title: The chaperone domain BRICHOS prevents CNS toxicity of amyloid-β peptide in Drosophila melanogaster.
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.
authors.affiliation: KI Alzheimer Disease Research Centre, NVS Department, Karolinska Institutet, Novum, 5th Floor, 141 86 Stockholm, Sweden.
authors.forename: Erik
authors.initials: E
authors.lastname: Hermansson
authors.affiliation: Department of Biochemistry, Institute for Cancer Research, Oslo University Hospital - The Norwegian Radium Hospital, 0379 Oslo, Norway.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schultz
authors.affiliation: Department of Genetics, University of Cambridge, Downing Street, Cambridge, CB2 3EH, UK.
authors.forename: Damian
authors.initials: D
authors.lastname: Crowther
authors.affiliation: Department of Biochemistry and Structural Biology, Lund University, PO Box 124, 221 00 Lund, Sweden.
authors.forename: Sara
authors.initials: S
authors.lastname: Linse
authors.affiliation: KI Alzheimer Disease Research Centre, NVS Department, Karolinska Institutet, Novum, 5th Floor, 141 86 Stockholm, Sweden.
authors.forename: Bengt
authors.initials: B
authors.lastname: Winblad
authors.affiliation: Department of Medical Cell Biology, Uppsala University, 751 23 Uppsala, Sweden.
authors.forename: Gunilla
authors.initials: G
authors.lastname: Westermark
authors.affiliation: KI Alzheimer Disease Research Centre, NVS Department, Karolinska Institutet, Novum, 5th Floor, 141 86 Stockholm, Sweden. Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, 751 23 Uppsala, Sweden. Institute of Mathematics and Natural Sciences, Tallinn University, Narva mnt 25, 101 20 Tallinn, Estonia. janne.johansson@ki.se jenny.presto@ki.se.
authors.forename: Jan
authors.initials: J
authors.lastname: Johansson
authors.affiliation: KI Alzheimer Disease Research Centre, NVS Department, Karolinska Institutet, Novum, 5th Floor, 141 86 Stockholm, Sweden. janne.johansson@ki.se jenny.presto@ki.se.
authors.forename: Jenny
authors.initials: J
authors.lastname: Presto
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D030801:Animals, Genetically Modified; D001921:Brain / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects*; D004331:Drosophila melanogaster / Q000378:metabolism* / Q000502:physiology; D018832:Molecular Chaperones / Q000378:metabolism*; D009043:Motor Activity; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*
chemical_list: D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer’s disease; Amyloid; Chaperone; Protein misfolding