title: Decreasing amyloid toxicity through an increased rate of aggregation.
abstract: Amyloid β is one of the peptides involved in the onset of Alzheimer's disease, yet the structure of the toxic species and its underlying mechanism remain elusive on account of the dynamic nature of the Aβ oligomerisation process. While it has been reported that incubation of Amyloid β (1-42) sequences (Aβ42) lead to formation of aggregates that vary in morphology and toxicity, we demonstrate that addition of a discrete macrocyclic host molecule, cucurbit[8]uril (CB[8]), substantially reduces toxicity in the neuronal cell line SH-SY5Y. The macrocycle preferentially targets Phe residues in Aβ42 complexing them in a 2 : 1 fashion in neighboring peptide strands. A small but significant structural 'switch' occurs, which induces an increased aggregation rate, suggesting a different cell-uptake mechanism for Aβ42 in the presence of CB[8]. Dramatically increasing the rate of Aβ42 aggregation with CB[8] bypasses the toxic, oligomeric state offering an alternative approach to counter Alzheimer's disease.
authors.affiliation: Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. oas23@cam.ac.uk.
authors.forename: Silvia
authors.initials: S
authors.lastname: Sonzini
authors.affiliation: Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. oas23@cam.ac.uk.
authors.forename: Helen F
authors.initials: HF
authors.lastname: Stanyon
authors.affiliation: Melville Laboratory for Polymer Synthesis, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. oas23@cam.ac.uk.
authors.forename: Oren A
authors.initials: OA
authors.lastname: Scherman
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D000682:Amyloid / Q000378:metabolism* / Q000633:toxicity*; D001952:Bridged-Ring Compounds / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D007093:Imidazoles / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D066263:Protein Aggregation, Pathological; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils
chemical_list: D000682:Amyloid; D001952:Bridged-Ring Compounds; D007093:Imidazoles; C507198:cucurbit(8)uril; D047028:Macrocyclic Compounds; D000099246:Cucurbit(n)urils