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 () and David Klenerman ()
Additional contact information
Suman De: University of Cambridge
David C. Wirthensohn: University of Cambridge
Patrick Flagmeier: University of Cambridge
Craig Hughes: University of Cambridge
Francesco A. Aprile: University of Cambridge
Francesco S. Ruggeri: University of Cambridge
Daniel R. Whiten: University of Cambridge
Derya Emin: University of Cambridge
Zengjie Xia: University of Cambridge
Juan A. Varela: University of Cambridge
Pietro Sormanni: University of Cambridge
Franziska Kundel: University of Cambridge
Tuomas P. J. Knowles: University of Cambridge
Christopher M. Dobson: University of Cambridge
Clare Bryant: University of Cambridge
Michele Vendruscolo: University of Cambridge
David Klenerman: University of Cambridge

Nature Communications, 2019, vol. 10, issue 1, 1-11

Abstract: 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.

Date: 2019
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09477-3

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DOI: 10.1038/s41467-019-09477-3

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