The chaperone domain BRICHOS prevents CNS toxicity of amyloid-β peptide in Drosophila melanogaster

Dis Model Mech. 2014 Jun;7(6):659-65. doi: 10.1242/dmm.014787. Epub 2014 Mar 28.

Abstract

Aggregation of the amyloid-β peptide (Aβ) into toxic oligomers and amyloid fibrils is linked to the development of Alzheimer's disease (AD). Mutations of the BRICHOS chaperone domain are associated with amyloid disease and recent in vitro data show that BRICHOS efficiently delays Aβ42 oligomerization and fibril formation. We have generated transgenic Drosophila melanogaster flies that express the Aβ42 peptide and the BRICHOS domain in the central nervous system (CNS). Co-expression of Aβ42 and BRICHOS resulted in delayed Aβ42 aggregation and dramatic improvements of both lifespan and locomotor function compared with flies expressing Aβ42 alone. Moreover, BRICHOS increased the ratio of soluble:insoluble Aβ42 and bound to deposits of Aβ42 in the fly brain. Our results show that the BRICHOS domain efficiently reduces the neurotoxic effects of Aβ42, although significant Aβ42 aggregation is taking place. We propose that BRICHOS-based approaches should be explored with an aim towards the future prevention and treatment of AD.

Keywords: Alzheimer’s disease; Amyloid; Chaperone; Protein misfolding.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Peptides / toxicity*
  • Animals
  • Animals, Genetically Modified
  • Brain / metabolism
  • Central Nervous System / drug effects*
  • Drosophila melanogaster / metabolism*
  • Drosophila melanogaster / physiology
  • Molecular Chaperones / metabolism*
  • Motor Activity
  • Peptide Fragments / metabolism
  • Peptide Fragments / toxicity*

Substances

  • Amyloid beta-Peptides
  • Molecular Chaperones
  • Peptide Fragments
  • amyloid beta-protein (1-42)