title: A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.
abstract: Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.
authors: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors: Samuel I A
authors: SIA
authors: Cohen
authors: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors: Paolo
authors: P
authors: Arosio
authors: Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, 141 86 Stockholm, Sweden.
authors: Jenny
authors: J
authors: Presto
authors: Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, 141 86 Stockholm, Sweden.
authors: Firoz Roshan
authors: FR
authors: Kurudenkandy
authors: Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, 141 86 Stockholm, Sweden.
authors: Henrik
authors: H
authors: Biverstal
authors: Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, 141 86 Stockholm, Sweden.
authors: Lisa
authors: L
authors: Dolfe
authors: Department of Biochemistry and Structural Biology, Lund University, Box 124, SE221 00 Lund, Sweden.
authors: Christopher
authors: C
authors: Dunning
authors: Department of Biochemistry and Structural Biology, Lund University, Box 124, SE221 00 Lund, Sweden.
authors: Xiaoting
authors: X
authors: Yang
authors: Department of Biochemistry and Structural Biology, Lund University, Box 124, SE221 00 Lund, Sweden.
authors: Birgitta
authors: B
authors: Frohm
authors: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors: Michele
authors: M
authors: Vendruscolo
authors: Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, 141 86 Stockholm, Sweden.|Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, The Biomedical Centre, Box 575, SE751 23 Uppsala, Sweden.|Institute of Mathematics and Natural Sciences, Tallinn University, Narva mnt 25, 101 20 Tallinn, Estonia P. O. Box 124, SE221 00 Lund, Sweden.
authors: Jan
authors: J
authors: Johansson
authors: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors: Christopher M
authors: CM
authors: Dobson
authors: Karolinska Institutet, Dept NVS, Center for Alzheimer Research, Division for Neurogeriatrics, 141 86 Stockholm, Sweden.
authors: André
authors: A
authors: Fisahn
authors: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors: Tuomas P J
authors: TPJ
authors: Knowles
authors: Department of Biochemistry and Structural Biology, Lund University, Box 124, SE221 00 Lund, Sweden.
authors: Sara
authors: S
authors: Linse
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D020285:Cryoelectron Microscopy; D004594:Electrophysiology; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D066263:Protein Aggregation, Pathological; D017510:Protein Folding; D017434:Protein Structure, Tertiary
chemical_list: D016229:Amyloid beta-Peptides; D018832:Molecular Chaperones