Insights into the consequences of co-polymerisation in the early stages of IAPP and Aβ peptide assembly from mass spectrometry

Lydia M. Young, Rachel A. Mahood, Janet C. Saunders, Ling Hsien Tu, Daniel P. Raleigh, Sheena E. Radford, Alison E. Ashcroft

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The precise molecular mechanisms by which different peptides and proteins assemble into highly ordered amyloid deposits remain elusive. The fibrillation of human amylin (also known as islet amyloid polypeptide, hIAPP) and the amyloid-beta peptide (Aβ-40) are thought to be pathogenic factors in Type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD), respectively. Amyloid diseases may involve co-aggregation of different protein species, in addition to the self-assembly of single precursor sequences. Here we investigate the formation of heterogeneous pre-fibrillar, oligomeric species produced by the co-incubation of hIAPP and Aβ-40 using electrospray ionisation-ion mobility spectrometry-mass spectrometry (ESI-IMS-MS)-based methods. Conformational properties and gas-phase stabilities of amyloid oligomers formed from hIAPP or Aβ40 alone, and from a 1:1 mixture of hIAPP and Aβ40 monomers, were determined and compared. We show that co-assembly of the two sequences results in hetero-oligomers with distinct properties and aggregation kinetics properties compared with the homo-oligomers present in solution. The observations may be of key significance to unravelling the mechanisms of amyloid formation in vivo and elucidating how different sequences and/or assembly conditions can result in different fibril structures and/or pathogenic outcomes.

Original languageEnglish
Pages (from-to)6990-6999
Number of pages10
JournalAnalyst
Volume140
Issue number20
DOIs
Publication statusPublished - 2015 Oct 21

ASJC Scopus subject areas

  • Analytical Chemistry
  • Biochemistry
  • Environmental Chemistry
  • Spectroscopy
  • Electrochemistry

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    Young, L. M., Mahood, R. A., Saunders, J. C., Tu, L. H., Raleigh, D. P., Radford, S. E., & Ashcroft, A. E. (2015). Insights into the consequences of co-polymerisation in the early stages of IAPP and Aβ peptide assembly from mass spectrometry. Analyst, 140(20), 6990-6999. https://doi.org/10.1039/c5an00865d