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

• 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 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 CNS. Co-expression of Aβ42 and BRICHOS results in delayed Aβ42 aggregation and dramatic improvements of both lifespan and locomotor function compared to flies expressing Aβ42 alone. Moreover, BRICHOS increases the ratio of soluble/insoluble Aβ42 and binds 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 may be explored towards future prevention and treatment of AD.

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