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Chem Biol. 2014 Jun 19;21(6):732-42. doi: 10.1016/j.chembiol.2014.03.014. Epub 2014 May 22.

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.

Author information

  • 1Department 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.
  • 2Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK.
  • 3Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
  • 4Laboratory of Molecular Biophysics, Institute for Research in Biomedicine, Baldiri Reixac 10-12, 08028 Barcelona, Spain.
  • 5Department of Chemical Engineering and Biotechnology, University of Cambridge, New Museums Site, Pembroke Street, Cambridge CB2 3RA, UK. Electronic address: gsk20@cam.ac.uk.

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.

Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

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PMID:
24856820
[PubMed - in process]
PMCID:
PMC4067742
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