD)
  • Amyloid beta-peptide oligomers
  • Electrospray ionization-ion mobility-mass spectrometry (ESI-IM-MS)
  • Multivariate statistical analysis (MVA)
  • AMYLOID-BETA-PROTEIN
  • MASS-SPECTROMETRY
  • NEURODEGENERATIVE DISEASES
  • PERSONALIZED MEDICINE
  • OXIDATION
  • POLYMORPHISM
  • AGGREGATION
  • INHIBITORS
  • STRATEGIES
  • OLIGOMERS

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