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

Abstract

Aggregation of the amyloid-beta peptide (A beta) 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 A beta 42 oligomerization and fibril formation. We have generated transgenic Drosophila melanogaster flies that express the A beta 42 peptide and the BRICHOS domain in the central nervous system (CNS). Co-expression of A beta 42 and BRICHOS resulted in delayed A beta 42 aggregation and dramatic improvements of both lifespan and locomotor function compared with flies expressing A beta 42 alone. Moreover, BRICHOS increased the ratio of soluble: insoluble A beta 42 and bound to deposits of A beta 42 in the fly brain. Our results show that the BRICHOS domain efficiently reduces the neurotoxic effects of A beta 42, although significant A beta 42 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

Amyloid; Alzheimer's disease; Protein misfolding; Chaperone

Published in

Disease Models and Mechanisms
2014, volume: 7, number: 6, pages: 659-665
Publisher: COMPANY OF BIOLOGISTS LTD

SLU Authors

• Hermansson, Erik

  • Karolinska Institute

• Johansson, Jan

  • Department of Animal Biosciences, Swedish University of Agricultural Sciences
    
  • Karolinska Institute
  • Tallinn University

• Presto, Jenny

  • Karolinska Institute

UKÄ Subject classification

Cell Biology

Publication identifier

• DOI: https://doi.org/10.1242/dmm.014787

Permanent link to this page (URI)

https://res.slu.se/id/publ/67534