Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms

Suman De, David C Wirthensohn, Patrick Flagmeier, Craig Hughes, Francesco A Aprile, Francesco S Ruggeri, Daniel R Whiten, Derya Emin, Zengjie Xia, Juan A Varela, Pietro Sormanni, Franziska Kundel, Tuomas P J Knowles, Christopher M Dobson, Clare Bryant, Michele Vendruscolo, David Klenerman

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Abstract

Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer's disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer's disease.

Original languageEnglish
Article number1541
Number of pages11
JournalNature Communications
Volume10
DOIs
Publication statusPublished - 4 Apr 2019

Keywords

  • Intrinsically disordered proteins
  • Nanoscale biophysics
  • Protein aggregation
  • Single-molecule biophysics

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