Oligomer diversity during the aggregation of the repeat-region of tau

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  • Magnus Kjaergaard
  • Alexander J. Dear, Cambridge University, United Kingdom
  • Franziska Kundel, Cambridge University, United Kingdom
  • Seema Qamar, University of Cambridge, United Kingdom
  • Georg Meisl, Cambridge University, United Kingdom
  • Tuomas P.J. Knowles, Cambridge University, United Kingdom
  • David Klenerman, Cambridge University, United Kingdom

The molecular mechanism of protein aggregation is of both fundamental and clinical importance as amyloid aggregates are linked to a number of neurodegenerative disorders. Such protein aggregates include macroscopic insoluble fibrils as well as small soluble oligomeric species. Time-dependent resolution of these species is prerequisite for a detailed quantitative understanding of protein aggregation; this remains challenging due to the lack of methods for detecting and characterizing transient and heterogeneous protein oligomers. Here we have used single molecule fluorescence techniques combined with mechanistic modelling to study the heparin-induced aggregation of the repeat region of tau, which forms the core region of neurofibrillary tangles found in Alzheimer's disease. We distinguish several sub-populations of oligomers with different stability and follow their evolution during aggregation reactions as a function of temperature and concentration. Employment of techniques from chemical kinetics reveals that the two largest populations structurally distinct from fibrils; and are both kinetically and thermodynamically unstable. The first population is in rapid exchange with monomers and held together by electrostatic interactions; the second is kinetically more stable, dominates at later times and is probably off-pathway to fibril formation. These more stable oligomers may contribute to other oligomer induced effects in the cellular environment, for example by overloading protein quality control systems. We also show that the shortest growing filaments remain suspended in aqueous buffer and thus comprise a third, smaller population of transient oligomers with cross-i¢ structure. Overall our data show that a diverse population of oligomers of different structures and half-lives are formed during the aggregation reaction with the great majority of oligomers formed not going on to form fibrils.

Original languageEnglish
JournalACS Chemical Neuroscience
Pages (from-to)3060-3071
Number of pages12
Publication statusPublished - 2018

    Research areas

  • aggregation mechanism, amyloid oligomers, kinetic modeling, single-molecule FRET, tau

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