title: Direct observations of amyloid β self-assembly in live cells provide insights into differences in the kinetics of Aβ(1-40) and Aβ(1-42) aggregation.
abstract: Insight into how amyloid β (Aβ) aggregation occurs in vivo is vital for understanding the molecular pathways that underlie Alzheimer's disease and requires new techniques that provide detailed kinetic and mechanistic information. Using noninvasive fluorescence lifetime recordings, we imaged the formation of Aβ(1-40) and Aβ(1-42) aggregates in live cells. For both peptides, the cellular uptake via endocytosis is rapid and spontaneous. They are then retained in lysosomes, where their accumulation leads to aggregation. The kinetics of Aβ(1-42) aggregation are considerably faster than those of Aβ(1-40) and, unlike those of the latter peptide, show no detectable lag phase. We used superresolution fluorescence imaging to examine the resulting aggregates and could observe compact amyloid structures, likely because of spatial confinement within cellular compartments. Taken together, these findings provide clues as to how Aβ aggregation may occur within neurons.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK; Department of Chemical and Biological Engineering, Division of Chemistry and Biochemistry, Chalmers University of Technology, Kemivägen 10, 41296 Gothenburg, Sweden. Electronic address: eline@chalmers.se.
authors.forename: Elin K
authors.initials: EK
authors.lastname: Esbjörner
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
authors.forename: Fiona
authors.initials: F
authors.lastname: Chan
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Rees
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
authors.forename: Miklos
authors.initials: M
authors.lastname: Erdelyi
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Leila M
authors.initials: LM
authors.lastname: Luheshi
authors.affiliation: Laboratory of Molecular Biophysics, Institute for Research in Biomedicine, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
authors.forename: Carlos W
authors.initials: CW
authors.lastname: Bertoncini
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
authors.forename: Clemens F
authors.initials: CF
authors.lastname: Kaminski
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK. Electronic address: gsk20@cam.ac.uk.
authors.forename: Gabriele S
authors.initials: GS
authors.lastname: Kaminski Schierle
mesh_terms: D016229:Amyloid beta-Peptides / Q000096:biosynthesis / Q000378:metabolism*; D002470:Cell Survival; D006801:Humans; D007700:Kinetics; D010446:Peptide Fragments / Q000096:biosynthesis / Q000378:metabolism*; D066329:Protein Aggregates; D066263:Protein Aggregation, Pathological; D014407:Tumor Cells, Cultured
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D066329:Protein Aggregates; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)