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

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

SUBMITTER: Hermansson E 

PROVIDER: S-EPMC4036473 | biostudies-other | 2014 Jun

REPOSITORIES: biostudies-other