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Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates

Journal Article


Abstract


  • The aggregates of the Ab peptide associated with Alzheimer's disease are able to both grow in size aswell as generate, through secondary nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: The Brichos domain, which suppresses specifically secondary nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Ab fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.

Authors


  •   Scheidt, Tom (external author)
  •   Lapinska, Urszula (external author)
  •   Kumita, Janet R. (external author)
  •   Whiten, Daniel (external author)
  •   Klenerman, David (external author)
  •   Mark R Wilson
  •   Cohen, Samuel N. (external author)
  •   Linse, Sara (external author)
  •   Vendruscolo, Michele (external author)
  •   Dobson, Christopher M. (external author)
  •   Knowles, Tuomas P. J. (external author)
  •   Arosio, Paolo (external author)

Publication Date


  • 2019

Citation


  • Scheidt, T., Lapinska, U., Kumita, J. R., Whiten, D. R., Klenerman, D., Wilson, M. R., Cohen, S. I. A., Linse, S., Vendruscolo, M., Dobson, C. M., Knowles, T. P. J. & Arosio, P. (2019). Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates. Science Advances, 5 (4), eaau3112-1-eaau3112-9.

Scopus Eid


  • 2-s2.0-85064739477

Start Page


  • eaau3112-1

End Page


  • eaau3112-9

Volume


  • 5

Issue


  • 4

Place Of Publication


  • United States

Abstract


  • The aggregates of the Ab peptide associated with Alzheimer's disease are able to both grow in size aswell as generate, through secondary nucleation, new small oligomeric species, that are major cytotoxins associated with neuronal death. Despite the importance of these amyloid fibril-dependent processes, their structural and molecular underpinnings have remained challenging to elucidate. Here, we consider two molecular chaperones: The Brichos domain, which suppresses specifically secondary nucleation processes, and clusterin which our results show is capable of inhibiting, specifically, the elongation of Ab fibrils at remarkably low substoichiometric ratios. Microfluidic diffusional sizing measurements demonstrate that this inhibition originates from interactions of clusterin with fibril ends with high affinity. Kinetic experiments in the presence of both molecular chaperones reveal that their inhibitory effects are additive and noncooperative, thereby indicating that the reactive sites associated with the formation of new aggregates and the growth of existing aggregates are distinct.

Authors


  •   Scheidt, Tom (external author)
  •   Lapinska, Urszula (external author)
  •   Kumita, Janet R. (external author)
  •   Whiten, Daniel (external author)
  •   Klenerman, David (external author)
  •   Mark R Wilson
  •   Cohen, Samuel N. (external author)
  •   Linse, Sara (external author)
  •   Vendruscolo, Michele (external author)
  •   Dobson, Christopher M. (external author)
  •   Knowles, Tuomas P. J. (external author)
  •   Arosio, Paolo (external author)

Publication Date


  • 2019

Citation


  • Scheidt, T., Lapinska, U., Kumita, J. R., Whiten, D. R., Klenerman, D., Wilson, M. R., Cohen, S. I. A., Linse, S., Vendruscolo, M., Dobson, C. M., Knowles, T. P. J. & Arosio, P. (2019). Secondary nucleation and elongation occur at different sites on Alzheimer's amyloid-b aggregates. Science Advances, 5 (4), eaau3112-1-eaau3112-9.

Scopus Eid


  • 2-s2.0-85064739477

Start Page


  • eaau3112-1

End Page


  • eaau3112-9

Volume


  • 5

Issue


  • 4

Place Of Publication


  • United States