Annexin A5 directly interacts with amyloidogenic proteins and reduces their toxicity

Biochemistry. 2009 Nov 10;48(44):10568-76. doi: 10.1021/bi900608m.


Protein misfolding is a central mechanism for the development of neurodegenerative diseases and type 2 diabetes mellitus. The accumulation of misfolded alpha-synuclein protein inclusions in the Lewy bodies of Parkinson's disease is thought to play a key role in pathogenesis and disease progression. Similarly, the misfolding of the beta-cell hormone human islet amyloid polypeptide (h-IAPP) into toxic oligomers plays a central role in the induction of beta-cell apoptosis in the context of type 2 diabetes. In this study, we show that annexin A5 plays a role in interacting with and reducing the toxicity of the amyloidogenic proteins, h-IAPP and alpha-synuclein. We find that annexin A5 is coexpressed in human beta-cells and that exogenous annexin A5 reduces the level of h-IAPP-induced apoptosis in human islets by approximately 50% and in rodent beta-cells by approximately 90%. Experiments with transgenic expression of alpha-synuclein in Caenorhabditis elegans show that annexin A5 reduces alpha-synuclein inclusions in vivo. Using thioflavin T fluorescence, electron microscopy, and electron paramagnetic resonance, we provide evidence that substoichiometric amounts of annexin A5 inhibit h-IAPP and alpha-synuclein misfolding and fibril formation. We conclude that annexin A5 might act as a molecular safeguard against the formation of toxic amyloid aggregates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid / metabolism*
  • Amyloid / toxicity
  • Animals
  • Animals, Genetically Modified
  • Annexin A5 / metabolism*
  • Apoptosis
  • Caenorhabditis elegans
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Electron Spin Resonance Spectroscopy
  • Humans
  • Islet Amyloid Polypeptide
  • Islets of Langerhans / metabolism
  • Islets of Langerhans / pathology
  • Microscopy, Confocal
  • Microscopy, Electron
  • Protein Folding
  • alpha-Synuclein / genetics
  • alpha-Synuclein / metabolism


  • Amyloid
  • Annexin A5
  • Islet Amyloid Polypeptide
  • alpha-Synuclein